Clinical trial NCT02335944
Conditions: Non Small Cell Lung Cancer
Keywords: non small cell lung cancer NSCLC EGF816 INC280 tyrosine kinase inhibitor c-MET
Sponsor: Novartis Pharmaceuticals
Start date: 2015-01-13; Completion date: 2020-11-10
Enrollment: 177 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to determine the maximum tolerated dose (MTD) / recommended phase 2 dose (RP2D) of nazartinib (EGF816) in combination with capmatinib (INC280) and to estimate the preliminary anti-tumor activity of nazartinib in combination with capmatinib in participants with advanced non-small cell lung cancer (NSCLC) with documented EGFR mutation.

Detailed description:
This study was designed as a Phase Ib/II, multi-center, open-label study starting with a Phase Ib dose escalation part followed by a Phase II expansion part. Oral nazartinib (once daily) and capmatinib (twice daily) was administered on a continuous schedule until participant experienced unacceptable toxicity, progressive disease (PD) and/or treatment was discontinued at the discretion of the investigator or withdrawal of consent/opposition to use data/biological samples. Study treatment could be continued beyond Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) defined PD, in the judgment of the investigator, when there was evidence of clinical benefit and the subject wished to continue with the study treatment.

In Phase Ib part, participants with NSCLC harboring EGFR activating mutations were enrolled. At the end of the Phase Ib part, once the MTD or RP2D of nazartinib in combination with capmatinib was declared, additional participants with NSCLC were enrolled in the Phase II part in order to assess the preliminary anti-tumor activity of nazartinib in combination with capmatinib. Participants with locally advanced or metastatic NSCLC were assigned into different groups according to their resistance mechanisms.

As per the Protocol amendment 7, an additional group (Group 5) was included into study CINC280X2105C, which was intended to support study CINC280L12301. After thorough and careful assessment of study CINC280L12301 enrollment status, projected study completion timelines, and the changing clinical landscape, Novartis made the decision to discontinue the study. Importantly, this decision was not driven by safety concerns; no new safety signals were observed in the study participants or in the ongoing capmatinib program. As such, Group 5 data was no longer needed and the new arm in study CINC280X2105C was not opened as planned.

Arms: arm 1: NSCLC participants who have previously documented EGFR mutation and progressed on EGFR TKI treatment. Participants were treated at a starting dose of 50 mg once a day for EGF816 and 200 mg twice a day for INC280 in fasted state arm 2: NSCLC participants with previously documented activating EGFR mutation, with any T790M and MET dysregulation status, who received one to three lines of systemic antineoplastic therapy prior to study entry including one line maximum of first or second generation EGFR TKI and who progressed on this EGFR TKI treatment line. Participants were treated at the RP2D of INC280 and EGF816 in fasted state arm 3: NSCLC participants harboring T790M mutation in de novo setting, irrespective of the activating mutation status who are treatment naïve or received maximum 2 lines of systemic antineoplastic therapy prior to study entry, but no therapy known to inhibit EGFR. Participants were treated at the RP2D of INC280 and EGF816 in fasted state arm 4: NSCLC participants with previously documented EGFR activating mutation, T790M negative, and any MET status who never received any prior line of systemic antineoplastic systemic therapy prior to study entry. Participants were treated at the RP2D of INC280 and EGF816 in fasted state arm 5: NSCLC participants with previously documented EGFR activating mutations and any T790M and MET status who were treatment naïve or failed maximum 2 prior lines of any systemic antineoplastic therapy for advanced disease. Participants were treated at the RP2D of INC280 and EGF816 in fed state arm 6: NSCLC participants with previously documented EGFR activating mutation, T790M negative, acquired MET amplification who have progressed on one prior line of therapy for advanced/metastatic NSCLC disease. Participants were to start with INC280 monotherapy (twice a day) and would have had the opportunity to continue to combination of EGF816 (once a day) and INC280 (twice a day) based on radiological disease progression evaluation by investigator's assessment per RECIST 1.1
Interventions: intervention 1: Capmatinib intervention 2: Nazartinib
Intervention descriptions: intervention 1: In the Phase 1, capmatinib was administered orally, twice per day, at a dose of 200 mg or 400 mg, in fasted state.

In the Phase II, participants received capmatinib at the RP2D (400 mg twice per day) in fasted state (Groups 1, 2 and 3) or fed state (Group 4).

Participants in Phase II Group 5 were to start with capmatinib monotherapy (fasted or fed state) and then would have had the opportunity to continue with the combination of nazartinib and capmatinib (fasted or fed state). intervention 2: In the Phase 1, nazartinib was administered orally, once a day, at a dose of 50 mg, 75 mg, 100 mg or 150 mg in fasted state.

In the Phase II, participants received nazartinib at the RP2D (100 mg once daily) in fasted state (Groups 1, 2 and 3) or fed state (Group 4). Participants in Phase II Group 5 were to start with capmatinib monotherapy (fasted or fed state) and then would have had the opportunity to continue with the combination of nazartinib and capmatinib (fasted or fed state).

Protocol documents:
Prot_000.pdf: 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of figures ...................................................................................................................... 6 
List of tables ........................................................................................................................ 6 
List of abbreviations ............................................................................................................ 9 
Glossary of terms ............................................................................................................... 14 
Amendment 07 (20-Oct-2021) .......................................................................................... 17 
Amendment 06 (11-Apr-2017) .......................................................................................... 27 
Amendment 05 (29-Jul-2016) ........................................................................................... 34 
Amendment 04 .................................................................................................................. 41 
Amendment 03 .................................................................................................................. 45 
Amendment 02 .................................................................................................................. 48 
Amendment 01 .................................................................................................................. 57 
Protocol summary .............................................................................................................. 60 
1 
Background ........................................................................................................................ 68 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 68 
1.2 
Introduction to investigational treatment(s) and other study treatment(s)............. 70 
1.2.1 
Overview of capmatinib (INC280) ....................................................... 70 
1.2.2 
Overview of nazartinib (EGF816) ........................................................ 72 
 
 75 
2 
Rationale ............................................................................................................................ 77 
2.1 
Study rationale and purpose................................................................................... 77 
2.2 
Rationale for the study design ............................................................................... 79 
2.3 
Rationale for dose and regimen selection .............................................................. 83 
2.4 
Rationale for choice of combination drugs ............................................................ 84 
2.5 
Rationale for choice of comparator drugs ............................................................. 84 
2.6 
Risks and benefits .................................................................................................. 84 
2.7 
Rationale for public health emergency mitigation procedures .............................. 85 
3 
Objectives and endpoints ................................................................................................... 85 
4 
Study design ...................................................................................................................... 88 
4.1 
Description of study design ................................................................................... 88 
4.2 
Timing of interim analyses and design adaptations ............................................... 95 
4.3 
Definition of end of the study ................................................................................ 96 
4.4 
Early study termination.......................................................................................... 97 
5 
Population .......................................................................................................................... 97 
5.1 
Study population .................................................................................................... 97 


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5.2 
Inclusion criteria .................................................................................................... 98 
5.3 
Exclusion criteria ................................................................................................. 101 
6 
Treatment ......................................................................................................................... 106 
6.1 
Study treatment .................................................................................................... 106 
6.1.1 
Dosing regimen ................................................................................... 107 
6.1.2 
Treatment duration .............................................................................. 108 
6.2 
Dose escalation guidelines for the Phase Ib part ................................................. 109 
6.2.1 
Starting dose rationale ......................................................................... 109 
6.2.2 
Provisional dose levels ........................................................................ 110 
6.2.3 
Guidelines for dose escalation and determination of MTD/RP2D ..... 111 
6.2.4 
Definitions of dose limiting toxicities ................................................. 114 
6.3 
Dose modifications for toxicities ......................................................................... 115 
6.3.1 
Dose modification and dose interruption ............................................ 115 
6.3.2 
Guidelines for screening, monitoring and management of HBV / 
HCV reactivation ................................................................................ 136 
6.3.3 
Guidelines for the management and dose modification of skin-
related toxicities .................................................................................. 140 
6.3.4 
Follow-up for toxicities ....................................................................... 142 
6.3.5 
Anticipated risks and safety concerns of the study drug ..................... 149 
6.4 
Concomitant medications .................................................................................... 149 
6.4.1 
Permitted concomitant therapy ........................................................... 149 
6.4.2 
Permitted concomitant therapy requiring caution and/or action ......... 150 
6.4.3 
Prohibited concomitant therapy .......................................................... 152 
6.4.4 
Use of bisphosphonates or RANKL inhibitor ..................................... 153 
6.4.5 
Permitted radiotherapy ........................................................................ 153 
6.5 
Participant numbering, treatment assignment...................................................... 154 
6.5.1 
Participant numbering ......................................................................... 154 
6.5.2 
Treatment assignment ......................................................................... 154 
6.6 
Study drug preparation and dispensation ............................................................. 155 
6.6.1 
Study drug packaging and labeling ..................................................... 156 
6.6.2 
Drug supply and storage ...................................................................... 156 
6.6.3 
Study drug compliance and accountability ......................................... 156 
6.6.4 
Disposal and destruction ..................................................................... 157 
7 
Visit schedule and assessments ....................................................................................... 157 
7.1 
Study flow and visit schedule .............................................................................. 157 
7.1.1 
Molecular pre-screening ...................................................................... 169 
7.1.2 
Screening ............................................................................................. 171 


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7.1.3 
Treatment period ................................................................................. 174 
7.1.4 
Discontinuation from study treatment and from study ....................... 174 
7.1.5 
Withdrawal of informed consent/Opposition to use data/biological 
samples ................................................................................................ 175 
7.1.6 
Follow-up for safety evaluations ......................................................... 176 
7.1.7 
Lost to follow-up ................................................................................. 176 
7.2 
Assessment types ................................................................................................. 177 
7.2.1 
Efficacy assessments ........................................................................... 177 
7.2.2 
Safety and tolerability assessments ..................................................... 179 
7.2.3 
Pharmacokinetics ................................................................................ 183 
7.2.4 
Biomarkers .......................................................................................... 187 
8 
Safety monitoring, reporting and committees ................................................................. 195 
8.1 
Adverse events ..................................................................................................... 195 
8.1.1 
Definitions and reporting .................................................................... 195 
8.1.2 
Laboratory test abnormalities .............................................................. 197 
8.1.3 
Adverse events of special interest ....................................................... 197 
8.2 
Serious adverse events ......................................................................................... 197 
8.2.1 
Definitions ........................................................................................... 197 
8.2.2 
SAE Reporting .................................................................................... 198 
8.3 
Pregnancy reporting ............................................................................................. 199 
8.4 
Warnings and precautions.................................................................................... 199 
8.5 
Data Monitoring Committee ................................................................................ 200 
9 
Data collection and database management ...................................................................... 201 
9.1 
Data confidentiality ............................................................................................. 201 
9.2 
Site monitoring .................................................................................................... 201 
9.3 
Data collection ..................................................................................................... 202 
9.4 
Database management and quality control .......................................................... 202 
10 Statistical methods and data analysis .............................................................................. 203 
10.1 
Analysis sets for Phase Ib and Phase II Groups 1 to 4 ........................................ 204 
10.1.1 
Full Analysis Set ................................................................................. 204 
10.1.2 
Safety Set ............................................................................................ 204 
10.1.3 
Per-Protocol Set .................................................................................. 204 
10.1.4 
Dose-determining set .......................................................................... 204 
10.1.5 
Pharmacokinetic analysis set for capmatinib /nazartinib .................... 204 
10.1.6 
Full pharmacokinetic analysis set for capmatinib /nazartinib ............. 205 
10.2 
Analysis sets for Phase II Group 5 ...................................................................... 206 


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10.2.1 
Full Analysis Set ................................................................................. 206 
10.2.2 
Evaluable Analysis Set ........................................................................ 206 
10.2.3 
Combination Analysis Set ................................................................... 206 
10.2.4 
Safety Set ............................................................................................ 206 
10.3 
Participant demographics/other baseline characteristics ..................................... 206 
10.4 
Treatments (study treatment, concomitant therapies, compliance) ..................... 206 
10.5 
Primary objective for Phase Ib and Phase II Groups 1 to 4 ................................. 207 
10.5.1 
Variable ............................................................................................... 207 
10.5.2 
Statistical hypothesis, model, and method of analysis ........................ 208 
10.5.3 
Handling of missing values/censoring/discontinuations ..................... 210 
10.5.4 
Supportive analyses ............................................................................. 211 
10.6 
Primary objective for Phase II Group 5 ............................................................... 211 
10.6.1 
Primary estimand ................................................................................ 211 
10.6.2 
Statistical model, hypothesis, and method of analysis ........................ 212 
10.6.3 
Handling of intercurrent events of the primary estimand ................... 212 
10.6.4 
Handling of missing values not related to intercurrent events ............ 212 
10.7 
Secondary objectives ........................................................................................... 213 
10.7.1 
Safety objectives ................................................................................. 213 
10.7.2 
Efficacy objectives .............................................................................. 215 
10.7.3 
Pharmacokinetics ................................................................................ 217 
 
 218 
10.9 
Interim analysis .................................................................................................... 218 
10.10 Sample size calculation........................................................................................ 221 
10.11 Power for analysis of key secondary variables .................................................... 224 
11 Ethical considerations and administrative procedures .................................................... 224 
11.1 
Regulatory and ethical compliance ...................................................................... 224 
11.2 
Responsibilities of the investigator and IRB/IEC ................................................ 224 
11.3 
Informed consent procedures ............................................................................... 224 
11.4 
Discontinuation of the study ................................................................................ 225 
11.5 
Publication of study protocol and results............................................................. 225 
11.6 
Study documentation, record keeping and retention of documents ..................... 226 
11.7 
Confidentiality of study documents and participant records ............................... 227 
11.8 
Audits and inspections ......................................................................................... 227 
11.9 
Financial disclosures ............................................................................................ 227 
12 Protocol adherence .......................................................................................................... 227 
12.1 
Amendments to the protocol ................................................................................ 227 


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13 References (available upon request) ................................................................................ 228 
14 Appendices ...................................................................................................................... 232 
14.1 
Appendix 1 - Guidelines for response, duration of overall response, TTF, 
TTP, progression-free survival and overall survival (based on RECIST 1.1) ..... 232 
14.1.1 
Introduction ......................................................................................... 233 
14.1.2 
Efficacy assessments ........................................................................... 233 
14.1.3 
Efficacy definitions ............................................................................. 242 
14.1.4 
Data handling and programming rules ................................................ 252 
14.1.5 
References (available upon request) ................................................... 256 
14.2 
Appendix 2 - Prior derivation for the Bayesian logistic regression model and 
hypothetical dose escalation scenarios ................................................................ 257 
14.2.1 
Statistical model .................................................................................. 257 
14.2.2 
Methodology for data down-weighting ............................................... 257 
14.2.3 
Prior specifications .............................................................................. 258 
14.2.4 
Hypothetical dose escalation scenarios ............................................... 263 
14.2.5 
Starting dose of the nazartinib tablet ................................................... 265 
14.2.6 
References (available upon request) ................................................... 266 
14.3 
Appendix 3 - Permitted concomitant medications requiring caution .................. 267 
14.4 
Appendix 4 - Prohibited concomitant medications ............................................. 270 
 
List of figures 
Figure 4-1 
Study design .......................................................................................... 92 
 
List of tables 
Table 1-1 
Superiority of EGFR TKIs over chemotherapy in EGFRmut 
NSCLC .................................................................................................. 68 
Table 3-1 
Objectives and related endpoints .......................................................... 86 
Table 6-1 
Dose and treatment schedule ............................................................... 107 
Table 6-2 
Provisional dose levels for nazartinib ................................................. 110 
Table 6-3 
Provisional dose levels for capmatinib ............................................... 111 
Table 6-4 
Criteria for defining dose-limiting toxicities in the Phase Ib part ....... 114 
Table 6-5 
Dose reduction steps for capmatinib ................................................... 116 
Table 6-6 
Dose Reduction steps for nazartinib ................................................... 116 
Table 6-7 
Criteria for dose reduction, interruption and re-initiation of 
nazartinib and capmatinib for adverse drug reaction .......................... 117 


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Table 6-8 
Dose modifications for capmatinib monotherapy (or if nazartinib 
permanently discontinued and capmatinib continued as 
monotherapy) ...................................................................................... 125 
Table 6-9 
Dose modifications for nazartinib (if capmatinib permanently 
discontinued and nazartinib continued as monotherapy) .................... 130 
Table 6-10 
Actions to be taken based on hepatitis B results screening ................. 137 
Table 6-11 
Guidelines for management of HBV reactivation ............................... 137 
Table 6-12 
Guidelines for management of HCV reactivation ............................... 139 
Table 6-13 
Guidelines for prevention and symptomatic care of rash/skin 
toxicities .............................................................................................. 140 
Table 6-14 
Management and dose modification for maculopapular rash1, 2 ......... 140 
Table 6-15 
Management and dose modification for other rashes including 
acneiform rash ..................................................................................... 142 
Table 6-16 
Toxicity follow-up evaluation ............................................................. 143 
Table 6-17 
Guidance to rule out other alternative causes of observed LFT 
abnormalities ....................................................................................... 148 
Table 7-1 
Visit evaluation schedule for Phase Ib and Phase II Groups 1 to 4 .... 159 
Table 7-2 
Visit evaluation schedule for Phase II Group 5 .................................. 163 
Table 7-3 
Imaging collection plan ....................................................................... 178 
Table 7-4 
ECOG performance status ................................................................... 180 
Table 7-5 
Central/local clinical laboratory parameters collection plan ............... 181 
Table 7-6 
Local 12-lead ECG collection plan ..................................................... 183 
Table 7-7 
Schedule of blood sample collections for capmatinib, nazartinib, 
and metabolite LMI258 PK assessment during Phase Ib dose 
escalation part...................................................................................... 184 
Table 7-8 
Schedule of blood sample collections for capmatinib, nazartinib 
and LMI258 PK assessment during Phase II part (first 10 
participants dosed in Group 3 and approximately 20 participants in 
Group 4) .............................................................................................. 186 
Table 7-9 
Schedule of blood sample collections for capmatinib, nazartinib 
and LMI258 PK assessment during Phase II part (rest of Group 3 
and Group 4 participants) .................................................................... 187 
Table 7-10 
Biomarker sample collection plan in the Phase Ib .............................. 190 
Table 7-11 
Biomarker sample collection plan in the Phase II ............................... 192 
Table 10-1 
Noncompartmental pharmacokinetic parameters ................................ 218 
Table 10-2 
Probability of success at the primary analysis based on various 
numbers of responders observed at the IA for Group 3 ...................... 219 
Table 10-3 
Predictive probability (PP) for ORR of capmatinib monotherapy at 
the final analysis based on various numbers of responders observed 
at the IA for Group 5 ........................................................................... 220 




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List of abbreviations 
Ab 
Antibody 
Ag 
Antigen 
ADME 
Administration, Distribution, Metabolism and Excretion 
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 the concentration-time Curve 
BAL 
Broncho-Alveolar Lavage 
BCG 
Bacille Calmette-Guerin 
BCRP 
Breast Cancer Resistance Protein 
BCS 
Biopharmaceutics Classification System 
b.i.d 
bis in die / twice daily 
BIRC 
Blinded Independent Review Committee 
BLRM 
Bayesian Logistic Regression Model 
BOR 
Best Overall Response 
bpm 
beats per minute 
BRAF 
v-raf murine sarcoma viral oncogene homolog B1 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CAS 
Combination Analysis Set 
cfDNA 
cell free Deoxyribo-Nucleic Acid 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CL 
Clearance 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
Maximum plasma concentration 
CMO&PS 
Chief Medical Office and Patient Safety 
CMV 
CytoMegaloVirus 
CNS 
Central Nervous System 
COVID-19 
Corona Virus Disease 2019 
CR 
Complete Response 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 


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CSR 
Clinical Study Report 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
CV 
Coefficient of Variance 
CYP 
Cytochrome P450 Enzymes 
DBP 
Diastolic Blood Pressure 
DCR 
Disease Control Rate 
DDS 
Dose Determining Set 
DDI 
Drug-Drug Interaction 
DILI 
Drug-Induced Liver Injury 
DLCO 
Diffusing capacity of the Lungs for Carbon monoxide 
DLT 
Dose Limiting Toxicity 
DOR 
Duration Of Response 
EAS 
Evaluable Analysis Set 
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; also known as ErbB1 
EOT 
End of Treatment 
ERCP 
Endoscopic retrograde cholangiopancreatography 
eSAE 
electronic Serious Adverse Event 
EU 
European Union 
EWOC 
Escalation With Overdose Control 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FISH 
Fluorescence In Situ Hybridization 
FU 
Follow-up 
GCN 
Gene Copy Number 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony-Stimulating Factor 
GGT 
Gamma-Glutamyl-Transferase 
GI 
Gastrointestinal 
GLDH 
Glutamate dehydrogenase 
GLP 
Good Laboratory Practice 
GM-CSF 
Granulocyte-Macrophage Colony-Stimulating Factor 
HBcAb 
Hepatitis B core antibody 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HBV-DNA 
Hepatitis B virus-DNA 
HC Ab 
Hepatitis C antibody 
hCG 
Human Chorionic Gonadotropin 


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HCV 
Hepatitis C virus 
HCV-RNA 
Hepatitis C virus-RNA 
HDPE 
High-Density PolyEthylene 
hERG 
human Ether-à-go-go-Related Gene 
Hgb 
Hemoglobin 
HGF 
Hepatocyte growth factor 
HIV 
Human Immunodeficiency Virus 
HSV 
Herpes Simplex Virus 
IA 
Interim Analysis 
IB 
Investigator’s brochure 
IC50 
Half maximal Inhibitory Concentration 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IgA 
Immunoglobulin A 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IHC 
Immuno-histochemistry 
IEC 
Independent Ethics Committee 
ILD 
Interstitial Lung Disease 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
i.v. 
Intravenous(ly) 
KRAS 
Kirsten RAt Sarcoma viral oncogene homolog 
LFT 
Liver Functional Test 
LLN 
Lower Limit of Normal 
LLOQ 
Lower Limit of Quantification 
MATE 
Multidrug And Toxic compound Extrusion transporter 
MCV 
Mean Corpuscular Volume 
MET 
Mesenchymal-to-Epithelial Transition factor 
METΔex14  
MET exon 14 skipping  
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
mut 
Mutated 
NCI 
National Cancer Institute 
NE 
Not Estimable 
NGS 
Next Generation Sequencing 
NRU 
Neutral Red Uptake 
NSCLC 
Non-Small Cell Lung Cancer 
NTI 
Narrow Therapeutic Index 
OATP 
Organic Anion Transporting Polypeptide 
ORR 
Overall Response Rate 
OS 
Overall Survival 


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p.o. 
per os/by mouth 
PAS 
Pharmacokinetic Analysis Set 
PBPK 
Physiologically Based PharmacoKinetic 
PD 
Progressive Disease  
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
PFT 
Pulmonary Function Test 
P-gp 
Permeability glycoprotein 
PHI 
Protected Health Information 
PK 
Pharmacokinetics 
PK/PD 
Pharmacokinetics/Pharmacodynamics 
PLT 
Platelet 
PoS 
Probability of success 
PP 
Predictive Probability 
PR 
Partial Response 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
q.d. 
quaque die/every day 
QTcF 
Corrected QT interval using Fridericia correction 
RANKL 
Receptor Activator of Nuclear factor Kappa-B Ligand 
RBC 
Red Blood Cell 
RP2D 
Recommended Phase 2 Dose 
RECIST 
Response Evaluation Criteria in Solid Tumors 
ROS1 
c-ros oncogene 1 
R value 
Ratio of ALT to ALP (both expressed as x ULN) 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SCLC 
Small Cell Lung Cancer 
SD 
Stable Disease 
SEC 
Safety Event Categories 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SOP 
Standard Operating Procedure 
T1/2 
Terminal elimination half-life 
TDAR 
T-cell Dependent Antigen Response 
TEC 
Tyrosine kinase Expressed in hepatocellular Carcinoma 
TKI 
Tyrosine Kinase Inhibitor 
Tmax 
Peak plasma concentration 
TTR 
Time To Response 
ULN 
Upper Limit of Normal 
US 
United States 
USA 
United States of America 
USPI 
United States Prescribing Information 
UV 
Ultra-Violet 


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VATS 
Video-assisted thoracic surgery 
Vss 
Steady state volume of distribution  
WCLC 
World Conference on Lung Cancer 
WoC 
Withdrawal of Consent 
WT 
Wild Type 


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Glossary of terms 
Adjuvant chemotherapy 
Anticancer medication administered following initial curative surgery and/or 
radiotherapy for newly diagnosed early disease (i.e., stages I-II) or optimally 
debulked advanced disease (stages III and IVa). Chemotherapy administered in 
these clinical situations will be considered adjuvant, unless there is evidence of 
disease progression prior to the start of chemotherapy or evidence of persistent 
macroscopic residual disease after surgery (i.e., non-optimally debulked 
advanced disease). 
Assessment 
A procedure used to generate data required by the study 
Biological Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study participant. 
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 newly enrolled participants treated at a specific dose and regimen (i.e. 
treatment group) at the same time. 
Cycles 
Number and timing or recommended repetitions of therapy are usually expressed 
as number of days (e.g. q28 days). 
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 drug 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. 
Dose level 
The dose of drug given to the participant (total daily or weekly etc.). 
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 source data/documents used at the point of care. 
End of the clinical trial 
The end of the clinical trial is defined as the last visit of the last participant or as 
defined by the protocol. 
Enrollment 
Point/time of participant entry into the study; the point at which informed consent 
must be obtained (i.e., prior to starting any of the procedures described in the 
protocol). The action of enrolling one or more participants. 
Estimand 
As defined in the ICH E9(R1) addendum, 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. 
Investigational 
drug/treatment 
The drug whose properties are being tested in the study. 
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. 
Medication number 
A unique identifier on the label of each study treatment package which is linked 
to one of the treatment groups of a study. 


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Neoadjuvant chemotherapy 
Anticancer medication administered prior to initial surgery. Stem cell transplant 
preparatory regimens should be considered as neoadjuvant. 
Palliative care 
Any treatment that alleviates pain and discomfort to improve quality of life of 
participants with end-stage disease. For example, zoledronic acid given to treat 
the pain from bone metastases or localized radiotherapy to treat pain from-pre-
existing bone metastases. These treatments must begin before the initiation of 
study treatment. Requirement of these treatments during the study is considered 
a sign of disease progression. 
Part 
A sub-division of a study used to evaluate specific objectives or contain different 
populations. For example, one study could contain a single dose part and a 
multiple dose part, or a part in participants with established disease and in those 
with newly-diagnosed disease. 
Participant 
A trial participant is a patient who has consented to participate in the study. 
“Participant" terminology is used in the protocol whereas term "Subject" is used 
in data collection 
Participant 
Number  
(Participant No.) 
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant and 
should be used to identify the participant throughout the study for all data 
collected, sample labels, etc. 
Period 
The subdivisions of the trial design (e.g., Screening, Treatment, Follow-up) which 
are described in the Protocol. Periods define the study phases and will be used 
in clinical trial database setup and eventually in analysis. 
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. 
Re-screening 
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. 
Screen failure 
A participant who did not meet one or more criteria that were required for 
participation in the study. 
Source Data/Document 
Source data refers to the initial record, document, or primary location from where 
data comes. The data source can be a database, a dataset, a spreadsheet or 
even hard-coded data, such as paper or eSource. 
Stage in cancer 
The extent of a cancer in the body. Staging is usually based on the size of the 
tumor, whether lymph nodes contain cancer, and whether the cancer has spread 
from the original site to other parts of the body. 
Start of the clinical trial 
The start of the study is defined as the signature of the informed consent by the 
first participant. 
Study treatment 
Includes any drug or combination of drugs in any study arm administered to the 
study participant as part of the required study procedures; includes 
investigational drug(s), control(s) or background therapy. 
In specific examples, it is important to judge investigational treatment component 
relationship relative to a study treatment combination; study treatment in this 
case refers to the investigational and non-investigational treatments in 
combination. 
Tele-visit 
Procedures or communications conducted using technology such as telephone 
or video-conference, whereby the participant is not at the investigative site where 
the investigator will conduct the trial. 
Therapeutic setting 
A setting of treatment whereby an antineoplastic agent is given to treat the cancer 
except in the adjuvant and neo-adjuvant setting. For example, targeted therapies 
(e.g., sunitinib, pazopanib, axitinib, everolimus, temsirolimus, bevacizumab) or 
immunotherapies (e.g., interferon, interleukin 2), chemotherapies, or hormonal 
therapies. 


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Treatment arm/group 
A treatment arm/group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts. Cohorts are not expanded, new cohorts are 
enrolled. 
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. 
Withdrawal 
of 
Consent 
(WoC) / Opposition to use of 
data /biological samples 
Withdrawal of consent occurs when a participant explicitly requests to stop use 
of their data and biological samples (opposition to use data and 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. 
Opposition to use data/biological samples occurs in the countries where 
collection and processing of personal data is justified by a different legal reason 
than consent. 


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Amendment 07 (20-Oct-2021)  
Amendment rationale  
As of 20-Oct-2021, a total of 177 participants have been enrolled in the study: 33 participants 
in Phase Ib and 144 in Phase II (Group 1 to Group 4). All participants from Phase Ib and Phase 
II Groups 1 to 4 had met one of the end of study completion criteria as considered under protocol 
amendment 6 and there are no participants receiving treatment. 
The main purpose of this amendment is to implement a new participant Phase II Group 5 to 
determine the efficacy and safety of capmatinib monotherapy. The rationale for this addition is 
based on the following: 
• Based on the preliminary clinical efficacy and safety data observed in NSCLC participants 
who received capmatinib in combination with nazartinib (a third generation EGFR TKI) 
therapy in this study, the Sponsor plans to establish the role of capmatinib in combination 
with the third generation EGF TKI in a population of participants with EGFRm, T790M 
negative, MET amplified, progressed on prior line of EGFR TKI treatment NSCLC. 
However, it is necessary to also consider the contribution of components; based on the 
clinical efficacy and safety data of Study [CINC280A2201] observed in a related population 
of NSCLC in EGFR WT, METex14 mutated, regardless of line of treatment. Furthermore, 
the contribution of capmatinib as monotherapy needs to be established in this EGFR mutant 
setting which then will pave the way for the optimal use of the combination in future trials. 
• There is limited data on the safety and efficacy of capmatinib monotherapy in NSCLC 
EGFR resistant MET amplified (Gautschi et al 2020) supporting further the proposed 
investigation. From the data provided by Wolf et al. (2020) which indicated that the median 
time to response for capmatinib was 6 weeks, data from this arm can be adequately regarded 
as a measure for the contribution of capmatinib monotherapy in this setting and will provide 
a significant step to further evaluate this new treatment strategy. 
The analysis of the primary objective for Phase II Group only was formulated using the 
estimands framework as the primary analysis and analysis of additional data of Phase Ib and 
Phase II Groups 1 to 4 had already occurred prior to opening enrollment of Group 5. 
Furthermore, the guidelines for management of selected toxicities have been updated to 
optimize the participant’s safety. These changes are not due to new safety findings. The lists of 
permitted and prohibited concomitant medications have been revised based on periodic update 
and aligned with the current [capmatinib Investigator’s Brochure] and [nazartinib Investigator’s 
Brochure]. 
Additionally, several protocol sections were amended to provide specific related guidance and 
clarification with regard to the event of a major healthcare disruption (e.g., a pandemic or 
epidemic). The assessment of Benefit/Risk concluded the absence of additional risks related to 
COVID-19 (Corona Virus Disease 2019). 
Finally, the background section has been updated with the most recent information gathered 
throughout the relevant literature and clinical studies results. 
Other editorial revisions and text corrections were made throughout the protocol for 
clarification, where required. 


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Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
The following changes have been implemented and the protocol has been updated to reflect all 
significant changes below:  
• Based on current Novartis protocol template, wording of “patient” and “subject” has been 
updated to “participant” throughout the document where appropriate 
• Based on current Novartis protocol template, remove wording of “REB” (Research Ethics 
Board) from expression “IRB/IEC/REB” throughout the document where appropriate. 
• Based on current Novartis protocol template, “withdrawal of consent” replaced by 
“withdrawal of informed consent/Opposition to use data/biological samples” or “consent 
withdrawal opposition” 
• Wording of “BID” has been updated to “b.i.d.” throughout the document where appropriate 
• Wording of “QD” has been updated to “q.d.” throughout the document where appropriate. 
• Wording of “c-MET” has been updated to “MET” throughout the document where 
appropriate 
• Wording of “INC280” has been updated to “capmatinib” throughout the document where 
appropriate 
• Wording of “EGF816” has been updated to “nazartinib” throughout the document where 
appropriate 
• Wording of “AZD9291” has been updated to “osimertinib” throughout the document where 
appropriate 
• Wording of “phase I”, “phase 1” or “part I” has been updated to “Phase Ib” throughout 
the document where appropriate 
• Wording of “Phase 2” or “part II” has been updated to “Phase II” throughout the 
document where appropriate 
• Language and grammar revised as needed 
• Re-numbering of sections due to addition of sections in the new protocol template versions 
• Sections referenced modified to align with section changes 
• Adding language regarding public health emergencies added where applicable 
• Title page: based on current Novartis protocol template, Novartis department has been 
updated and the list of authors was removed 
• Table of contents updated 
• List of appendices has been removed as they are listed in the Table of contents 
• List of figures updated 
• List of tables has been updated 
• List of abbreviation has been updated 
• Glossary of terms: updated based on current Novartis protocol template 


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• Protocol summary: updated purpose and rationale, primary and secondary objectives, study 
design, key inclusion and exclusion criteria, investigational and reference therapy, data 
analysis based on the changes highlighted in the amendment rationale 
• Section 1 Background: updated the whole section to reflect the current clinical and safety 
evidence 
• Section 2.1 Study rationale and purpose: 
• clarified rationale for combination therapy of nazartinib and capmanitib 
• added rationale for capmatinib monotherapy 
• Section 2.2 Rationale for the study design: included rationale for inclusion of new Phase II 
Group 5 
• Section 2.3 Rationale for dose and regimen selection: included rationale for capmatinib 
monotherapy which can be administered with or without food 
•  Section 2.6 Risks and benefits: added rationale for recommended starting dose of 
capmatinib monotherapy 
• Section 2.7 Rationale for public health emergency mitigation procedures: new section added 
to align with latest Novartis protocol template in order to provide the rationale for public 
health emergency mitigation procedures 
• Table 3-1 Objectives and related endpoints: updated to add the primary, secondary 
 
objectives of newly added Phase II Group 5 
• Section 4.1 Description of study design: updated to reflect the inclusion of Phase II Group 
5 
• Figure 4-1 Study design: revised the study flow chart to reflect the implementation of Phase 
II Group 5 
• Section 4.2 Timing of interim analyses and design adaptations:  
• Clarified that interim analysis will be conducted for Phase II Group 3 and 5 participants 
• Added interim analysis for Phase II Group 5 participants 
• Section 4.3 Definition of end of study: 
• Added interim CSR to report final analysis of participants in Phase Ib and Phase II 
Groups 1 to 4 
• Updated the primary analysis and end of study definitions due to the inclusion of Phase 
II Group 5 
• Clarified post trial access of study medication if participant continues to demonstrate 
clinical benefit  
• Section 4.4 Early study termination: updated to align with other Novartis-sponsored study 
protocols 
• Section 5.1 Study population: 
• Updated sub-section title to align with latest Novartis protocol template  
• Updated to define Phase II Group 5 participant population 
• Section 5.2 Inclusion criteria: 
• Updated inclusion criterion 3, 4, 9 for enrollment into Phase II Group 5 


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• Added includion criterion 15 for enrollment into Phase II Group 5 
• Added inclusion criterion 16 for participants to have a life expectancy of at least 3 
months to align with the program standard language 
• Added inclusion criterion 17 for participants willing and able to comply with scheduled 
visits, treatment plan and laboratory tests to align with the program standard language 
• Section 5.3 Exclusion criteria: 
• Updated exclusion criterion 2, 4, 6, 13. 15, 17 and 19 for enrollment into Phase II Group 
5 
• Clarify exclusion criterion 5 for safety concerns or compliance 
• Added exclusion criterion 24 for participants with known hypersensitivity to capmatinib 
or nazartinib, or any excipient of these agents 
• Added exclusion criteria 27 to include requirement for specific timing of receiving a 
live vaccine prior to starting study treatment 
• Clarified the exclusion critera 8 to include HIV participants only when the disease is 
under control, the suppressed viral loads as defined by local guidelines and on 
established ART for at least four weeks prior to enrollment. 
• Updated exclusion criteria 10 as per updated safety guidance 
• Updated exclusion criteria 16 for the CTCAE version used for Phase II Group 5 
participants 
• Clarified exclusion criteria 19 for for QT interval prolongation and/or Torsades de 
Pointe 
• Updated exclusion criterion 22 and 23 to align with latest Novartis protocol template 
• Added exclusion criterion 25 and 26 for enrollment into Phase II Group 5 
• Added exclusion criterion 27 to exclude participants with live vaccines injection within 
30 days prior to the first dose of study treatment  
• Section 6.1 Study treatment: updated the study treatment for newly added Phase II Group 5 
• Table 6-1 Dose and treatment schedule: 
• Removed dose strength of 50 mg for Capmatinib as this was never produced and used 
in the study 
• Added footnote for Phase II Group 5 participants 
• Section 6.1.1 Dosing regimen 
• Added dosing regimen requirement for Phase II Group 5 participants 
• Added food conditions for Phase II Group 5 participants 
• Section 6.1.2 Treatment duration: 
• Updated language for withdrawal of consent/opposition to use data/biological samples 
to align with other Novartis-sponsored study protocols 
• Added treatment duration for Phase II Group 5 participants 
• Added guidance for treatment beyond progression disease from the investigator 
judgement 
• Section 6.3.1 Dose modification and dose interruption 


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• Clarified the criteria for dose re-escalation 
• Clarified that events not included in the study protocol or the reference guidance 
documents should be managed according to local practices 
• Replaced Table 6-5 of “recommended dose reduction steps for the Phase II part” by 
“dose reduction steps for capmatinib” 
• Added new Table 6-6 for “dose reduction steps for nazartinib” 
• Updated Table 6-7 entirely to align with the latest safety guidelines  
• Added new Table 6-8 for “Dose modifications for capmatinib monotherapy (or if 
nazartinib permanently discontinued and capmatinib continued as monotherapy)” 
• Added new Table 6-9 for “Dose modifications for nazartinib (if capmatinib 
permanently discontinued and nazartinib continued as monotherapy)” 
• Section 6.3.2 Guidelines for screening, monitoring and management of HBV / HCV 
reactivation (including Table 6-10, Table 6-11, Table 6-12): updated the monitoring of 
HBV-DNA from every 12 weeks to every 4 weeks and monitoring of HVC-RNA from every 
8 weeks to every 4 weeks as per new safety guidance 
• Section 6.3.4 Follow-up for toxicities: 
• Clarify that unscheduled assessment should be performed in all cases where toxicity 
monitoring is recommended more frequently than defined by the schedule of 
assessments 
• Added Table 6-16 Toxicity follow-up evaluation 
• Section 6.3.4.1 Follow up on potential QTcF prolongation: added a follow-up action in case 
of QTcF >500 ms and after confirming ECG reading at site, if QTcF > 500 ms 
• Section 6.3.4.2 Follow up on potential drug-induced liver injury (DILI) cases: 
• Updated as per latest safety guidelines 
• Added Table 6-17 for guidance to rule out other alternative causes of observed LFT 
abnormalities 
• Section 6.4.1 Permitted concomitant therapy: clarified that each concomitant drug must be 
individually assessed against all exclusion criteria/prohibited medication as per latest 
Novartis template 
• Section 6.4.1.1 Permitted concomitant therapy of capmatinib in combination with nazartinib: 
• Added sub-title 
• Move paragraph on use of bisphosphonates from this sub section to new sub  
section 6.4.4. 
• Section 6.4.1.2 Permitted concomitant therapy of capmatinib monotherapy in Phase II 
Group 5: added sub-section due to the addition of Phase II Group 5 
• Section 6.4.2.1 Permitted concomitant therapy of capmatinib in combination with nazartinib 
requiring caution and/or action: 
• Added sub-title 
• Clarification on the classification of the medications 


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• Section 6.4.2.2 Permitted concomitant therapy of capmatinib monotherapy requiring 
caution and/or action in Phase II Group 5: added sub-section due to the addition of Phase II 
Group 5 
• Section 6.4.3 Prohibited concomitant therapy: added sentence that if during the course of 
the trial prohibited concomitant medication cannot be avoided study treatment must be 
interrupted until an assessment of the potential safety risk has been performed 
• Section 6.4.3.1 Prohibited concomitant therapy with capmatinib and nazartinib: 
• Added sub-title 
• Clarified the language to prohibit “live” vaccine during the trial (including COVID-19 
vaccines) 
• Section 6.4.3.2 Prohibited concomitant therapy with capmatinib monotherapy in Phase 
II Group 5: added sub-section due to the addition of Phase II Group 5 
• Section 6.4.4 Use of bisphosphonates or RANKL inhibitor: added new sub-section 
• Section 6.4.5 Permitted radiotherapy: added new sub-section 
• Section 6.5.1 Participant numbering: Replaced Oracle RDC by EDC interface (generic term)  
• Section 6.5.2 Treatment assignment: updated to define Phase II Group 5 treatment 
assignment 
• Section 6.6 Study drug preparation and dispensation: added language regarding public 
health emergencies 
• Section 6.6.1 Study drug packaging and labeling: updated to define Phase II Group 5 drug 
packaging and labeling 
• Section 7.1 Study flow and visit schedule: 
• Added language regarding public health emergencies 
• Updated Table 7-1 title to “Visit evaluation schedule for Phase Ib and Phase II Groups 
1 to 4” 
• Added Table 7-2 for “Visit evaluation schedule for Phase II Group 5” 
• Section 7.1.1 Molecular pre-screening:  
• Clarified Met dysregulation definition for Phase II Group 5 participants 
• Added Phase II Group 5 EGFRm and Met dysregulation documentation requirements 
• Section 7.1.2 Screening: update screening requirements for Phase II Group 5 participants 
• Section 7.1.2.1 Information to be collected on screening failures: added requirements to be 
collected for screen failed participants in Phase II Group 5 
• Section 7.1.3 treatment period: updated language for withdrawal of consent/opposition to 
use data/biological samples to align with other Novartis-sponsored study protocols 
• Section 7.1.4 Discontinuation from study treatment and from study: 
• Update sub-title to “Discontinuation from study treatment and from study” as per latest 
Novartis protocol template 
• Updated language for withdrawal of consent/opposition to use data/biological samples 
to align with other Novartis-sponsored study protocols 
• Clarified participants who discontinue from study treatment definition 


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• Added discontinuation from study definition  
• Section 7.1.5 Withdrawal of informed consent/Opposition to use data/biological samples: 
• Updated sub-title to Withdrawal of consent/Opposition to use data/biological samples 
as per latest Novartis protocol template 
• Updated withdrawal of consent language and definition as per latest Novartis protocol 
template 
• Added paragraph on Personal and Coded data as per Novartis protocol template 
• Section 7.1.6: Follow-up for safety evaluations: Updated the survival follow-up paragraph 
as not applicable for participants in Phase II Group 5. 
• Section 7.1.7 Lost to follow-up: Clarified withdrawal, discontinuation from study treatment 
and discontinuation from study language as per latest Novartis protocol template 
• Section 7.2.1 Efficacy assessments: 
• Clarified that BIRC evaluation may be used except for Phase II Group 5 
• Added language for re-baseline requirements to enter extension part for Phase II Group 
5 participants 
• Table 7-3 Imaging collection plan: updated to include requirements of EoT/Re-baseline 
for Phase II Group 5 participants 
• Added language regarding public health emergencies 
• Section 7.2.2 Safety and tolerability assessments: added language regarding public health 
emergencies 
• Section 7.2.2.1 Physical examination: 
• Clarified physical examination for Phase II Group 5 
• Added reference to newly added table 7-2 
• Section 7.2.2.2 Vital signs: added reference to newly added table 7-2 
• Section 7.2.2.3 Height and weight: added reference to newly added table 7-2 
• Section 7.2.2.4 Performance status: 
• Rephrase definition of ECOG 
• Added reference to newly added table 7-2 
• Section 7.2.2.5 Laboratory evaluations: 
• Added that for Phase II Group 5 laboratory evaluations will be done locally 
• Added reference to newly added table 7-2 
• Added language regarding public health emergencies 
• Section 7.2.2.5.1 Hematology: added reference to newly added table 7-2 
• Section 7.2.2.5.2 Clinical chemistry: added reference to newly added table 7-2 
• Section 7.2.2.5.3 Coagulation: added reference to newly added table 7-2 
• Section 7.2.2.5.4 Urinalysis: added reference to newly added table 7-2 
• Section 7.2.2.5.5 HBV and HCV testing: added reference to newly added table 7-2 
• Section 7.2.2.5.6 Pregnancy and assessments of fertility: added language regarding public 
health emergencies 


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• Section 7.2.2.6 Cardiac assessments: 
• Added reference to newly added Table 7-2 and Table 7-6 
• Table 7-6: Added a note that PK post dose are not applicable for new Group 5 
• Section 7.2.3 Pharmacokinetics: added a note that no PK samples will be collected for newly 
added Group 5 
• Section 7.2.4 Biomarkers: added language regarding public health emergencies 
• Section 7.2.4.1 Biomarker assessments in tumor: 
• Clarified the assessments performed for newly added Group 5 and marked the others 
as Not Applicable 
• Updated the section to allow Met amplication status determined also by local testing 
with retrospective central testing for Phase II Group 5 
• Section 7.2.4.2: updated Table 7-11 for biomarker sample collection in newly added Group 
5 
• Section 8 Safety monitoring, reporting and committees: updated title as per latest Novartis 
protocol template 
• Section 8.1.1 Definitions and reporting: 
• Updated AE definition as per Novartis protocol template 
• Clarified non reporting of SAE in case of progression of malignancy as per latest 
Novartis protocol template 
• Updated CTCAE version to 5.0 for new Phase II Group 5 
• Section 8.1.3 Adverse event of special interest: remove list of AESI from the protocol as 
this is referenced in the IB 
• Section 8.2.2 SAE reporting: 
• Update sub title as per latest Novartis protocol template 
• Clarified immediate reporting to align with health authority requirements as per latest 
Novartis protocol template 
• Section 8.3 Pregnancy reporting: 
• Updated sub-title to align with latest Novartis protocol template 
• Updated Pregnant Participants and Pregnant Partners language for clarity as per latest 
Novartis protocol template 
• Section 8.5 Data Monitoring Committee: 
• Clarified that the interim analysis written in the protocol was for Phase II Group 3 
• Added interim analysis for newly added Phase II Group 5  
• Section 9 Data collection and database management: updated title as per latest Novartis 
protocol template  
• Section 9.1 Data Confidentiality: Clarified key sensitive personally identified information 
as per latest Novartis protocol template 
• Section 9.4 Database management and quality control: 
• Updated the method for archiving participant data at the investigational site 
• Updated the database lock wording as per the new Novartis protocol template 




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• Clarified that male participants must be informed that if a female partner becomes 
pregnant while he is enrolled in the study 
• Added language regarding public health emergencies 
• Section 13: updated the reference list as appropriate 
• Section 14.3: Appendix 3 
• Update Table 14-14 name to clarified that it applied to the combination therapy 
• Added Table 14-15 to list the permitted concomitant medication requiring caution with 
Capmatinib monotherapy in Phase II Group 5 
• Section 14.4: Appendix 4 
• Update Table 14-16 name to clarified that it applied to the combination therapy 
• Table 14-16: Clarified the language to prohibit “live” vaccine during the trial (including 
COVID-19 vaccines) 
• Added Table 14-17 to list the prohibited concomitant medication requiring caution with 
Capmatinib monotherapy in Phase II Group 5 
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 06 (11-Apr-2017) 
Amendment rationale 
As of 31-Mar-2017, a total of 93 patients have been enrolled in the study. In the phase Ib dose 
escalation part, 33 patients have been enrolled. The phase II expansion part was opened for 
enrollment in March 2016 and 60 patients have been enrolled (54 patients in Group 1 [EGFRm, 
any T790M, any c-MET, 2/4L NSCLC, EGFR TKI resistant], 2 patients in Group 2, [de novo 
T790M+, any c-MET, 1/3L NSCLC, EGFR TKI-naïve], and 4 patients in Group 3 [EGFRm, 
T790M negative, any c-MET, 1L NSCLC]). All patients enrolled in the Phase II part have 
received the recommended phase 2 dose (RP2D), i.e., INC280 400 mg BID + EGF816 100 mg 
QD. As of 19-Dec-2016, enrollment in phase II group 1 was completed. 
The main purpose of this amendment is to add in phase II a new group 4 of patients (N=30) 
with EGFRmut, any T790M, any c-MET, in order to assess the safety and tolerability of the 
combination therapy when taken with food (unrestricted meal type). Patients must have locally 
advanced or metastatic NSCLC with EGFR activating mutation (e.g., L858R and/or ex19del), 
be treatment-naïve for advanced disease (1L) or have failed (defined as intolerance to treatment 
or documented disease progression) a maximum of 2 prior lines of systemic antineoplastic 
therapies in advanced setting (2/3L) prior to study entry. 
Safety data from phase Ib part of this study showed high frequency of upper gastrointestinal 
(GI) adverse effects (AEs) with nausea (62.5%), vomiting (31.3%) being some of the most 
common AEs when combination therapy INC280/EGF816 was administered at the RP2D of 
INC280 400mg BID/EGF816 100 mg QD on fasting conditions. Fasting condition is defined as 
fasting from food at least one hour before and two hours after a meal [INC280 Investigator’s 
Brochure, edition 7]. The majority of GI events were of CTCAE grade 1 or 2 and were managed 
with standard approaches, including anti-emetics. 
In comparison the incidence of gastro intestinal AEs with currently approved therapy, such as 
erlotinib, a first generation EGFR TKI, is lower for nausea (33%) and vomiting (23%). 
To improve the tolerability profile of the combination therapy, it is proposed in this new group 
4 to administer study medication with food, as dosing with food has been shown to improve the 
GI tolerability of some multi-kinase inhibitors such as imatinib (Gleevec®) and bosutinib 
(Bosulif®). Imatinib does not exhibit a food effect, although it is recommended that imatinib be 
taken with food to minimize GI irritation (Gleevec® prescribing information). In a food-effect 
trial, a high-fat meal increased bosutinib exposure by 2-fold. Bosutinib showed better 
tolerability when co-administered with food; as a result, bosutinib was co-administered with a 
meal in patient trials and is advised to be taken once daily with food in the label (Bosulif® 
prescribing information). 
In the current study, EGF816 and INC280 combination is administered on an empty stomach 
defined as fasting from food at least one hour before or two hours after a meal. Preliminary PK 
results at RP2D (EGF816 100 mg QD/INC280 400 mg BID) showed that INC280 steady-state 
exposure (AUC,ss) is similar to those observed in single-agent studies with INC280, whereas 
EGF816 AUC,ss is ~35% higher compared to the exposure observed in the single agent study 
with EGF816. Similar extent of EGF816 AUC,ss increase is also observed when combined with 


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INC280 200 mg BID, indicating that EGF816 exposure increase may have reached a plateau 
when combined with INC280 at dose of 200 mg BID or higher. 
No dedicated food effect study has been conducted for EGF816. EGF816 was predicted to be a 
highly permeable compound based on the results from Caco-2 cell monolayer study. The in 
vitro solubility is excellent over the pH range tested (pH range 1 to 6.8) and in simulated 
intestinal fluid for both fasted and fed state. Therefore, it is characterized as biopharmaceutics 
classification system (BCS) class I compound with low food effect risk. In the ongoing single 
agent EGF816 study [EGF816X2101], EGF816 can be administered with or without food. 
For Phase II Group 4 (EGFRm, any T790M, any c-MET, 1L (treatment naive) 2/3L 
antineoplastic), patients will be given INC280/EGF816 combination with food. Based on the 
food-effect result in healthy volunteer, the steady state exposure increase of INC280 when given 
with food is expected to be 11-46% compared to the exposure observed under fasted condition. 
It is unlikely that an increase of INC280 exposure with food will lead to further increase of 
EGF816 exposure given that interaction between INC280 and EGF816 seems to have reached 
a plateau at INC280 dose of 200 mg BID or higher and the MTD has not been reached with 
INC280 given at 400mg BID under fasted condition. 
Given the known safety profile of INC280/EGF816 combination, their known or expected food 
effect, and the observation that food has improved the GI tolerability of other multi-kinase 
inhibitors, this Phase II Group 4 will evaluate the safety and PK of INC280 400mg BID + 
EGF816 100 mg QD when administered with food. 
Furthermore, amendment 6 implements other substantial changes as follows: 
• Update related to INC280 safety: updates were made in the clinical overview section based 
on the most current Investigator’s Brochure edition 7 (cut-off date 28-Sep-2016). 
• Provide preliminary data in Section 1.2.3.2 about clinical experience of INC280 and 
EGF816 combination treatment 
• Corrected the exclusion criterion for patients with asymptomatic serum amylase and lipase > 
Grade 2, to clarify that patient will now meet exclusion criterion even if only one of the two 
parameters (asymptomatic serum amylase or lipase) is > Grade 2. 
• Added the collection of an optional on-treatment biopsy with paired cfDNA sample to 
identify emergence of potential resistance markers during treatment as well as understand 
the correlation between tissue and plasma biomarker status. 
Other non-substantial changes were made to provide more clarity to the protocol: 
• Clarifies the exclusion criterion for patients with brain metastases. 
• Clarifies the interpretation of study discontinuation after dose interruption 


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Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
The following sections of the protocol were changed: 
• List of abbreviations 
• Updated RAP to SAP in this section and throughout the document 
• Protocol summary 
• Updated study design, key inclusion and exclusion criteria, study objectives, data 
analysis based on the changes highlighted in the amendment rationale 
• Corrected exclusion criterion on Creatinine Clearance to align with Section 5.3 
• Section 1.2.1 Overview of INC280 (capmatinib) 
• Updated according to last version of the INC280 Investigator’s Brochure (Ed. 7, data 
cut-off date 28-Sep-2016) 
• Clarified the SAE related to cough and shortness of breath to add more clinical 
information 
• Section 1.2.2 Overview of EGF816 
• Updated with most recent efficacy data from the single agent trial 
• Section 1.2.3. Overview of INC280 and EGF816 
• New section added to provide preliminary clinical safety and efficacy data on phase Ib 
patients of the current study as of 01-Aug-2016 
• Section 2.1 Study rationale and purpose 
• Editorial changes and clarified that data are related to 1st and 2nd generation EGFR-TKI 
• Updated the word cMET amplification to cMET dysregulation because both 
amplification and overexpression are mechanism of resistance; this update was done 
throughout the document 
• Section 2.2 Rationale for the study design 
• Added in Group 2 that dual TKI inhibitor are excluded to align with the rest of the 
protocol 
• Included rationale for inclusion of new phase II group 4 receiving the combination 
therapy in non-fasted conditions 
• Section 2.5 Rationale for choice of comparator drugs 
• New section added to align with other Novartis-sponsored study protocols; this section 
is not applicable for this clinical study 
• Section 2.6 Risks and Benefits 
• New section added to align with other Novartis-sponsored study protocols in order to 
provide summary of risks and benefits of the combination treatment 
• Table 3-1 Objectives and related endpoints 
• Updated to add the primary objective of newly added phase II group 4 
• Clarified that efficacy analysis is based on investigator’s assessment 


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• Updated the secondary objective and endpoint due to phase II group 4 addition 
• Section 4.1 Description of study design 
• Updated to reflect the inclusion of phase II group 4 
• Clarified the tissue sample requirement for phase II group 4 
• Clarified that enrollment of treatment-naïve patients will be prioritized in phase II group 
3 and de novo T790M patients enrollment be prioritized in phase II Group 4 and that 
this allocation will be managed via IRT 
• Section 4.2 Timing of interim analyses and design adaptations 
• Clarified that interim analysis will only be conducted for phase II group 3 patients 
• Clarified that if futility is concluded enrollment of treatment-naïve patients in groups 3 
and 4 may be stopped while enrollment in other opened groups of pre-treated patients 
will continue 
• Section 4.3 Definition of end of study 
• Clarified that the primary analysis for the different groups may occur at different times 
due to the expected difference in enrollment completion for each group 
• Figure 4-1 Study design 
• Revised the study flow chart to reflect the implementation of phase II Group 4 
• Section 5-1 Patient population 
• Updated to define phase II Group 4 patient population 
• Section 5-2 Inclusion criteria 
• Added inclusion criterion for enrollment into phase II group 4 
• Section 5-3 Exclusion criteria 
• Added exclusion criterion for enrollment into phase II group 4 
• Clarified criterion for patients with brain metastases and removed the discrepancy 
regarding the washout period for brain radiotherapy (2 weeks required for brain 
radiotherapy) 
• Updated criterion for asymptomatic serum amylase and lipase 
• Clarified that presence of other malignancies is also an exclusion criterion 
• Clarified that completely resected basal or squamous cell carcinoma are exceptions 
• Removed the washout period for the whole brain radiotherapy 
• Section 6.1.1 Dosing regimen 
• Added dosing regimen requirement for phase II group 4 patients 
• Clarified that full PK will be performed at C1D1 and C2D1 on first ten phase II group 
3 patients and approximately 20 patients in phase II group 4 
• Section 6.3.1 Dose modification and dose interruption 
• Clarified the criteria for dose modification, interruption and dose reduction steps 
• Table 6-6 updated to clarify that patients with combined elevated AST/ALT and total 
bilirubin must be discontinued 
• Section 6.5.2 Treatment assignment 


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• Added phase II group 4 
• Clarified the difference between groups 4 and the remaining groups in terms of 
fasting conditions 
• Section 7-1 Study Flow and Visit schedule 
• Added meal recording on C1D1 and C2D1 for full PK patients in the visit evaluation 
schedule table 
• Added optional on treatment biopsy 
• Added optional whole blood sample (to be paired with optional on treatment biopsy) 
• Section 7.1.1 Molecular pre-screening 
• Added phase II group 4 EGFRm documentation requirement 
• Clarified that the tumor sample to be provided can be newly obtained or archival 
• Added the timepoint of tumor sample collection 
• Section 7.2.1 Efficacy assessments 
• Updated to clarify that the results of the central Blinded Independent Review 
Committee (BIRC) evaluations may be used for secondary analyses purposes 
• Section 7.2.3.3 Pharmacokinetics sampling during Phase II part 
• Addition of full PK sampling for approximately 20 patients in phase II Group 4 
• Added that the remaining phase II group 4 patients will have sparse PK 
• Updated Tables 7-7 and 7-8 according to above-mentioned changes 
• Section 7.2.4.1 Biomarker assessment in tumor 
• Clarify that archival or newly obtained biopsy should be available at time of 
prescreening 
• Addition of optional on treatment biopsy 
• Addition of optional blood sample to be taken if an optional on treatment biopsy is 
performed 
• Updated Table 7-10 for phase II group 4 patients and addition of optional on-
treatment biopsy and paired optional cell-free DNA 
• Section 8.1.3 Adverse event of special interest 
• New section added to align with other Novartis-sponsored study protocols and clarify 
the AEs of special interest for the combination therapy 
• Section 8.2.2 Reporting 
• Changed Novartis pharmacovigilance group name from Drug Safety Epidemiology 
department to Chief Medical Office and Patient Safety department 
• Section 10 Statistical methods and data analysis 
• Addition of phase II Group 4 
• Clarified within the entire Section 10 that primary analysis in the different groups 
may occur at different times due to expected difference in enrollment completion 
• Clarified that if required, additional analysis sets will be defined in the Statistical 
Analysis Plan (SAP) 


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• Section 10.1 
• Section 10.1.2 Safety Set 
• Clarified that one dose means one dose of any component of the study treatment 
• Section 10.1.5 Pharmacokinetic analysis set for INC280/EGF816 
• Added INC280 and EGF816 to the header to clarify that an analysis sets per 
investigational drug will be created 
• Clarified the definition of PK evaluability 
• Section 10.1.6 Full pharmacokinetic analysis set for INC280/EGF816 
• New section added to clarify the definition of the Full pharmacokinetic analysis set 
and PK profile evaluability 
• Section 10.4 Primary objective 
• Added the primary objective, the definition, and number of patients in Group 4 
• Section 10.4.1 Variable 
• Added the variable analyzed for Group 4 
• Section 10.4.2.2 Phase II 
• Added the planned analysis of frequency of AEs for Group 4 
• Section 10.5.2.1 Secondary efficacy endpoints 
• Added ORR as secondary efficacy endpoint for Group 4 
• Clarified that if available, the results of the central evaluations by BIRC may be used 
for secondary analyses purposes 
• Section 10.5.3 Pharmacokinetics 
• Added the planned PK analysis for Group 4 and its comparison with PK data in 
fasting conditions 
• Clarified how the concentration data will be listed and summarized 
• Table 10-1 units of the parameters were updated 
• Section 10.7 Interim Analysis 
• Clarified that enrollment of treatment-naïve patients may be stopped if futility is 
concluded 
• Added for PoS 0.14 the number of responders i.e. 9/20 
• Section 10.8 Sample size calculation 
• Updated the approximate number of patients to be enrolled in phase II with the 
addition of 30 patients in group 4 
• Clarified that credible intervals are based on the posterior distribution for different 
observed number of responses and not on different assumed true observed number of 
responses (also updated Table 10-3) 
• Added rationale for full PK patients sample size in phase II group 4 
• New Table 10-5 introduced to provide the expected 90% confidence interval 
• Section 11.5 Publication 
• Updated to align with Novartis-sponsored study protocols 


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• Section 13 Appendices 
• Added new cited references 
• Section 14.1 – Appendix 1 
• Updated to include most recent guidelines for response version 3.2 dated 11-Feb-2016 
based on RECIST 1.1 
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 05 (29-Jul-2016) 
Amendment rationale 
As of 11-Jul-2016, in the Phase I part (dose-escalation) of the study, 33 patients have been 
enrolled from 7 sites in 6 countries in 7 cohorts using 5 different dose levels. On 23-Feb-2016, 
during the fifth dose-escalation teleconference, the Recommended Phase 2 Dose (RP2D) was 
discussed with all Investigators participating in the Phase I part and Novartis. As per protocol, 
before a drug dosage can be declared to be the Maximum Tolerated Dose or the RP2D, at least 
six patients should have been treated at that dosage. Among the eleven first patients who 
received INC280 400 mg BID + EGF816 100 mg QD during the dose-escalation part of the 
study, one of them experienced a Dose Limiting Toxicity. The other ten patients generally 
tolerated the treatment. Therefore, based on the available safety, pharmacokinetic and efficacy 
data and on the Bayesian Logistic Regression Model conclusions, the Investigators and Novartis 
agreed to declare the RP2D at the dose level of INC280 400 mg BID + EGF816 100 mg QD. 
The Phase II part (expansion phase) of the study was opened for enrollment in March 2016. As 
of 11-Jul-2016, 14 patients had started the study treatment. All patients enrolled in the Phase II 
part will receive the RP2D, i.e., INC280 400 mg BID + EGF816 100 mg QD. 
The main purpose of this amendment is to better define the patient population to be enrolled in 
the Phase II part of the study (expansion phase). A new group is being added (Group 3), and 
the sample size of Group 2 is being revised. 
Each group has a different patient population determined by specific and mutually exclusive 
EGFR mutations and the number of prior lines of systemic antineoplastic therapy: 
• Phase II Group 1 (EGFRmut, any T790M, any c-MET, 2/4L antineoplastic, EGFR TKI 
resistant): 
• Locally advanced or metastatic NSCLC with EGFR activating mutation (L858R and/or 
ex19del) who received one to three lines of systemic antineoplastic therapy prior to 
study entry including one line maximum of 1st or 2nd generation EGFR TKI (e.g. 
erlotinib, gefitinib, afatinib) and who progressed on this EGFR TKI treatment line. 
• The presence or the absence of the EGFR T790M mutation is associated with different 
prognosis. Therefore, the sub-groups are being detailed to account for the different 
EGFR T790M resistance mutation status, and the statistical analyses will be 
independently performed on the patients harboring the T790M mutation (minimum of 
20 patients), and on the patients not harboring the T790M mutation (minimum of 20 
patients). Furthermore, the decision criterion for the analysis of all 40 patients in Group 
1 is being removed. 
• Phase II Group 2 (EGFRmut, de novo T790M, any c-MET, 1/3L antineoplastic, EGFR TKI 
naïve): 
• Locally advanced or metastatic NSCLC with a “de novo” EGFR T790M mutation who 
are treatment naïve or received a maximum of two lines of systemic antineoplastic 
therapy prior to study entry but no therapy known to inhibit EGFR. 
• The estimated incidence of “de novo” T790M mutation is low (<1% of all lung cancer). 
Therefore, the sample size is being revised from ≥ 20 to approximately 5 patients if any 


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identified before the enrollment in Group 1 and Group 3 is complete. The purpose of 
Group 2 is to collect preliminary safety and efficacy data in this rare patient population. 
• Phase II Group 3 (EGFRmut, T790M negative, any c-MET, 1L antineoplastic): 
• Locally advanced or metastatic NSCLC with EGFR activating mutation (L858R and/or 
ex19del) who never received any prior line of systemic antineoplastic systemic therapy 
prior to study entry. 
• New group, N≥40 patients. 
• EGF816 is a 3rd-generation irreversible EGFR TKI that selectively inhibits activating 
and acquired resistance mutants (L858R, ex19del and T790M), while sparing wild type 
EGFR. Inhibitors of EGFR-mutant L858R and ex19del, such as 1st and 2nd generation 
EGFR TKIs, have been well validated as therapeutic agents for advanced NSCLC 
patients who are treatment naive. Based on the mechanism of action, EGF816 will 
likely have similar clinical activity in this patient population. Despite high response 
rates to EGFR TKIs, most patients with EGFR-mutant NSCLC ultimately relapse 
(Kobayashi 2005). Dysregulation of the c-MET pathway is implicated as a 
therapeutically tractable resistance mechanism. MET is amplified in 21% of NSCLCs 
with EGFR TKI resistance, and dysregulated in 57% of EGFR-mutant NSCLC patients 
(Bean 2007, Huang 2014). INC280 is being studied in combination with gefitinib and 
has shown 50% ORR in patients with c-MET highly amplified (GCN ≥6) NSCLC 
resistant to EGFR TKIs (Wu 2016). Therefore, it is expected that the co-administration 
of a highly potent c-MET inhibitor with an EGFR TKI will prevent the development of 
resistance in the first line setting. Group 3 will allow to explore the hypothesis that 
targeting the activating resistance mutants together with the two main EGFR resistance 
mechanisms, T790M and c-MET, may prevent the acquisition of resistance to EGFR 
TKIs. A sample size of fourty patients will provide acceptable operating characteristics 
to assess the preliminary anti-tumor activity of the study treatment. 
• An interim analysis for futility is implemented in this patient group (performed on 
approximately 20 patients). It will allow stopping the enrollment or treatment of the 
patients in case lack of efficacy is concluded. 
Furthermore, Amendment 5 implements other substantial changes as follows: 
• Introduces the Recommended Phase 2 Dose and the dose reduction steps starting from the 
RP2D. 
• Implements a requirement of ECOG performance status of 0-1 for all patients to be enrolled 
in the study to ensure that patients will be able to receive potential benefit from study 
treatment. It has been well documented that performance status is among the most important 
prognostic factors for survival of patients with NSCLC. 
• Removes the exclusion criterion on fasting plasma glucose ≥160 mg/dL (≥8.9 mmol/L) in 
the absence of evidence of impact on the glycemia in light of the most recent available 
clinical data and according to the latest versions of INC280 and EGF816 Investigator 
Brochures (INC280: Ed. 6, data cut-off date 28-Sep-2015. EGF816: Ed. 5, clinical data cut-
off date 18-Dec-2015, safety data cut-off date 27-May-2016). 
• Introduces a new dose strength (150 mg) for INC280 tablets. 






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• Updated title 
• Table 6-1 Dose and treatment schedule 
• Added INC280 150 mg tablet dose strength 
• Table 6-4 Criteria for defining dose-limiting toxicities in the Phase I part 
• Updated title 
• Section 6-3 Dose modification for toxicities 
• Updated title 
• Section 6.3.1 Dose modification and dose interruption 
• Added table with recommended dose reduction steps in the Phase II part of the trial 
• Table 6-11 Management of dose modification for maculopapular rashes 
• Clarified recommended clinical reassessment frequency every week 
• Added footnote clarifying the conditions for study drugs re-introduction 
• Table 6-12 Management of dose modification for other rashes 
• Clarified recommended clinical reassessment frequency every 2 weeks 
• Section 6.4.2 Permitted concomitant therapy requiring caution and/or action 
• Updated INC280 potency for enzymes inhibition 
• Removed statement on short acting gastric acid modulators 
• Section 6.4.3 Prohibited concomitant therapy 
• Removed restriction on proton pump inhibitors 
• Section 6.5.2 Treatment assignment 
• Added Phase II Group 3 
• Section 6.6.1 Study drug packaging and labeling 
• Added INC280 150 mg dose strength 
• Section 7.1 Study flow and visit schedule 
• Clarified that the +3 days visit window around C2D1 applies to the Phase I part of the 
trial 
• Table 7-1 Visit evaluation schedule 
• Updated Biomarkers sections according to the main changes provided in the protocol 
• Section 7.1.1 Molecular pre-screening 
• Updated to reflect the new group added in the Phase II part 
• Added a note to allow for the use of Novartis designated central laboratory results 
obtained as part of pre-screening in other Novartis sponsored studies 
• Section 7.2.1 Efficacy assessments 
• Added collection of imaging data for potential retrospective imaging data reading for 
patients enrolled in cohorts using the RP2D in the Phase I part of the trial 
• Section 7.2.2.5 Laboratory evaluations 
• Clarified the conditions for local laboratory results data collection in the eCRF in the 
Phase II part of the trial 


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• Section 7.2.4.1 Biomarker Assessments in Tumor 
• Added wording to allow for collection of additional optional samples 
• Table 7-6 Local 12-lead ECG collection plan 
• Clarified the timeframe for ECG realization the days of PK sampling 
• Table 7-8 Schedule of blood sample collections for INC280, EGF816 and LMI258 PK 
assessment during Phase II part (first 10 patients dosed) 
• Added missing dose reference numbers 
• Table 7-9 Schedule of blood sample collections for INC280, EGF816 and LMI258 PK 
assessment during Phase II part (rest of patients) 
• Added missing dose reference numbers 
• Section 7.2.4.1 Biomarker assessments in tumor 
• Updated to clarify the samples requirements in the Phase I and in the Phase II 
• Section 7.2.4.2 Assessment of c-MET and EGFR status in cfDNA samples 
• Added additional time-points for blood sample collection during the course of the 
study. 
• Table 7-10 Biomarker collection plan in the Phase Ib part 
• Updated the table presentation and wording on optional sample collection 
• Table 7-11 Biomarker collection plan in the Phase II part 
• Created to detail the tumor samples requirements in the expansion phase 
• Section 8.5 Data Monitoring Committee 
• Added rationale for the absence of DMC in the Phase II part of the trial 
• Section 10 Statistical methods and data analysis 
• Added conditions for primary analysis achievement 
• Clarified the primary objective and the primary variable of the Phase II analysis 
• The analysis methodology for the Phase II Group 1 was revised by introducing a 
separate estimation of the ORR for patients with T790M mutation and without 
• Changed the planned analysis of Phase II Group 2 to descriptive because of the 
reduced sample size in this group 
• Introduced Phase II Group 3 in the primary endpoint definition and specified the 
analysis 
• Clarified the analysis of adverse events and replaced so-called safety event categories 
by adverse events of special interest 
• Provided more details for the secondary efficacy endpoint section and added time to 
response 
• Added interim analysis methodology and the stopping rule for Phase II Group 3 
• Modified the operating characteristics for the Phase II Group 1 based on the changed 
analysis and added operating characteristics for Phase II Group 3 
• Table 10-1 Noncompartmental pharmacokinetic parameters 
• Corrected the definition of accumulation ratio 


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• Section 13 References 
• Added two references 
• Appendix 3 - Permitted concomitant medications requiring caution 
• Removed H2 receptor antagonist 
• Appendix 4 - Prohibited concomitant medications 
• Removed proton pump inhibitors restriction 
IRB/IEC/REB Approval 
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. In addition, if 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 amended protocol. 


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Amendment 04 
Amendment rationale 
As of 21-Sep-2015, 15 patients have been enrolled in the Phase Ib part (dose-escalation) of the 
study at 7 sites in 6 countries in Asia, Europe and Canada. 
The main purpose of this amendment is to implement a centralization of analysis for the 
resistance mutations EGFRT790M and c-MET oncogene amplification at a Novartis designated 
central laboratory for all patients entering into Phase II, in order to simplify the overall study 
logistics, and improve the quality and robustness of the resistance mechanisms data and 
analyses through use of uniform testing methods with controlled reproducibility and 
repeatability characteristics. 
Furthermore, Amendment 4 implements other changes as follows: 
• The 50 mg dose strength of EGF816 tablets is being introduced, which will decrease the 
number of tablets to be administered potentially allowing for better compliance and comfort 
of patients. 
• In order to optimize the patient safety and the toxicity monitoring as well as to align Novartis 
study protocols, the QTcF eligibility criterion and the management guidelines for pancreatic 
toxicity have been revised. Therefore, the exclusion criterion for QTcF has been updated 
implementing specific QTcF requirements for male and female patients respectively. The 
exclusion criteria, the corresponding Dose-limiting toxicity definition and the list of 
prohibited concomitant medications with known QTcF prolongation effect are also being 
updated accordingly for consistency with other Novartis Oncology sponsored studies. The 
amendment also provides the investigators with modified dose modification rules for 
pancreatic toxicity. 
• Exclusion criteria for patients with out of range laboratory values and for contraception use 
are being updated for consistency with other Novartis Oncology sponsored studies. The 
Note for exceptions to prior anti-cancer therapies is being removed for the same reason. 
• Of note, the changes in selection criteria provided in this amendment have very little impact 
on the level of heterogeneity among studies used for deriving priors for the Bayesian 
Logistic Regression Model. Therefore, the same priors for the model parameters can be used 
in analyzing the data from the updated population. In addition, the dose-DLT data observed 
in this study thus far are still valid according to the refined population and DLT criteria. 
• The definition of the end of study is being updated to detail study continuation conditions 
after completion of the primary analysis until all patients are discontinued, or until another 
clinical trial becomes available for all ongoing patients to be transferred to that clinical study 
and continue to receive INC280 + EGF816. 
• Serious Adverse Event reporting process is being updated to allow for possible electronic 
reporting to the Sponsor, and for consistency with other Novartis Oncology sponsored 
studies. 
• The possibility of using bisphosphonates during the study is being clarified. 
• The use of an Interactive Response Technology system in the Phase II part of the study is 
being detailed to specify the enrollment and the study drug dispensation tracking via the 


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application. The time-points for IRT registration by study site personnel are also being 
detailed. 
• Modalities and conditions for patient re-screening after screen failure are being introduced, 
together with screening assessments to be performed again during the new screening phase. 
• The glossary of terms is being updated for consistency with the CRF Completion Guidelines 
document. 
• The time-points for PFS rate analysis are being updated for consistency with visit evaluation 
schedule. 
Changes to the protocol: 
• List of abbreviations: 
• Added eSAE, NTI 
• Glossary of Terms: 
• Added definition of Adjuvant chemotherapy, Neoadjuvant chemotherapy, Palliative 
care, Therapeutic setting, Treatment line (regimen) 
• Protocol summary: 
• Added definition of Phase II Group 1 and Phase II Group 2 
• Updated selection criteria 
• Section 4.1 Description of study design 
• Added centralization of resistance mechanisms testing in the Phase II part of the study 
• Corrected typo 
• Section 4.3 Definition of End of Study 
• Added conditions of study continuation after primary analysis completion 
• Updated circumstances of end of study 
• Section 5.2 Inclusion criteria 
• Updated criterion on molecular testing requirements to reflect the centralization of 
resistance mechanisms analyses in the Phase II part of the study 
• Revised list of prior EGFR-TKI therapies for Phase II patients for consistency with 
Phase Ib patients 
• Section 5.3 Exclusion criteria 
• Corrected typo on HGF targeting therapy 
• Removed Note for exceptions to prior anti-cancer therapies 
• Added detailed criterion on cardiac repolarization abnormalities 
• Revised abnormal laboratory value thresholds for platelets, glucose, serum creatinine 
• Added method of calculation for creatinine clearance 
• Updated list of highly effective contraceptive methods 
• Section 6.1.1 Dosing regimen 
• Added 50 mg EGF816 tablets dose strength 
• Section 6.2.1 Starting dose 


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• Corrected typo in rationale 
• Table 6-4 Criteria for defining Dose Limiting Toxicities: updated pancreatic toxicities 
according to revised dose adjustment recommendations in case of amylase and lipase 
elevations. Corrected typo. 
• Table 6-5 Criteria for interruption and re-initiation of EGF816 and INC280 
• Updated amylase/lipase dose adjustments. Corrected typo. 
• Added reference to new protocol section on follow-up for potential QTcF prolongation 
events. 
• Section 6.3.4.1 Follow up on potential QTcF prolongation is being added 
• Section 6.3.4.2 Follow up for potential drug-induced liver injury (DILI) cases: corrected 
typo 
• Section 6.4.1 Permitted concomitant therapy 
• Added possibility of use of bisphosphonates during the study 
• Section 6.4.3 Prohibited concomitant therapy 
• Added medications with known risk of QT interval prolongation and/or known risk to 
cause Torsades de Pointe 
• Section 6.5.1 Patient numbering 
• Added IRT registration time-points 
• Section 6.5.2 Treatment assignment 
• Added functionality of IRT for group allocation and study drug dispensation 
• Section 6.6.1 Study drug packaging and labeling 
• Added 50 mg EGF816 tablets dose strength 
• Table 7-1 Visit evaluation schedule 
• Corrected typo 
• Added IRT registration time-points 
• Updated molecular pre-screening requirements to reflect the centralization of resistance 
mechanisms analyses in the Phase II part of the study. 
• Section 7.1.1 Molecular pre-screening 
• Updated molecular pre-screening requirements to reflect the centralization of resistance 
mechanisms analyses in the Phase II part of the study. 
• Section 7.1.2 Screening 
• Added modalities and conditions for re-screening 
• Section 7.2.4 Biomarkers and Table 7-9 Biomarker sample collection plan 
• Updated molecular pre-screening requirements to reflect the centralization of resistance 
mechanisms analyses in the Phase II part of the study. 
• Section 8.1 Adverse events 
• Added collection of CTCAE Grade 5 events as a seriousness criterion 
• Section 8.2 Serious Adverse Events 
• Revised process for initial SAE reporting and follow-up information submission. 


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• Section 10.5.2 efficacy objectives 
• Updated PFS rate analysis time-points 
• Appendix 4 Prohibited concomitant medications 
• Added medications with known risk of QT interval prolongation and/or known risk to 
cause Torsades de Pointe 
IRB/IEC/REB Approval 
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. In addition, if 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 amended protocol. 


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Amendment 03 
Amendment rationale 
As of 11-Aug-2015, 14 patients have been enrolled in the Phase Ib part (dose-escalation) of the 
study at 7 sites in 6 countries in Asia, Europe and Canada. 
The main purpose of this amendment is to provide detailed information about an Urgent Safety 
Measure related to EGF816. As of 08-July-2015, 2 serious adverse events (SAEs) of viral 
hepatitis B (HBV) reactivation have been reported in 2 patients participating in the 
CEGF816X2101 study (A phase I/II, multicenter, open-label study of EGF816, administered 
orally as single-agent in adult patients with EGFRmut solid malignancies). One case had a fatal 
outcome, and the second case was medically significant. The fatal case concerned a patient who 
received EGF816 capsules at a dose of 225 mg QD, had HBV infection in the past, and was not 
on antiviral treatment at study entry. The patient developed a HBV reactivation 7 months after 
EGF816 initiation and died due to hepatic failure despite initiation of antiviral treatment after 
HBV reactivation was confirmed. The second patient also received EGF816 capsules at a dose 
of 225 mg QD, had a history of chronic HBV diagnosed on an unknown date, and was not on 
antiviral treatment at the time of study entry. HBV reactivation was detected in this patient 
while approximately 10 weeks on study. Antiviral treatment was immediately initiated, EGF816 
was interrupted, and the HBV infection was brought under control. The patient later resumed 
EGF816 at the same dose of 225 mg QD. The viral reactivation in these two patients was likely 
due to immunosuppression related to EGF816. Reactivation of HBV and viral hepatitis C (HCV) 
has been reported with other anticancer therapies that suppress the immune system. To ensure 
the safety of all patients participating in the CINC280X2105C trial, changes have been made to 
the protocol to implement safety measures regarding the reactivation of HBV and HCV. 
As a consequence, the following eligibility criteria were revised: 
• To exclude patients with other malignancies, who underwent a bone marrow or solid organ 
transplant, with a known history of human immunodeficiency virus infection, or receiving 
immunosuppressive agents or chronic corticosteroids at study entry; 
• To allow patients with either HBsAg positive or HBV-DNA positive to enroll into the study 
if willing to take antiviral therapy1-2 weeks prior to first dose of study treatment and 
continue antiviral therapy for at least 4 weeks after the last dose of study treatment; 
• To allow new patients with negative hepatitis C antibody (HC Ab) or who are HC Ab 
positive but with an undetectable level of HCV-RNA into the study. Patients with detectable 
HCV-RNA are not eligible to enroll into the study. 
Of note, the changes in selection criteria provided in this amendment do not affect the 
heterogeneity among studies used in the model. In addition, the dose-DLT data observed in this 
study thus far are still valid according to the refined population. 
Finally, a recommendation of skin biopsy in case of maculopapular rash was added to the 
guideline for the management of skin-related toxicities that was introduced in Amendment 02. 
The purpose of this recommendation is to further investigate the pathophysiological mechanism 
related to the adverse event. 


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Changes to the protocol: 
• Updated Section 1.2.2 Overview of EGF816: 
• Updated Section 1.2.2.1.1 Non-clinical pharmacokinetics based on most recent 
available data. 
• Updated Section 1.2.2.1.3 Nonclinical toxicology summary to include preclinical 
results showing inhibition of TEC family kinases by EGF816 and their potential role in 
EGF816 effects. 
• Updated Section 1.2.2.2 Clinical experience with information on the 2 SAEs of the 
HBV reactivation in patients participating in CEGF816X2101. Updated preliminary 
efficacy and safety results based on currently available data. 
• Section 5.2 Inclusion criteria: 
• Added a criterion to allow new patients with either HBsAg positive or HBV-DNA 
positive to enroll into the study if willing to take antiviral therapy 1-2 weeks prior to 
1st dose of EGF816 treatment and continue on antiviral therapy for at least 4 weeks 
after the last dose of EGF816. 
• Added a criterion to allow new patients with negative hepatitis C antibody (HC Ab) or 
are HC Ab positive but with an undetectable level of HCV-RNA into the study. Patients 
with detectable HCV-RNA are not eligible to enroll into the study. 
• Section 5.3 Exclusion criteria: 
• Added a criterion related to exclusion of other malignancies. 
• Added a criterion to exclude patients who have undergone a bone marrow or solid organ 
transplant. 
• Added a criterion related to exclusion of human immunodeficiency virus (HIV) 
seropositivity. 
• Added a criterion to exclude patients receiving concomitant immunosuppressive agents 
or chronic corticosteroids use at the time of study entry. 
• Corrected the exception of criterion 15 instead of 10 (due to new criteria previously 
added) 
• Updated Table 6-5 Criteria for interruption and re-initiation of EGF816 and INC280 to 
include hepatitis B and C testing as applicable in case of hepatotoxicity, and to include 
recommendations in case of HBV or HCV reactivation. 
• Added Section 6.3.2 Guidelines for screening, monitoring and management of HBV and 
HCV reactivation. 
• Added Table 6-6 to summarize actions to be taken based on hepatitis B screening results. 
• Added Table 6-7 to summarize guidelines for management of HBV reactivation. 
• Added Table 6-8 to summarize guidelines for management of HCV reactivation. 
• Renumbered Tables 6-6, 6-7 and 6-8 in Amendment 02 to Tables 6-9, 6-10 and 6-11 due to 
the insertion of Section 6.3.2 
• Updated Table 6-11 to recommend consideration of skin biopsy in the event of a 
maculopapular rash. 


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• Updated Sections 6.4.2 and 6.4.3 to include additional permitted concomitant therapies 
requiring caution and/or action, and additional prohibited concomitant medications. 
• Updated Table 7-1 Visit evaluation schedule to include hepatitis B and C screening and 
monitoring 
• Updated Section 7.1.2 Screening to detail hepatitis B and C requirements before study 
treatment initiation. 
• Updated Section 7.1.2.2 Patient demographics and other baseline characteristics to include 
HBV and HCV status collection within patient characteristics data. 
• Updated Section 7.2.2.5 Laboratory evaluation and Table 7-4 Central/local clinical 
laboratory parameters collection plan to include hepatitis B and C testing at screening and 
as applicable during the study conduct. 
• Added Section 7.2.2.5.5 HBV and HCV testing to list viral serology investigations within 
mandatory laboratory evaluations. 
• Updated Table 14-15 Prohibited concomitant medications in Section 14.4 Appendix 4 based 
on last update from the Oncology Clinical Pharmacology Drug-Drug Interaction Database 
(release date: Apr-2015) 


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Amendment 02 
Amendment rationale 
As of 29-Jun-2015, nine patients have been enrolled in the Phase Ib part of the study (dose-
escalation) from 4 sites in 4 countries. 
The main purpose of this amendment is to introduce a formulation change for EGF816 from 
capsules to tablets (viable formulation for commercialization). 
During the course of the trial, parallel safety cohorts with tablets will be introduced to describe 
the pharmacokinetic properties of the combination with the new formulation, and to confirm or 
declare the MTD/RP2D of the combination with the new formulation. 
Furthermore, Amendment 2 implements other important changes as follows: 
Rationale for the update related to EGF816 safety: 
Because rash, particularly maculopapular rash or rash pruritic, is an adverse event frequently 
observed following treatment with EGF816, recommended guidelines for management and 
dose modification of rash/skin toxicities were provided. 
In addition, EGF816 program level updates were made in the clinical overview section. 
Rationale for the update related to INC280 safety: 
Concurrent elevation of ALT and/or AST and total bilirubin: After 28-Sep-2014 (cut-off date 
of the current [Investigator’s Brochure], a female patient experienced a serious, unexpected, 
possibly related adverse event of abnormal liver function tests during treatment with a 
combination of INC280 and gefitinib while enrolled in the study [CINC280X2202]. The 
investigator assessed the adverse event suspected to be related to the combination of INC280 
and gefitinib. This adverse event met the lab criteria of Hy’s Law and the hepatotoxicity could 
not be attributed solely to either drug alone or to the combination. 
The protocol is therefore being amended to update the dose modifications guideline for 
hepatotoxicity in regard to discontinuing study medication(s) with concurrent elevation of ALT 
and/or AST >3×ULN and total bilirubin >2×ULN with ALP <2×ULN, in the absence of signs 
of cholestasis, hemolysis, and alternative causes of the liver injury (e.g., concomitant use of 
hepatotoxic drug(s), alcoholic hepatitis, etc.). Specific work-up for potential Hy’s law cases has 
been added to the protocol. The dose modification rules and the dose limiting toxicity for liver 
toxicity as well as the follow-up evaluations for hepatic toxicities have also been updated 
accordingly. 
Photosensitization: Based on the preclinical data which suggests photosensitization potential of 
INC280, precautionary measures against ultraviolet exposure are being included in the protocol 
in addition to the information provided in the Investigator’s Brochure. 
In addition, the clinical overview of INC280 was updated based on the Investigator’s Brochure 
last update (current version is now 5.2 with cut-off date 28-Sep-2014). 


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Rationale for the changes in eligibility criteria: 
• Update of exclusion criteria 
• EGFR TKIs to be taken into consideration as prior lines of treatment were specified in 
exclusion criterion 1. 
• To allow patients with controlled brain metastasis to enter the trial, the exclusion 
criterion 6 was modified. 
• Parameters and conditions were included in exclusion criterion 8 to better define 
patients with uncontrolled cardiovascular disease, 
• To reduce the washout period from 4 weeks to 2 weeks for patients who received 
radiotherapy for all other localizations than lung or whole brain, or in case of palliative 
radiotherapy, the exclusion criterion 12 was modified. 
• To exclude patients with relevant elevations for glucose and alkaline phosphatase, out 
of range laboratory values for these parameters were included to exclusion criterion 15. 
In addition, electrolytes (potassium, magnesium, phosphorus, total calcium (corrected 
for serum albumin)) are added to be within normal ranges or corrected during the 
screening period. 
• The exclusion criterion 21 for the contraception period after study treatment 
discontinuation was updated from 7 days to 3 months based on currently available 
pharmacokinetics data for EGF816. 
• Addition of exclusion criteria: 
• To exclude patients with interstitial lung disease to reflect the potential class effect of 
EGFR TKIs observed for first and second generation EGFR TKIs. 
• To ensure adequate drug absorption, patients with significant gastro-intestinal (GI) 
function impairment were excluded; 
To exclude patients who have not recovered from all toxicities related to prior anticancer 
therapies to grade ≤ 1 (CTCAE v 4.03);Rationale for the update related to molecular screening: 
• Eligibility criteria for defining c-MET dysregulation have been refined based on 
experience with individuals enrolled in other INC280 studies in the EGFR TKI resistant 
setting e.g. [CINC280X2202]. The study will focus on the high c-MET dysregulation 
cohort defined as either a gene amplification (GCN≥4) and those with IHC 3+ 
overexpression. The recent publication by Schildhaus et al suggests that, in NSCLC, 
the use of GCN rather than gene ratio by FISH is better able to define amplified patients 
based on the biology of the amplicon. Therefore we removed the reference to ratio as a 
way of defining amplification. Finally the GCN determining enrollment is modified to 
4 copies to enable a greater clarity on the cut-off for amplification to determine patients 
most likely to respond to the combination of EGF816 with INC280. 
• To better define the patient population, the mutational status pre-requirements for Phase 
Ib and Phase II Group 1 were updated to clarify that EGFR mutation L858R and/or 
ex19del need to be locally documented, and updated for Phase II Group 2 because de 
novo EGFRT790M mutation may occur without the presence of EGFR mutation 
L858R and/or ex19del. In addition, local analytical method characteristics for 
acceptable T790M mutational status testing were updated. 




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Rationale for other updates: 
The hypothetical dose-escalation scenarios presented in Appendix 2 of the protocol were 
updated based on the currently available data in INC280 and EGF816 single-agent studies used 
in the model. 
Of note, the changes in selection criteria provided in this amendment do not affect the 
heterogeneity among studies used in the model. In addition, the dose-DLT data observed in this 
study thus far are still valid according to the refined population, together with the new hepatic 
DLT definition (no cases observed within patients enrolled with the previous version of the 
protocol). Therefore, the selection criteria update and the DLT definition update do not affect 
the BLRM results. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
List of abbreviations 
• Added ADME, ALP, BAL, BID, cfDNA, DBP, DOCE, FISH, FU, GCP, GCN, GGT, GI, 
IC50, IHC, IRT, LFT, mut, NGS, NOAEL, NRU, PTT, QTcF, SBP, UV definition 
Glossary list 
• Added/removed and amended definitions. 
Section 1.2.1 Overview of INC280 
• Amended presentation of INC280 based on the data from 28-Sep-2014 (data cut-off date 
for Investigator’s Brochure update) 
Section 1.2.1.1 Non-clinical experience 
• Added potential for photosensitization for INC280 observed in in vitro assays. 
Section 1.2.1.2 Clinical experience 
• Added the efficacy and safety summaries of INC280 based on the data from 28-Sep-2014 
(data cut-off date for Investigator’s Brochure update) and the data from 30-Jan-2015 for 
study 
. 
Section 1.2.2.2 Clinical experience 
• Added the efficacy and safety summaries of EGF816 based on the data from 02-Feb-2015 
in CEGF816X2101 study. 
• Added Figure 1-1 to provide EGF816 clinical activity observed at all dose levels tested. 
Section 4.1 Description of study design 
• Revised the definition of activating and resistance EGFR mutations. Revised the definition 
of c-MET dysregulation. 
• Removed EGFR L858R or ex19del for Phase II Group 2 in Figure 4-1. 
• Revised molecular pre-screening requirements. 


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• Removed requirement for archival or newly obtained tumor biopsy sample submission to 
central lab at baseline. 
Section 4.4 Early study termination 
• Updated language for patient withdrawal. 
Section 5.1 Patient population 
• Revised mutation status pre-requirements for Phase Ib and Phase II Group 1, and for Phase 
II Group 2. 
Section 5.2 Inclusion criteria 
• Revised baseline EGFR mutation characteristics, and local results or biopsy collection 
requirements. 
• Removed mandatory requirement for archival tumor from prior to previous EGFR TKI 
treatment submission. 
Section 5.3 Exclusion criteria 
• Added EGFR-TKIs to be taken into consideration as prior lines of treatment. 
• Added exception to one previous treatment line with an approved EGFR-TKI to allow study 
entry in case of EGFR-TKI discontinuation due to adverse event. 
• Added exception to patient with controlled brain metastases to participate in the trial. 
• Updated exclusion criterion in case of uncontrolled cardiovascular disease. 
• Updated exclusion criterion in case of out of range laboratory values. 
• Added exclusion criterion for patients with abnormal potassium, magnesium, phosphore, 
total calcium laboratory values. 
• Added exclusion criterion in case of history or presence of interstitial lung disease. 
• Added exclusion criterion for patients who have not recovered from all prior anticancer 
therapies related toxicities to grade ≤ 1 (CTCAE v 4.03). 
• Added exclusion criterion for patients with impairment of GI function. 
• Removed specific bilirubin abnormal value for Gilbert’s syndrome patients. 
• Removed definition of pregnancy for pregnant women exclusion criterion. 
• Revised the contraception period after study treatment discontinuation from 7 days to 3 
months. 
Table 6-1 Dose and treatment schedule 
• Added EGF816 Tablets. 
• Added footnote to clarify that “additional dose strengths might be added”. 
Section 6.1.1 Dosing regimen 
• Added the word tablet where previously only EGF816 capsules were mentioned. 
• Added pomegranate and juice within list of fruits that should be avoided during the study 
treatment period. 
• Added precautionary measures regarding ultraviolet exposure. 
Section 6.2.1 Starting dose rationale 


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• Added starting dose rationale for the formulation change from EGF816 capsules to tablets. 
Table 6-2 Provisional dose levels for EGF816 
• Specified that starting dose applies for EGF816 capsule formulation. 
Table 6-3 Provisional dose levels for INC280 
• Specified that starting dose applies for EGF816 capsule formulation. Section 6.2.3 
Guidelines for dose escalation and determination of MTD/RP2D 
• Added consequences of EGF816 formulation change on BLRM and cohorts implementation 
in the dose-escalation phase of the study. 
Table 6-4 Criteria for dose-limiting toxicities 
• Clarified that AST or ALT = grade 3 and skin and subcutaneous disorders = grade 3 have 
to be observed during > 7 consecutive days. 
• Revised the definition of AST and/or ALT > grade 3 and > grade 2 total bilirubin and ALP 
< 2 x ULN to meet Hy’s Law case definition. 
Table 6-5 Criteria for interruption and re-initiation of EGF816 and INC280 
• Revised guidance for hepatic investigations dose modification recommendations. 
• Added guidance for discontinuation based on definition of Hy’s Law. 
• Revised cardiac investigations definition. 
• Revised gastro-intestinal disorders definition. 
• Removed rash/photosensitivity recommended dose modifications. 
• Removed respiratory recommended dose modifications. 
• Added LFTs definition in footnote. 
Section 6.3.2 Guidelines for the management and dose modification of skin related toxicities 
• Added new section on guidelines for prevention and symptomatic care of rash/skin toxicities, 
and management and dose modification for maculopapular rash and other rashes. 
Section 6.3.3 Follow-up for toxicities 
• Revised requirements and duration for follow-up for Drug-Induced Liver Injury. 
Section 6.4.1 Permitted concomitant therapy 
• Added palliative bone radiation and anticoagulation treatment. 
Section 6.4.2 Permitted concomitant therapy requiring caution and/or action 
• Removed EGF816 effect on CYP2D6 and CYP2C8. 
• Added EGF816 and P-gp interaction. 
Section 6.5 Patient numbering, treatment assignment 
• Added that IRT will be used for Phase II patients. 
Section 6.5.1 Patient numbering 
• Added paragraph on IRT use for Phase II patients. 
Section 6.6.1 Study drug packaging and labeling 
• Added label information for IRT use with Phase II patients. 


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• Added word ‘tablet’ throughout the text where previously only EGF816 capsules were 
mentioned. 
• Added packaging details for EGF816 tablets. 
Section 7.1 Study flow and visit schedule 
• Clarified duration of Cycle 1 visit windows. 
Table 7-1 Visit evaluation schedule 
• Added IRT registration. 
• Added headers for assessment sub-types. 
• Added assessments for optional whole blood sample. 
• Revised biomarkers assessment definition. 
• Added blood sample collection for c-MET and EGFR status determination in cfDNA. 
• Revised footnotes related to biomarker assessments. 
• Addition of optional study on sensitivity and resistance mechanisms to INC280 
Section 7.1.1 Molecular pre-screening 
• Revised activating and resistance mutational status pre-requirements. 
• Added local analytical method characteristics for acceptable T790M mutational status 
testing. 
• Revised c-MET dysregulation definition. 
• Changed Phase II Group 2 screening requirements. 
• Replaced IHC with FISH as main method of c-MET expression analysis. 
• Section 7.1.2 Screening Removed requirement for archival or newly obtained tumor biopsy 
sample submission to central lab at baseline. 
• Defined the duration of the screening period. 
Section 7.1.4 Discontinuation of Study Treatment 
• Updated information in line with new patient withdrawal language. 
• Added the duration of maximum study drug interruption authorized as per protocol. 
• Added that study drug discontinuation has to be recorded in the IRT. 
• Removed Section 7.1.4.1 Criteria for premature patient withdrawal. 
Section 7.1.5 Withdrawal of consent 
• Added new section in line with new language for withdrawal of consent. 
Section 7.1.6 Follow-up for safety evaluations 
• Amended section title. 
• Updated section in line with new language for withdrawal of consent. 
Section 7.1.7 Lost to follow-up 
• Added new section in line with new language for withdrawal of consent. 
Section 7.2.1 Efficacy assessments 
• Added collection of imaging data for potential blinded central review. 




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• Removed statement that the outputs from the BLRM (mainly the summary of the 
distribution of DLT rates at different dose levels) will be summarized in a separate 
document. This statement was initially intended for internal documentation only. 
Section 14.3 Appendix 3 - Permitted concomitant medications requiring caution 
• Removed CYP2C8 or CYP2D6 sensitive substrate category. 
• Updated with current information for concomitant medications used with caution. 
Section 14.4 Appendix 4 - Prohibited concomitant medications 
• Removed CYP2D6 substrate with NTI category. 
• Updated with current information for concomitant medications prohibited. 
IRB/IEC/REB Approval 
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. In addition, if 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 amended protocol. 


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Amendment 01 
Amendment rationale 
This amendment addresses the following revisions suggested by a regulatory authority: 
• To reduce EGF816 starting dose to 50 mg qd, 
• To clarify the subsequent escalation of EGF816 and INC280 doses and 
• To revise the DLT definitions by adding Grade 2 pneumonitis as dose-limiting toxicity. 
• To provide the latest available clinical safety and PK data for EGF816 and INC280 tablet 
formulation 
• To provide updated hypothetical scenarios in reflection of the reduced starting dose of 
EGF816 and the updated priors based on the updated safety information. 
Additional changes for clarification were also made (please see below Changes to the protocol 
for details). 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
Section 1.2.1.2.1 Clinical safety 
• Addition of safety data of INC280 tablet 
Section 1.2.1.2.2 Clinical pharmacokinetics 
• Addition of pharmacokinetic data of INC280 tablet 
Section 1.2.2.2 Clinical experience 
• Addition of safety data of EGF816 
Section 2.3 Rational for dose and regimen selection 
• Reduction of EGF816 starting dose 
• Deletion of wording regarding adjustment of starting doses prior to enrollment of patients 
in the trial 
Section 4.1 Description of study design 
• Correction of the number of patients to be enrolled in Phase II Group 2 to N=20 in Figure 
4-1 Study design 
Section 5.3 Exclusion criteria 
• Correction of a typographical error in exclusion criterion #4 
Section 6.1.1 Dosing regimen 
• Reduction of EGF816 starting dose 
• Deletion of wording regarding adjustment of starting doses prior to enrollment of patients 
in the trial 
• Deletion of “Patients will consume another glass of water approximately two hours after 
each dosing” as this is not applicable to INC280 tablets and EGF816. 


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Section 6.2.1 Starting dose rationale 
• Reduction of EGF816 starting dose 
• Deletion of wording regarding adjustment of starting doses prior to enrollment of patients 
in the trial 
Section 6.2.2 Provisional dose levels 
• Split Table 6-2 Provisional dose levels for EGF816 and INC280 into two tables (Table 6-2 
provisional dose levels for EGF816 and Table 6-3 provisional dose levels for INC280) 
• Reduction of EGF816 starting dose 
• Revision of EGF816 provisional dose levels 
Section 6.2.3.2 Dose cohort modification 
• Reduction of EGF816 starting dose 
• Deletion of wording regarding adjustment of starting doses prior to enrollment of patients 
in the trial 
Section 6.2.4 Definitions of dose limiting toxicities 
• Addition of Grade 2 pneumonitis as DLT in Table 6-4 (Table 6-3 in original protocol 
version)– Criteria for defining dose-limiting toxicities 
Section 6.3.1. Dose modification and dose interruption 
• Addition of criteria for dose modification for pneumonitis in Table 6-5 (Table 6-4 in original 
protocol version) Criteria for interruption and re-initiation of EGF816 and INC280 
treatment. 
• Clarification of diarrhea grade 2 dose modification recommendation in Table 6-5 to 
maintain INC280 dose level if diarrhea returns as grade 2 and resolves to ≤ grade 1 
Section 7 Study flow and visit schedule 
• Formatting correction of Table 7-1 Visit evaluation schedule to have prior/concomitant 
medication information collected at Cycle 1 Day 1 
Section 8.1.1 
1. “Delete for NOVDD Trials as outcome is not collected” has been deleted as it is instruction 
text from the Novartis protocol template which should not appear in the final version of the 
protocol. 
Section 10.1.5 Pharmacokinetic analysis set 
• Deletion of repeated text “patients will be removed from the determination of individual 
INC280, EGF816 or LMI258 PK parameters on case by case basis.” 
Section 14.2 Appendix 2- Operating characteristics of the Bayesian logistic regression mode 
and hypothetical dose escalation scenarios 
• Addition of newly available dose-DLT data on EGF816 and INC280 from the single 
agent studies to update the distribution of DLT rates 
• Modification of the hypothetical dose escalation scenarios in Table 14-11 using the 
newly available single agent and the new starting dose combination. 


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IRB/IEC/REB Approval 
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. In addition, if 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 amended protocol. 


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Protocol summary 
Protocol number 
CINC280X2105C 
Title 
A phase Ib/II, multicenter, open-label study of EGF816 in combination with INC280 in 
adult patients with EGFR mutated non-small cell lung cancer 
Brief title 
Study of safety and efficacy of EGF816 in combination with INC280 in non-small cell 
lung cancer patients with EGFR mutation 
Sponsor and 
Clinical Phase 
Novartis 
Phase Ib/II 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
The purpose of this study is to determine the maximum tolerated dose (MTD) or 
recommended phase 2 dose (RP2D) of nazartinib in combination with capmatinib and to 
estimate the preliminary anti-tumor activity of nazartinib in combination with capmatinib 
in participants with advanced non-small cell lung cancer with documented EGFR 
mutation. 
To explore the hypothesis that targeting the two main EGFR resistance mechanisms, 
acquisition of T790M and MET dysregulation, may prevent or overcome the acquired 
resistance to EGFR TKIs, by combining the third generation EGFR TKI, nazartinib, and 
the highly selective and potent MET inhibitor, capmatinib, in non-small cell lung cancer 
participants with documented EGFR mutation who have developed resistance to EGFR 
TKI treatment or who never received any prior line of systemic antineoplastic therapy for 
advanced disease (For participants in Phase II Groups 1 to 4, antineoplastic systemic 
therapy administered as adjuvant or neo-adjuvant treatment more than six months prior 
to study enrollment is not considered a prior line of therapy for purpose of this study). 
To explore the hypothesis that capmatinib monotherapy is safe and beneficial to 
participants in EGFR mut, T790M negative, EGFR TKI resistant MET amplified NSCLC. 
Primary 
Objective(s) 
Phase Ib part: To estimate the MTD or RP2D of nazartinib in combination with 
capmatinib. 
Phase II part: To estimate the preliminary anti-tumor activity of nazartinib in combination 
with capmatinib (Groups 1, 2 and 3) and to characterize the safety and tolerability of 
nazartinib in combination with capmatinib when taken with food (Group 4). 
To estimate the preliminary anti-tumor activity (ORR) of capmatinib monotherapy (Group 
5). 
Secondary 
Objectives 
To characterize the safety and tolerability of nazartinib in combination with capmatinib 
(Phase Ib/II Groups 1 to 4). 
To characterize the PK of nazartinib in combination with capmatinib when given in 
combination under fasted state or with food (Phase Ib/II Groups 1 to 4). 
To evaluate the preliminary anti-tumor activity of nazartinib in combination with 
capmatinib (Phase Ib/ Phase II Groups 1 to 4). 
To estimate the preliminary anti-tumor activity (DOR, DCR, and PFS) of capmatinib 
monotherapy (Phase II Group 5) 
To characterize the safety and tolerability of capmatinib monotherapy as well as 
capmatinib in combination with nazartinib therapy (Phase II Group 5). 
Study design 
This study has been designed as a Phase Ib/II, multi-center, open-label study starting 
with a Phase Ib dose escalation part followed by a Phase II part. 
At the end of the Phase Ib part, once the MTD or RP2D has been declared, additional 
participants with NSCLC will be enrolled in the Phase II part in order to assess the 
preliminary anti-tumor activity of nazartinib in combination with capmatinib. In an 
additional group (Phase II Group 5), preliminary anti-tumor activity will be evaluated in a 
two-stage design. This group will enroll 10 participants at the first stage with a futility 
analysis. At the second stage, additional participants will be enrolled provided that the 
futility analysis did not show any evidence of lack of efficacy of the capmatinib 
monotherapy. 
Participants with locally advanced or metastatic NSCLC will be assigned into different 
groups according to their resistance mechanisms: 


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Phase II Group 1: 
Previously documented EGFR activating mutation 
Any T790M, any MET 
Who received 1 to 3 lines of systemic antineoplastic therapy (chemotherapy and/or 
targeted therapy) before study entry, including 1 line maximum of first or second 
generation EGFR TKI 
Who progressed on the prior line of first or second generation EGFR TKI 
Phase II Group 2: 
Documented de novo EGFR T790M mutation 
Who are treatment naïve or received maximum 2 lines of systemic antineoplastic therapy 
(chemotherapy and/or targeted therapy) prior to study entry, but no therapy known to 
inhibit EGFR 
Phase II Group 3: 
Previously documented EGFR activating mutation 
T790M negative, any MET 
Who never received any prior line of systemic antineoplastic systemic therapy 
(chemotherapy and/or targeted therapy) prior to study entry 
Phase II Group 4: 
Previously documented EGFR activating mutation 
Any T790M, any MET 
Who are treatment naïve or failed (defined as intolerance to treatment or documented 
disease progression) maximum 2 prior lines of any systemic antineoplastic therapy for 
advanced disease. 
Group 4 participants will take the combination therapy with food (unrestricted meal type) 
whilst Phase Ib and Phase II Groups 1, 2 and 3 participants take the combination therapy 
under fasting condition. 
Phase II Group 5: 
Previously documented EGFR activating mutation (e.g., L858R and/or ex19del), T790M 
negative, acquired MET amplification who have progressed on one prior line of therapy 
for advanced/metastatic NSCLC disease. Enrollment of participants who have 
progressed on prior line with osimertinib will be a minimum of 50% of the planned total 
number of participants while participants who progressed on other third generation 
EGFR TKI will represent a maximum of 10% of the planned total number of participants. 
Population 
Adult participants with non-small cell lung cancer who have EGFR mutations. 
Key Inclusion 
criteria 
• 
Participants (male or female) ≥ 18 years of age. 
• 
Participants in Phase Ib and Phase II Groups 1 to 4 with histologically 
documented, locally advanced or recurrent (stage IIIB who are not eligible for 
combined modality treatment) or metastatic (Stage IV) non-small cell lung cancer. 
Participants in Phase II Group 5 must have stage IIIB/IIIC (not amenable to 
curative surgery, chemoradiation or radiation) or stage IV NSCLC at the time of 
study entry according to AJCC version 8. 
• 
Participants in Phase Ib and Phase II Ggroups 1 to 4 must have locally 
documented EGFR mutation L858R and/or ex19del (or other rare activating 
mutations that confer sensitivity to first and second generation EGFR inhibitors (e.g. 
L861Q, G719X, S768I), or a characterized de novo EGFRT790M mutation. 
Biomarker requirements for participants in Phase II Group 5 are detailed in 
Inclusion criteria 15. 
• 
Presence of at least one measurable lesion according to RECIST 1.1 as per 
Appendix 1. 
• 
Eastern Cooperative Oncology Group (ECOG) performance status ≤1. 
• 
Participants must be screened for HBV. Participants who are either HBsAg positive 
or HBV-DNA positive must be willing and able to take antiviral therapy 1-2 weeks 
prior to first dose of study treatment (capmatinib+nazartinib) and continue on 
antiviral therapy for at least 4 weeks after the last dose of study treatment 


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(capmatinib +nazartinib). Additional management of the participants would be 
provided by a physician with expertise in management of HBV, if needed. 
• 
Participants must be screened for HCV. Participants must have negative hepatitis 
C antibody (HCV-Ab) or positive HCV-Ab but with an undetectable level of HCV-
RNA. Note: participants with detectable HCV-RNA are not eligible to enroll into the 
study. 
• 
For Phase Ib: participants must have either an acceptable local result, detailing 
their MET and EGFRT790M status in a biopsy collected at or post progression on 
the previous EGFR TKI therapy or sufficient tumor material available from a biopsy 
collected at or post progression on the previous EGFR-TKI therapy for central 
assessment of MET and EGFRT790M. For Phase II, participants must have 
sufficient material available for results from central assessment of MET and 
EGFRT790M. The biopsy must be collected at or post progression on last EGFR 
TKI treatment line for Group 1 and Group 5, at any time for Groups 2, 3 and 4 at any 
time (if treatment-naïve) or at/or any time after progression on last antineoplastic 
therapy for advanced setting (if 2/3L participants); if biopsy is not available after last 
treatment, the most recent available archival biopsy should be collected. 
• 
Phase Ib only: documented progression of disease according to RECIST 1.1 while 
on continuous treatment with EGFR TKI (e.g. erlotinib, gefitinib or afatinib). 
• 
Phase II Group 1 only: participants with acquired resistance to EGFR TKI treatment 
defined as documented clinical benefit (CR [any duration], PR [any duration], or SD 
for at least 6 months) on prior first or second generation EGFR TKI therapy (e.g. 
erlotinib, gefitinib or afatinib); and subsequently demonstrated progression 
according to RECIST 1.1. 
• 
Phase II Group 2 only: advanced NSCLC participants who have not been 
previously treated with any therapy known to inhibit EGFR, who received a 
maximum of two previous treatment lines of systemic antineoplastic therapies in the 
advance setting, and harbor de novo T790M mutation as per central assessment. 
• 
Phase II Group 3 only: participants must be naïve for any systemic antineoplastic 
therapy in the advanced setting (NSCLC stage IIIB or IV). 
• 
Phase II Group 4 only: participants who are treatment-naïve or have failed (defined 
as intolerance to treatment or documented disease progression) a maximum of two 
previous treatment lines of systemic antineoplastic therapies in the advanced 
setting. 
• 
Phase II Group 5 only: 
• Histologically or cytologically confirmed diagnosis of NSCLC (excluding squamous 
cell carcinoma) with all the following: 
• EGFR mutations known to be associated with EGFR TKI sensitivity. This must be 
assessed as part of the participant standard of care by a validated test for EGFR 
mutations, as per local regulations. Exon 19 del, L858R, either alone or in 
combination with other EGFR sensitivity mutation assessed by a Clinical Laboratory 
Improvement Amendments (CLIA) certified USA laboratory or an accredited local 
laboratory outside the USA must be documented in the participant source documents 
before the participant can be consented for pre-screening for MET amplification 
status. 
• EGFR T790M negative status for participants who have progressed on first or second 
generation EGFR TKI, or third generation EGFR TKI other than osimertinib, as per 
tissue-based result from a CLIA-certified USA laboratory or an accredited local 
laboratory outside of the USA, by a validated test according to local regulations. 
Results must be documented in the participant source documents before the 
participant can be consented for pre-screening for MET amplification. If a local 
T790M result is not available, T790M status in tissue per central Novartis-desginated 
laboratory result is required. 
• MET gene amplification defined as: Gene copy number (GCN) ≥ 5 per tissue-based 
result from a CLIA-certified USA laboratory or an accredited local laboratory outside 
of the USA by a test that is validated according to local regulations with results 
documented in the participant source documents. An adequate amount of tumor 
tissue (archived or if not available, newly obtained biopsy sample) must be available 


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at the time of enrollment for central assessment of MET gene amplification status. If 
a local result is not available, a tumor tissue sample must be submitted and 
determined as MET amplified (GCN ≥ 5) per central Novartis-designated laboratory. 
• Histological transformation from NSCLC into small cell lung cancer (SCLC) 
following previous EGFR TKI treatment are excluded. 
• Participants must have progressed on one prior line of therapy either to first/second 
generation EGFR TKIs, osimertinib or other third generation EGFR TKIs for 
advanced/metastatic disease (stage IIIB/IIIC [not amenable to curative surgery, 
chemoradiation or radiation or stage IV NSCLC). Acquired resistance to EGFR TKI 
treatment is defined as documented clinical benefit (CR [any duration], PR [any 
duration], or SD for at least 6 months) on prior first/ second EGFR TKIs (e.g., erlotinib, 
gefitinib, afatinib, dacomitinib), osimertinib or other third generation EGFR TKI such 
as almonertinib and furmonertinib and subsequently demonstrated radiological 
disease progression. 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 systemic chemotherapies will count as one prior line of treatment if relapse 
occurred within 12 months from the end of the neo-adjuvant or adjuvant systemic 
therapy. Adjuvant osimertinib therapy will count as prior line of EGFR TKI treatment 
if relapse occurs during the adjuvant osimertinib therapy. 
• Participants must have a life expectancy of at least 3 months. 
• Willing and able to comply with scheduled visits, treatment plan and laboratory tests. 
Please refer to Section 5.2 for complete list of inclusion criteria. 
Key Exclusion 
criteria 
• Phase Ib: 
• 
More than one previous treatment line with erlotinib, gefitinib or afatinib. 
• 
Previous treatment with any investigational agent known to inhibit EGFR (mutant 
or wild-type). 
• 
Participants who have received more than three prior lines of antineoplastic 
therapy (including EGFR TKI) in the advanced setting. 
• 
Phase II: 
Group 1: 
• 
More than three prior lines of systemic antineoplastic therapies (including 
EGFR TKI) in the advanced setting. 
• 
More than one previous treatment line with first or second generation EGFR 
TKI (e.g. erlotinib, gefitinib, afatinib) in the advanced setting. 
• 
Previous treatment with an investigational or marketed third generation EGFR 
TKI (e.g. osimertinib, CO-1686, nazartinib). 
• 
Previous treatment with other investigational or marketed agent known to inhibit 
EGFR (e.g. EGF monoclonal antibody therapy, dual TKI inhibitor). 
Group 2: 
• 
More than two previous treatment lines of systemic antineoplastic therapies in 
the advance setting. 
• 
Previous treatment with an investigational or marketed agent that inhibits 
EGFR. EGFR inhibitors include (but not limited to) all generations of EGFR 
TKI (e.g. erlotinib, gefitinib, afatinib, osimertinib, CO-1686, nazartinib) or other 
anti-EGFR or EGF monoclonal antibody therapy or dual TKI inhibitors. 
Group 3: 
• 
De novo EGFR T790M mutation identified by central assessment 
• 
Previous treatment with any systemic antineoplastic therapy in the advanced 
setting (NSCLC stage IIIB or IV). Participants who received only one cycle of 
systemic antineoplastic therapy in the advanced setting are allowed. 
Group 4: 
• 
More than two previous treatment lines of systemic antineoplastic therapies in 
the advanced setting. 


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• 
Previous treatment with an investigational or marketed third generation EGFR 
TKI (e.g. osimertinib, CO-1686, nazartinib). 
• 
Previous treatment with an investigational or marketed agent that inhibits EGFR 
(e.g.: EGF monoclonal antibody therapy or dual TKI inhibitors). 
• 
Previous treatment with a MET inhibitor or HGF-targeting therapy 
• 
Participants with symptomatic brain metastases. However, participants with 
asymptomatic/controlled brain metastases may participate in the trial. If 
treatment is required these participants must have completed any planned 
radiation therapy and/or surgery > 2 weeks prior to the first dose of study 
treatment and remain asymptomatic. Participants must be neurologically 
stable, having no new neurologic deficits on clinical examination, and no new 
findings on central nervous system imaging. Participants taking steroids must 
have been on a stable dose for two weeks prior to the first dose of study 
treatment. 
For Phase II Group 5: 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. 
• 
Presence or history of another malignancy 
Exception: Participants who have been disease-free for 3 years, or participants with 
a history of adequately treated in-situ carcinoma of the uterine cervix, completely 
resected basal or squamous cell carcinoma, non-melanomatous cancer of skin, 
history of stage IA melanoma that has been cured, are eligible. 
For Phase II Group 5: 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. 
• 
Undergone a bone marrow or solid organ transplant. 
• 
Known history of human immunodeficiency virus (HIV) seropositivity (HIV testing is 
not mandatory). 
For Group 5: Participants with known history of testing positive for human 
immunodeficiency virus (HIV) infection, and with a history of Acquired 
ImmunoDeficiency Syndrome (AIDS) defining 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. 
HIV Participants coinfected with hepatitis virus 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. 
• 
Participants receiving concomitant immunosuppressive agents or chronic 
corticosteroids use at the time of study entry except for control of brain metastases, 
topical applications, inhaled sprays, eye drops or local injections. 
• 
Participants with clinically significant, uncontrolled cardiovascular disease, such as: 
• 
Unstable angina within 6 months prior to screening. 
• 
Myocardial infarction within 6 months prior to screening. 
• 
Participants with a history of documented congestive heart failure (New 
York Heart Association functional classification III-IV). 
• 
Participants with uncontrolled hypertension defined as a Systolic Blood 
Pressure (SBP) ≥ 160 mm Hg and/or Diastolic Blood Pressure (DBP) ≥ 
100 mm Hg, with or without anti-hypertensive medication. Initiation or 
adjustment of antihypertensive medication(s) is allowed prior to 
screening. 


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• 
Ventricular arrhythmias. 
• 
Supraventricular and nodal arrhythmias not controlled with medication. 
• 
Other cardiac arrhythmia not controlled with medication. 
• 
Participants with corrected QT (QTc) ≥470 ms using Fridericia correction 
(QTcF) on the screening electrocardiogram (ECG) (using the average 
QTcF of the triplicate ECGs). 
• 
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). 
• 
Participants have received anti-cancer therapies within the following time frames 
prior to the first dose of study treatment: 
• 
Conventional cytotoxic chemotherapy: ≤ 4 weeks (≤ 6 weeks for 
nitrosoureas and mitomycin-C). 
• 
Biologic therapy (e.g., antibodies): ≤ 4 weeks. 
• 
Non-cytotoxic small molecule therapeutics: ≤ 5 half-lives (if half-life 
known) or ≤ 2 weeks   
• 
Other investigational agents: ≤ 4 weeks. 
• 
For Phase II Group 5: Previous anti-cancer and investigational agents 
within 4 weeks or ≤ 5 x half-life of the agent (whichever is shorter) before 
first dose of capmatinib. 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. 
• 
For Phase II Group 5: Treatment with a prior first or second generation 
EGFR TKIs (e.g., erlotinib, gefitinib, afatinib, dacomitinib), osimertinib or 
another third generation EGFR TKIs within 14 days or approximately 5x 
half-life, whichever is shorter, of the first dose of study treatment (if 
sufficient washout time has not occurred due to schedule or PK 
properties, an alternative appropriate washout time based on known 
duration and time to reversibility of drug related adverse events could be 
agreed upon by Novartis and the Investigator). 
• 
Radiation therapy (palliative setting is allowed.): ≤ 4 weeks, for asymptomatic brain 
metastases ≤ 2 weeks. 
• 
Major surgery: ≤ 2 weeks 
For Phase II Group 5: Major surgery (e.g., intra-thoracic, intra-abdominal or intra-
pelvic) within 4 weeks prior (2 weeks for resection of brain metastases) to starting 
capmatinib or who have not recovered from side effects of such procedure. Video-
assisted thoracic surgery (VATS) and mediastinoscopy will not be counted as major 
surgery and participants can be enrolled in the study ≥ 1 week after the procedure. 
• 
Participants that have not recovered from all toxicities related to prior anticancer 
therapies to grade ≤ 1 (CTCAE version 5.0). (Participants with any grade of alopecia 
are allowed to enter the study). 
• 
Participants in Phase Ib and Phase II Groups 1 to 4 have out of range laboratory 
values defined as: 
• 
Absolute Neutrophil Count (ANC) < 1.5 x 109/L (1.5 x 103/µL) 
• 
Hemoglobin (Hgb) < 9 g/dL (90 g/L) 
• 
Platelets (PLT) < 75 x 109/L (75 x 103/µL) 
• 
Total bilirubin > 1.5 x upper limit of normal (ULN) 
• 
AST and/or ALT > 3 x ULN, except for participants with liver metastasis 
who may not be included if AST and/or ALT > 5 x ULN 
• 
Alkaline phosphatase (ALP) > 5 x ULN 
• 
Calculated creatinine clearance < 45 mL/min using Cockroft-Gault 
formula 
• 
Asymptomatic serum amylase or lipase > Grade 2 


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• 
Serum amylase or serum lipase CTCAE grade ≥ 1 with signs and/or 
symptoms suggesting pancreatitis or pancreatic injury (e.g. elevated P-
amylase, abnormal imaging findings of pancreas, etc.) 
Participants in Phase II Group 5 have out of range laboratory values defined as: 
• 
Absolute Neutrophil Count (ANC) <1.5 x 109/L (1.5 x 103/µL) without 
growth factor support 
• 
Hemoglobin (Hgb) <9 g/dL (90 g/L) 
• 
Platelets (PLT) <100 x 109/L (100 x 103/µL) 
• 
Total bilirubin >1.5 x upper limit of normal (ULN) 
• 
AST and/or ALT > 2.5 x ULN except for participants with liver metastasis, 
who may not be included if AST and/or ALT > 5 x ULN 
• 
Alkaline phosphatase (ALP) >5 xULN 
• 
Calculated creatinine clearance (using Cockcroft-Gault formula) < 50 
mL/min 
• 
Asymptomatic serum amylase increase grade 1 and 2 are allowed if at 
the beginning of the study is 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 
• 
Participants who have impairment of GI function or GI disease that may significantly 
alter the absorption of study treatment (e.g., ulcerative diseases, uncontrolled 
nausea, vomiting, diarrhea, or malabsorption syndrome) 
• 
For Phase II Group 5: Carcinomatous meningitis 
• 
For Phase II Group 5: Known EGFR T790M positive, Known C797S positive, 
known druggable molecular alterations (such as ROS1, BRAF, KRAS etc.) who 
might be candidates for alternative targeted therapies as applicable per local 
regulations and treatment guidelines 
• 
Participants who received live vaccines (e.g., intranasal influenza, measles, mumps, 
rubella, oral polio, Bacille Calmette-Guerin (BCG), yellow fever, varicella, TY21a 
typhoid vaccines and COVID 19 vaccines) within 30 days prior to the first dose of 
study treatment 
Please refer to Section 5.3 for complete list of exclusion criteria 
Investigational and 
reference therapy 
nazartinib (EGF816) and capmatinib (INC280) 
Efficacy 
assessments 
Tumor assessment per RECIST 1.1 based on investigator’s assessment 
Safety 
assessments 
Incidence and severity of AEs and SAEs, including changes in laboratory values, vital 
signs and ECGs. 
Other assessments 
Plasma concentration vs. time profiles, plasma PK parameters, 
. 


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Data analysis 
For the primary objective of Phase Ib, estimation of the maximum tolerated dose (MTD) 
of the combination treatment will be based upon the estimation of the probability of dose 
limiting toxicity in cycle 1, using an adaptive Bayesian logistic regression model guided 
by the escalation with overdose control principle. 
For the primary objectives of Phase II, the overall response rate (ORR) will be estimated 
using Bayesian analysis with a minimally informative prior (Groups 1 to 3). For Group 4 
the frequency of adverse events will be assessed. For Group 5, the ORR for capmatinib 
monotherapy will be estimated. 
The study data will be analyzed and reported based on all participants’ data of Phase Ib 
and Phase II Groups 1 to 4 up to the time when all participants have completed at least 
six cycles of treatment or discontinued the study treatment earlier. Phase II Group 5 data 
will be analyzed and reported when all stage 1 and stage 2 participants in this group 
have completed at least six cycles of treatment or discontinued the study treatment 
earlier. 
An interim analysis for ORR is planned in Group 3 when approximately 20 (50%) of the 
participants have been enrolled and followed up for at least 4 cycles of treatment or 
discontinued study treatment. The primary intent of this interim analysis is to be able to 
stop the enrollment of treatment-naïve NSCLC participants in first line NSCLC (Ggroup 
3) early if there is evidence of lack of efficacy (futility). 
No interim analysis is planned for Groups 1, 2 and 4. However, individual participant data 
will be reviewed on an ongoing basis by the study team across the duration of the trial 
(Section 8.5). 
An interim analysis (IA) of the ORR is planned in Group 5 after 10 participants have been 
enrolled in the stage 1 and followed up for at least 2 tumor assessments while on 
monotherapy treatment, had radiological disease progression based on investigator’s 
assessment per RECIST 1.1, or discontinued study treatment prior to that time. The 
intent of this interim analysis is to be able to stop the enrollment if there is evidence of 
lack of efficacy (futility) of the capmatinib monotherapy. Recruitment will be on temporary 
halt while conducting the IA. 
Individual participant data will be reviewed on an ongoing basis by the study team with 
regard to safety and efficacy.  
Key words 
NSCLC, nazartinib (EGF816), capmatinib (INC280), TKI, T790M, MET 


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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
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 were expected in 
the United States (US) (Siegel et al 2019) and 280,000 in the European Union  
(Malvezzi et al 2019). 
In Western countries, 10-15% non-small cell lung cancer (NSCLC) participants express 
epidermal growth factor receptor (EGFR) mutations in their tumors (accounting for 20000 to 
30000 new participants per year in the USA), and Asian countries have reported rates as high 
as 30-40%. The predominant oncogenic EGFR mutations (L858R and exon 19 deletion 
(ex19del)) account for about 90% of EGFR mutant NSCLC. This results in the activation of 
multiple pathways that promote survival, proliferation, angiogenesis and metastasis 
(Mendelsohn 2000; Hirsch 2003; Lynch 2004; Paez 2004; Pao 2004). De novo EGFRT790M 
mutations are rare (<1% of all lung cancers) when identified by standard sensitivity methods 
and occur concurrently with EGFR mutations L858R or ex19del (Yu et al 2014). 
EGFR is an established critical therapeutic target for lung cancer. Numerous trials with first 
generation EGFR inhibitors (e.g., erlotinib and gefitinib) and more recently with the second 
generation (e.g., afatinib) have been conducted in the EGFR mutant NSCLC population. These 
trials have consistently demonstrated superior efficacy of EGFR tyrosine kinase inhibitors 
(TKIs) over chemotherapy (Table 1-1). EGFR TKIs’ response rates in EGFR mutant NSCLC 
participants range from approximately 60 to 80% versus 20 to 30% for the chemotherapy 
control arms. Similarly, median progression free survival (PFS) is prolonged via EGFR TKI 
first line treatment on average by 50%; ranging from 8 to 11 months, as compared to 4 to 6 
months for chemotherapy control arms. 
Table 1-1 
Superiority of EGFR TKIs over chemotherapy in EGFRmut NSCLC 
Trial 
Compound 
RR (%) 
Median PFS (mo) 
Median OS (mo) 
TKI 
Chemo 
TKI 
Chemo 
TKI 
Chemo 
IPASS (mut+) 
(Mok et al 2009) 
Gefitinib 
71.2 
47.3 
9.5 
6.3 
21.6 
21.9 
First-SIGNAL (mut+) 
(Han et al 2012) 
Gefitinib 
84.6 
37.5 
8.4 
6.7 
30.6 
26.5 
WJTOG 
(Mitsudomi et al 2010) 
Gefitinib 
62.1 
32.2 
9.2 
6.3 
30.9 
NR 
NEJ002 
(Inoue et al 2009) 
Gefitinib 
73.7 
30.7 
10.8 
5.4 
27.7 
26.6 
OPTIMAL 
(Zhou et al 2011) 
Erlotinib 
83 
36 
13.7 
4.6 
22.6 
28.8 
EURTAC 
(Rosell et al 2012) 
Erlotinib 
58 
15 
9.7 
5.2 
19.3 
19.5 
Afatinib (LUX-Lung 3) 
(Keating 2014) 
Afatinib 
56 
23 
11.1 
6.9 
28.1 
28.2 


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Trial 
Compound 
RR (%) 
Median PFS (mo) 
Median OS (mo) 
TKI 
Chemo 
TKI 
Chemo 
TKI 
Chemo 
Afatinib (LUX-Lung 6) 
(Keating 2014) 
Afatinib 
66.9 
23 
11 
5.6 
22.1 
22.2 
Although remarkable response rates are seen in participants with EGFR mutations that are 
treated with EGFR TKIs (~ 80%), the responses are of limited duration because eventually 
participants develop “acquired resistance”. 
Several resistance mechanisms have been identified, the most common being a secondary 
mutation at the threonine gatekeeper residue at position 790, T790M, which develops in up to 
50% of NSCLC participants harboring a primary EGFR mutation treated with first or second 
generation EGFR TKIs. Although the results from the [AURA3] and the [FLAURA] trials led 
to the approval of osimertinib (a third generation TKI with activity in NSCLCs harbouring the 
T790M mutation as first- and second-line treatment), it should be noted that 20% of these 
participants did not respond to osimertinib. C797S mutation was observed in one third of this 
resistant population, the osimertinib resistance could be linked to the novel C797S mutation, 
whereas in many other cases MET amplifications as a resistance bypass mechanism causing 
EGFRmut-TKI resistance have been identified suggesting that a combination of a MET and a 
EGFRmut inhibitor may be of benefit to overcome the observed resistance in these NSCLC 
participants (Papadimitrakopoulou et al 2018, Ramalingam et al 2018). The basic mechanism 
by which MET amplification causes EGFR-TKI resistance is associated with the activation of 
EGFR-independent phosphorylation of ErbB3 and downstream activation of the PI3K/AKT 
pathway, providing a bypass signaling pathway even in the presence of an EGFR-TKI 
(Engelman et al 2007) suggesting that co-targeting both, EGFR and MET is required to 
overcome resistance to EGFR-TKIs due to MET amplification. The MET amplification in 
NSCLCs was found to be 2–5%. However, the incidence of MET amplification was higher in 
NSCLC participants treated with erlotinib or gefitinib, ranging from 5% to 22% 
(Liang and Wang 2020). Several lines of evidence, however, suggest that MET gene 
amplification is another important mechanism for TKI resistance in NSCLCs and is detectable 
in approximately 5–22% of NSCLC participants with acquired resistance to first-generation 
EGFR-TKIs (Wang et al 2018). 
The following results were reported from a phase Ib/II study with capmatinib and gefitinib in 
NSCLC participants with acquired resistance to gefitinib, erlotinib, or afatinib and MET 
amplifications (gene copy number ≥ 6) (Wu et al 2018). Overall, 61 participants were treated 
in phase Ib and 100 participants were treated in Phase II. In the phase Ib part ORR was 23% 
across all doses and was regardless of the MET status. Increased activity, however, was 
observed in participants with a high MET copy number, with a Phase II ORR of 47%. The most 
common drug-related adverse events were nausea (28%), peripheral edema (22%), decreased 
appetite (21%), and rash (20%). In contrast to a number of other combination studies, the 
combination of capmatinib and gefitinib was found to be tolerable. From this study the authors 
concluded that capmatinib in combination with an EGFRmut TKI can restore sensitivity in TKI-
resistant NSCLC participants harbouring EGFR mutations. The contribution of a capmatinib 
alone, however, was not evaluated. 
Collectively, MET amplification is observed as one of the key resistant mechanism of EGFR 
TKIs. 


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Combination treatment of MET inhibitor and EGFR TKI showed a clinical meaningful response 
rate in high MET copy number participants who progress on EGFR TKI treatment. However, 
there is very limited data regarding efficay of MET inhibitor monotherapy in the EGFR TKI 
resistant population to demonstrate the contribution of component in the combination therapy. 
1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) 
1.2.1 
Overview of capmatinib (INC280) 
Capmatinib (INC280) is a small molecule, 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). Capmatinib is currently approved by the FDA 
for the treatment of adult participants with metastatic non-small cell lung cancer (NSCLC) 
whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 
skipping mutation. Approval has been reported also in Japan, Brazil, Switzerland, Taiwan, India 
and Hong Kong. 
Based on the efficacy and safety data from Phase II GEOMETRY 1 study [CINC280A2201]: 
in previously treated participants with locally advanced or metastatic NSCLC harboring MET 
14 exon skipping mutation, Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 
confirmed major responses (including a complete response [CR]) evaluated by Blinded 
Independent Review Committee (BIRC) were observed in 28 out of 69 (ORR 41%, [95% CI, 
29-53) evaluable participants (defined as those with at least one post-baseline tumor assessment 
or have discontinued treatment at the time of the data cut-off) and median DOR was 9.7 months 
[95% CI 6-13.0]. Median progression-free survival (mPFS) was 5.4 months [95% CI 4.2 – 7.0]. 
Moreover, intracranial responses were observed in 7 out of 13 evaluable participants with brain 
metastases at baseline. Four participants had complete resolution of lesion (Wolf et al 2020). 
Please refer to the current [capmatinib Investigator’s Brochure] for more detailed information. 


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1.2.2 
Overview of nazartinib (EGF816) 
Nazartinib is a targeted covalent irreversible EGFR inhibitor that selectively inhibits activating 
and acquired resistance mutants (L858R, ex19del and T790M), while sparing WT EGFR. 
Nazartinib has shown significant efficacy in EGFR mutant (L858R, ex19del and T790M) 
cancer models (in vitro and in vivo) with no indication of WT EGFR inhibition at efficacious 
concentrations. 


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2 
Rationale 
2.1 
Study rationale and purpose 
Currently approved first and second generation EGFR TKIs are effective in activated EGFR 
mutant NSCLC (Section 1.1), however nearly all participants develop resistance. 
Documented mechanisms of acquired resistance to nazartinib include EGFR C797S mutations, 
deletion in mTOR, B-RAF fusions, MET amplification, and concurrent p53 and RB1 truncating 
mutations associated with small cell transformation (Tan et al 2017). Currently it is unclear if 
the prevalence of resistance alterations with this compound differs significantly to osimertinib. 






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The design of the Phase II part is to characterize the anti-tumor activity, safety, tolerability and 
PK of nazartinib and capmatinib when administered in combination at the selected dose in 
NSCLC participants with documented activating EGFR mutation (L858R, ex19del) or de novo 
T790M mutation. The primary endpoint of antitumor activity is the overall response rate (ORR) 
per RECIST 1.1 as determined by the Investigators’ assessment. 
The Phase II part will consist of 5 groups (Figure 4-1), each having distinctive enrollment 
criteria and a different rationale for exploration. 
For the purpose of this study, common EGFR activating/sensitizing mutations are L858R point 
mutation and exon 19 deletions which account for approximately 90% of the cases. Other rare 
EGFR mutations such as L861Q, G719X, and S768I are also considered activating/sensitizing 
mutations for enrollment onto the Phase II part. 
The acquired resistance mutants are defined as follows: 
• “T790M positive” or “T790M+” when the T790M mutation is present; 
• “MET dysregulation positive” or “MET dysregulation+” when tumor sample analysis 
shows either: 
• IHC 3+ (defined as ≥50% of cells staining with high intensity) and/or 
• MET gene copy number ≥ 4 
In Group 5 “MET amplification” is defined as MET gene copy number (GCN) ≥ 5 
 In addition, a treatment line is defined as a combination of medications, or single-agent 
medication, used to treat the disease indication. If the medication in a single-agent treatment 
line or any of the medication(s) in a combination therapy were interrupted due to reasons other 
than disease progression (for example: toxicity, physician’s decision, etc.), and this was 
followed by re-challenge with the same medication or different ‘substitute’ medication(s), 
without evidence of progression, then all of these medications should be considered as a single 
treatment line. 
Group 1 (EGFRmut, any T790M, any MET, 2/4L antineoplastic, EGFR TKI 
resistant) 
Group 1 will enroll at least 40 NSCLC participants with locally documented activating EGFR 
mutation (L858R, ex19del) who received one to three lines of systemic antineoplastic therapy 
prior to study entry including one line maximum of first or second generation EGFR TKI (e.g., 
erlotinib, gefitinib, afatinib) and who progressed on this EGFR TKI treatment line. 
The participants in Group 1 will be assigned according to their acquired resistance mechanism 
in 4 sub-groups: 
• 1a. EGFRL858R/ex19del NSCLC with acquired mutation T790M 
(T790M+, MET dysregulation-) 
• 1b. EGFRL858R/ex19del NSCLC with demonstrated MET dysregulation 
(T790M-, MET dysregulation+) 
• 1c. EGFRL858R/ex19del NSCLC with both acquired T790M and MET dysregulation 
(T790M+, MET dysregulation+) 








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Consistent with its approved label, capmatinib single agent can be administered with or without 
food. 
The selected starting dose of nazartinib 50 mg q.d. in combination with capmatinib tablet 
starting dose of 200 mg b.i.d., is supported by the risk assessment (EWOC) within the BLRM 
derived from current single-agent dose-DLT data and predicted interaction. 
2.4 
Rationale for choice of combination drugs 
This study is designed to explore if the combination of the EGFR inhibitor, nazartinib, and MET 
inhibitor, capmatinib, will provide clinical benefit to 1) NSCLC participants whose tumors have 
developed resistance to EGFR TKI treatment through acquiring T790M mutation and/or MET 
pathway dysregulation and possibly overcome this resistance as well as 2) NSCLC EGFR 
inhibitor treatment naïve participants who harbor T790M de novo mutation and possibly 
overcome this resistance and prevent acquiring resistance through MET dysregulation 
(Section 2.1). 
2.5 
Rationale for choice of comparator drugs 
Not applicable. 
2.6 
Risks and benefits 
The purpose of this study is to investigate capmatinib in combination with nazartinib in adult 
participants with advanced/metastatic non-small cell lung cancer, harboring EGFR mutations 
(e.g.: L858R and/or ex19del) and provide a new and valuable therapeutic option for this 
participant population. Preclinical as well as clinical data suggest that the combination of 
capmatinib plus nazartinib may overcome the acquisition of resistance to EGFR TKIs or 
overcome the acquired resistance to EGFR TKIs. 
 
 
Appropriate eligibility criteria and specific DLT definitions, as well as specific dose 
modification and stopping rules, are included in Section 5 and Section 6 of this protocol. 
Recommended guidelines for prophylactic or supportive management of study-drug induced 
adverse events are provided in Section 6.3. The risk to participants in this trial may be 
minimized by compliance with the eligibility criteria and study procedures as well as close 
safety lab and clinical monitoring. 
During the dose escalation part of the study, all available safety and pharmacokinetic data were 
reviewed by participating investigators and Novartis at dose escalation meetings after the 
completion of each cohort in the phase Ib. The RP2D dose was determined at the dose level of 
capmatinib 400 mg b.i.d. + nazartinib 100 mg q.d. Capmatinib 400 mg b.i.d. correspond to the 
recommended dose utilized for monotherapy clinical studies. Refer to the [nazartinib and 
capmatinib Investigator’s Brochures] for further information. 
The treating physician must inform the Novartis medical monitor if, during the treatment period, 
any signs or symptoms are observed that are not consistent with the toxicities discussed in the 
[capmatinib Investigator’s Brochure] and [nazartinib Investigator’s Brochure]. The potential 
risks associated with the combination therapy will be carefully assessed and monitored 
following the procedure defined in the protocol. 


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The preliminary clinical safety data from the combination therapy indicate that the majority of 
adverse events receiving capmatinib and nazartinib (regardless of dose and formulation) have 
been mild or moderate. In addition, this study incorporates routine safety monitoring and 
regularly scheduled assessments to identify and report any adverse event or potential safety 
issues. However, there may be unforeseen risks with any study treatment which could be serious. 
Refer to the [capmatinib Investigator’s Brochure] and [nazartinib Investigator’s Brochure] for 
further information. 
Based on the available data, the overall risk/benefit assessment of nazartinib in combination 
with capmatinib is supportive of the conduct of this study in NSCLC participants in the context 
of this study. 
2.7 
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 are listed in relevant sections of the study protocol. 
Notification of the 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. 
3 
Objectives and endpoints 
Objectives and related endpoints are described in Table 3-1 below. 


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Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
 
Refer to Section 10.5.4. 
Phase Ib: To estimate the MTD or RP2D of nazartinib in combination 
with capmatinib 
Incidence of DLTs 
 
Phase II: To estimate the preliminary anti-tumor activity of nazartinib 
in combination with capmatinib (Groups 1, 2 and 3) 
Objective response rate (ORR) per RECIST 1.1 based on 
investigator’s assessment 
 
To characterize the safety and tolerability of nazartinib in combination 
with capmatinib when taken with food (Group 4) 
Safety: Incidence and severity of AEs and SAEs 
Tolerability: Dose interruptions, reductions and dose intensity 
 
To estimate the preliminary anti-tumor activity of capmatinib 
monotherapy (Group 5) 
ORR per RECIST 1.1 based on investigator’s assessment for 
capmatinib monotherapy 
Refer to Section 10.6. 
Secondary 
 
Refer to Section 10.7. 
Phase Ib/II (Groups 1 to 4): To characterize the safety and tolerability 
of nazartinib in combination with capmatinib 
Safety: Incidence and severity of AEs and SAEs, including changes 
in hematology and chemistry values, vital signs and ECGs 
Tolerability: Dose interruptions, reductions and dose intensity 
 
Phase Ib: To evaluate the preliminary anti-tumor activity of nazartinib 
in combination with capmatinib 
ORR, PFS, time to response (TTR), duration of response (DOR) and 
disease control rate (DCR) based on investigator’s assessment and 
overall survival (OS) 
 
Phase II (Groups 1 to 4): To evaluate the preliminary anti-tumor 
activity of nazartinib in combination with capmatinib 
PFS, TTR, DOR, DCR and ORR (Group 4 only) based on 
investigator’s assessment and OS 
 
Phase Ib/II (Groups 1 to 4): To characterize the PK of nazartinib and 
capmatinib when given in combination under fasted state or with food 
Plasma concentration vs time profiles. 
Plasma PK parameters of nazartinib and capmatinib 
 
Phase II (Group 5):  
 
 
To estimate the preliminary anti-tumor activity of capmatinib 
monotherapy 
DOR, DCR, and PFS based on investigator’s assessment for 
capmatinib monotherapy 
 
To characterize the safety and tolerability of capmatinib monotherapy 
as well as capmatinib in combination with nazartinib therapy 
Safety: Incidence and severity of AEs and SAEs, including changes 
in hematology and chemistry values, vital signs and ECGs 
Tolerability: Dose interruptions, reductions and dose intensity 
 


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Objective 
Endpoint 
Analysis 
ORR is defined as proportion of participants with best overall response of PR+CR per RECIST 1.1; DOR is defined as the time from first documented response (PR or 
CR) to the date of first documented disease progression or death due to any cause; DCR is defined as the proportion of participants with best overall response of CR, 
PR, or SD;  
PFS is defined as the time from the date of first dose of study treatment to the date of first documented disease progression (per RECIST 1.1) or death due to any cause; 
TTR is defined as the time between date of start of treatment until first documented response (CR or PR); OS is defined as the time from first dose of study treatment to 
the date of death due to any cause. 


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4 
Study design 
4.1 
Description of study design 
This study has been designed as a Phase Ib/II, multi-center, open-label study starting with a 
Phase Ib dose escalation part followed by a Phase II part. Oral nazartinib (once daily) and 
capmatinib (twice daily) will be administered on a continuous schedule until participant 
experiences unacceptable toxicity, progressive disease and/or treatment is discontinued at the 
discretion of the investigator or withdrawal of consent/opposition to use data/biological samples. 
Note: the study treatment may be continued beyond RECIST 1.1 defined progressive disease if, 
in the judgment of the investigator, there is evidence of clinical benefit and the participant 
wishes to continue with the study treatment. The judgment of the investigator should be 
documented in the Case Report Form (CRF) and the continued evidence of clinical benefit 
should be updated on a regular basis. 
In Phase Ib and Phase II Group 1 (EGFRmut, any T790M, any MET, 2/4L antineoplastic, EGFR 
TKI resistant), Group 3 (EGFRmut, T790M negative, any MET, 1L antineoplastic),Group 4 
(EGFRmut, any T790M, any MET, 1L (treatment naïve) 2-3L antioneoplastic, with food) and 
Group 5 (EGFRmut, T790M-, MET GCN≥5, EGFR TKI resistant) participants with NSCLC 
harboring EGFR activating mutations (L858R and/or ex19del, additionally other rare mutations 
L861Q, G719X, or S768I will satisfy eligibility criteria) will be enrolled. For Phase II Group 2 
(EGFRmut, de novo T790M, any MET, 1/3L antineoplastic, EGFR TKI naïve), participants 
with NSCLC, harboring de novo EGFR T790M mutation, without prior EGFR TKI treatment 
will be enrolled. 
In the Phase Ib part at least 18 participants who have progressed on previous EGFR TKI 
treatment (e.g., post erlotinib, gefitinib or afatinib) will be enrolled. An adaptive BLRM with 
EWOC will guide the dose escalation to determine the MTD or RP2D. Before a drug dosage 
can be declared to be the MTD or RP2D, at least six participants should have been treated at 
that dosage. 
Once the MTD or RP2D has been declared, additional participants with NSCLC will be enrolled 
in the Phase II part as shown in Figure 4-1 in order to assess the preliminary anti-tumor activity 
of nazartinib in combination with capmatinib. 
In the Phase II Group 1 (EGFRmut, any T790M, any MET, 2/4L antineoplastic, EGFR TKI 
resistant), participants with a previously documented EGFRmutL858R/ex19del NSCLC, who 
develop resistance to EGFR TKI treatment (e.g., post erlotinib, gefitinib or afatinib) will be 
enrolled and assigned according to their acquired resistance mechanism to one of four sub-
groups: 
• sub-group 1a: EGFRmutL858R/ex19del NSCLC with acquired mutation T790M (T790M+, 
MET dysregulation-). 
• sub-group 1b: EGFRmutL858R/ex19del NSCLC with demonstrated MET dysregulation 
(T790M-, MET dysregulation+). 
MET dysregulation is defined as either 




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In the Phase II Group 5 (EGFRmut, T790M-, MET GCN≥5, 2L, EGFR TKI resistant) 
approximately 30 NSCLC participants with locally documented activating EGFR mutation (e.g., 
L858R, ex19del) who must have progressed on one prior line of therapy (either to first/second 
generation EGFR TKIs, osimertinib or other third generation EGFR TKIs) for 
advanced/metastatic disease (stage IIIB/IIIC [stage IIIB/IIIC [not amenable to curative surgery, 
chemoradiation or radiation] or stage IV NSCLC) will be enrolled in a two-stage design. 
Enrollment of participants who have progressed on prior line with osimertinib will be a 
minimum of 50% of the planned total number of participants while participants who progressed 
on other third generation EGFR TKI will represent a maximum of 10% of the planned total 
number of participants. 
In Stage 1, 10 MET amplified (centrally confirmed) participants, among which at least 50% 
priorly treated with osimertinib will be enrolled. The decision to continue enrollment in Stage 
2 will be based on the futility interim analysis evaluating the ORR as per RECIST 1.1 while on 
capmatinib monotherapy treatment (see Section 4.2). If futility is concluded, the study will not 
proceed to Stage 2. If the Group 5 is not declared futile, additional 20 participants will be 
enrolled in Stage 2. 
To adjust for potential discordance between local vs central MET amplification testing results 
in Phase II Group 5, additional participants may be enrolled to ensure there are at least 10 in 
stage 1 and 30 in total MET amplified participants centrally confirmed by Novartis-designated 
laboratory. 
Data from participants in Group 5 will be reviewed on an ongoing basis to monitor the safety 
and efficacy/lack of efficacy. Independent from the interim analysis, the enrollment into Stage 1 
could be stopped (early) if there is a safety concern or evidence of lack of efficacy, defined as 
one of the following: 
• No responders in the first 10 MET amplified (centrally confirmed) participants 
• Onset of new brain metastasis in 2 participants 
• 10 participants permanently discontinue capmatinib monotherapy before completion of the 
second tumor assessment because according to investigator judgement participants are not 
benefiting from capmatinib monotherapy treatment. 
Participants will start the treatment with capmatinib monotherapy and may be followed with 
capmatinib in combination with nazartinib upon capmatinib monotherapy radiological disease 
progression based on investigator’s assessment per RECIST 1.1. 
Treatment can be continued with capmatinib in combination with nazartinib until radiological 
disease progression based on investigator’s assessment per RECIST 1.1 or other reasons for 
treatment discontinuation as defined in the protocol in Section 7.1.4. 
Group allocation will be managed by IRT. 
In Phase II Group 5, MET amplification (GCN≥5) status can be determined per validated local 
laboratory, or central Novartis laboratory if local results not available. A mandatory biopsy 
sample collected any time after progression on prior line of EGFR TKI must be submitted at 
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In all Phase II groups, an appropriate biopsy sample must be available for resistance mechanism 
analysis by a Novartis designated central laboratory. This biopsy sample should have been 
collected: 
• At or any time after progression on the last treatment line by EGFR TKI in Group 1 
(EGFRmut, any T790M, any MET, 2/4L antineoplastic, EGFR TKI resistant) ; 
• At any time in Group 2 (EGFRmut, de novo T790M, any MET, 1/3L antineoplastic, EGFR 
TKI naïve) and Group 3 (EGFRmut, T790M negative, any MET, 1L antineoplastic). 
• At any time in treatment-naïve participants or at/or any time after progression on the last 
treatment line for advanced disease in Group 4 (EGFRmut, any T790M, any MET, 1/3L 
antineoplastic). 
At or any time after progression on prior line of EGFR TKI for Group 5 (EGFRmut, any T790M, 
MET Gene Copy Number (GCN) ≥ 5, 2L antineoplastic, EGFR TKI resistant). 
Details on sample size and operating characteristics are provided in Section 10.9. 
Details of the biomarker collection plan are presented in Section 7.2.4. 


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Figure 4-1 
Study design 
 


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Molecular pre-screening 
• For both the Phase Ib and the Phase II Group 1 (EGFRmut, any T790M, any MET, 2/4L 
antineoplastic, EGFR TKI resistant), Group 3 (EGFRmut, T790M negative, any MET, 1L 
antineoplastic),  Group 4 (EGFRmut, any T790M, any MET, 1/3L antineoplastic), and 
Group 5 (EGFRmut, T790M-, MET GCN≥5, 2L, EGFR TKI resistant) parts of the study, 
documented proof of the presence of either exon 19 deletion and/or L858R mutation (or 
other rare activating mutations that confer sensitivity to first and second generation EGFR 
TKI (e.g. L861Q, G719X, S768I)) in EGFR is required for all participants enrolled in the 
study. This could have been determined at any point prior to screening. EGFR activating 
mutation status is determined by a local laboratory. A laboratory report showing evidence 
of EGFR activating mutations must be available in the source documents. For participants 
harboring G719X mutations, a local report showing either the exact mutation type 
(G719A/S/C/U) or G719X is acceptable. 
• Additionally for Phase Ib, MET dysregulation and EGFRT790M mutation testing should be 
performed locally or by the Novartis designated central laboratory on a newly obtained 
tumor sample or on an archival tumor sample obtained at or any time after progression on 
prior EGFR TKI therapy. EGFRT790M status can be determined locally utilizing: 
• In the United States: QIAGEN Therascreen EGFR RGQ PCR assay 
• In the other countries: either Roche Cobas or QIAGEN Therascreen test 
• If EGFRT790M status is not available locally or if it is available locally but determined 
by a test other than those outlined above, central assessment of EGFRT790M will be 
performed by a Novartis-designated central laboratory. 
• Local assessment of MET-amplification using fluorescence in situ (FISH) or 
immunohistochemistry (IHC) and assessed in a biopsy collected at or any time after the 
progression on prior EGFR TKI will be acceptable for study entry. Central assessment 
of MET amplification will be performed at a Novartis-designated central laboratory if 
MET molecular assessment is not available locally. 
• For Phase II Group 1(EGFRmut, any T790M, any MET, 2/4L antineoplastic, EGFR TKI 
resistant), EGFRT790M testing and MET dysregulation analysis must be performed by the 
Novartis designated central laboratory on a newly obtained tumor sample or on an archival 
tumor sample obtained at or any time after the last progression on prior EGFR TKI before 
study entry. 
• For Phase II Group 2 (EGFRmut, de novo T790M, any MET, 1/3L antineoplastic, EGFR 
TKI naïve) and Phase II Group 3 (EGFRmut, T790M negative, any MET, 1L antineoplastic) 
EGFRT790M mutation testing and MET dysregulation analysis must be performed by the 
Novartis designated central laboratory on a newly obtained tumor sample or on an archival 
tumor sample collected at any time before study entry. 
• For Phase II Group 4 (EGFRmut, any T790M, any MET, 1L (treatment naïve) 2-3L 
antineoplastic) EGFRT790M mutation testing and MET dysregulation analysis must be 
performed by the Novartis designated central laboratory on a newly obtained tumor sample 
or on an archival tumor sample collected at any time before study entry (if treatment-naïve) 
or at/or any time after progression on last antineoplastic treatment (if 2/3L participants); if 
biopsy is not available after last treatment, the most recent available archival biopsy 


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should be provided.For Phase II Group 5 (EGFRmut, T790M-, MET GCN≥5, 2L, EGFR 
TKI resistant), in order to be considered eligible for the study, participants must have 
documentation of EGFR activating mutant and T790M negative NSCLC by a tissue-based 
test (for additional details see Section 5.2). The results from procedures performed as part 
of the local standard practices (prior to enrolling in the trial) will satisfy the inclusion 
criteria. If T790M testing is not available locally, confirmation of T790M status at a 
Novartis-designated central laboratory is required to confirm the participant's eligibility. In 
this case, the tumor sample provided should be indicated in the appropriate eCRF and 
requisition forms. Eligible participants must have MET amplification confirmed by either a 
validated local or central laboratory (Phase II Group 5 only, see Section 5.2) or a Novartis 
designated central laboratory (all other Phase II groups). For participants enrolled with local 
results, MET amplification will be retrospectively confirmed using a validated FISH test 
that detects MET amplification via DNA derived from formalin fixed, paraffin-embedded 
human tissue at the Novartis-designated laboratory. 
All participants must sign the pre-screening consent to allow for the collection, and submission 
of tumor biopsy samples to the Novartis designated central laboratory for analysis, or to allow 
for anonymized local laboratory reports access as applicable. 
Refer to Section 7.1.1 and Section 7.2.4 for further details. 
Screening period 
The screening period begins once the participant has signed the study informed consent. 
Participants will be evaluated against study inclusion and exclusion criteria and safety 
assessments (Table 7-1, Table 7-2 and Section 7.1.2). 
Treatment period 
The treatment period will begin on Cycle 1 Day 1. The study treatment will be administered in 
28-days cycles. 
30-day follow-up (FU) period 
30 days after the last administration of study treatment, participants will be followed up for 
safety evaluations (Table 7-1, Table 7-2 and Section 7.1.6). 
Disease progression FU 
Participants who discontinue study treatment for any reason other than disease progression will 
be followed up for progression of disease (Section 7.1.6). 
Survival FU 
All participants, except participants from Phase II Group 5, will be followed for survival 
(Section 7.1.6). 


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4.2 
Timing of interim analyses and design adaptations 
No formal interim analyses are planned in the Phase Ib part of the study. However, the dose-
escalation design foresees that decisions based on the current data are taken before the end of 
the study (Section 6.2.3). 
During the Phase II part, an interim analysis to assess futility is planned for Phase II Group 3 
and Group 5. In addition, data from participants in the Phase II part will be reviewed on an 
ongoing basis to monitor the safety and tolerability of the MTD/RP2D. 
Interim analysis for Phase II Group 3 
During the Phase II part, an interim analysis to assess futility is planned on Phase II Group 3 
(EGFRmut, T790M negative, any MET, 1L antineoplastic) when approximately 20 participants 
have completed at least 4 cycles of treatment or discontinued treatment prior to that time. 
Assessment of futility will be based on the calculated Bayesian probability of success (PoS). 
The Phase II Group 3 (EGFRmut, T790M negative, any MET, 1L antineoplastic) will be 
stopped for futility if the PoS is less than 10% at the interim analysis. 
If applicable, enrollment of participants into the Phase II Group 3 (EGFRmut, T790M negative, 
any MET, 1L antineoplastic) will continue between the time the required data for participants 
in the interim analysis are observed and the time the results of the IA are available. Enrollment 
of participants into groups not evaluated in the interim analysis will also continue. 
If futility is concluded, the enrollment of 1L participants (Group 3 and 1L participants in Group 
4) may be stopped. Enrollment in opened groups with pre-treated participants will continue. 
Detailed information on the statistical considerations for the interim analysis is provided in 
Section 10.8 and Section 10.9. The internal clinical trial team will perform the analysis and 
make the decision, as described in Section 8.5. 
Interim analysis for Phase II Group 5 
An interim analysis to assess futility is planned on Phase II Group 5 (EGFRmut, T790M-, MET 
GCN≥5, 2L, EGFR TKI resistant) when 10 participants have completed at least 2 tumor 
assessments while on treatment with capmatinib monotherapy and have been assessed as MET 
amplified (centrally confirmed), had radiological disease progression per RECIST 1.1 or 
discontinued treatment, whichever is earlier. The intent of this interim analysis is to be able to 
stop the enrollment if there is evidence of lack of efficacy (futility) of the capmatinib 
monotherapy. Recruitment will be on temporary halt while conducting the IA. 
The decision to stop for futility at the interim will be based on the predictive probability (PP) 
of final observed ORR ≥ historical control ORR (35%) (Section 10.8) and will be calculated 
based on the actual number of evaluable participants at the interim analysis. The group will be 
stopped for futility if the respective PP is less than 1% at the interim analysis. With 10 evaluable 
participants for the interim analysis, if no response (CR or PR per RECIST 1.1 based on 
investigator assessment) is observed while the participants were on monotherapy, then Group 
5 will be stopped for futility. 


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All evaluable participants at the time of the data cut-off for the interim analysis will be used to 
obtain the futility boundary using the PP criteria. The futility boundary will be calculated 
according to the actual number of evaluable participants in the interim analysis. 
The statistical considerations for the interim analysis can be found in Section 10.8. 
4.3 
Definition of end of the study 
The primary analysis will be conducted after all participants have completed 6 cycles (about 6 
months of treatment) or all participants have permanently discontinued study treatment, 
whichever comes first. Due to the expected difference in enrollment completion for each group, 
the primary analysis for the different groups may occur at different times. The primary 
analysis/analyses data for participants in Phase Ib and Phase II Groups 1 to 4 has been 
summarized in the primary clinical study report (CSR) released in November 2019. The final 
analysis for participants in groups 1 to 4 will be included in an interim CSR. 
The primary analysis for Group 5 will be performed when all participants in the group have 
completed at least 6 cycles of capmatinib monotherapy or discontinued capmatinib 
monotherapy prior to that time. If participants are ongoing at that time, a further final CSR 
might be prepared. This report will become the final CSR for the study. Following the cut-off 
date(s) for the analysis reported in the primary CSR(s), the study will remain open. Ongoing 
participants will continue to receive study treatment (capmatinib + nazartinib) and be followed 
as per the schedule of assessments, as long as participants derive benefit from the capmatinib + 
nazartinib combination. 
The end of study is defined as the earliest occurrence of one of the following: 
• All participants have died or discontinued from the study 
• Futility/Lack of efficacy (only for Group 5 Stage 1, please refer to section 4.1) 
• Another clinical study becomes available that can continue to provide capmatinib 
monotherapy or capmatinib in combination with nazartinib in this participant population 
and all participants ongoing are eligible to be transferred to that clinical study 
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. Participants who continue to demonstrate clinical 
benefit will be eligible to receive study drug. Study treatment will be provided via an extension 
of the study, a rollover study requiring approval by responsible health authority and ethics 
committee, or through another mechanism at the discretion of the sponsor.  
The sponsor reserves the right to terminate access to study drug if any of the following occur:  
a) the marketing application is rejected by responsible health authority 
b) the study is terminated due to safety concerns 
c) the participant can obtain medication from a government sponsored or private health 
program 
d) therapeutic alternatives become available in the local market 


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4.4 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Reasons for early 
termination: 
• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
• Discontinuation of study drug development 
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should this be necessary, the participant should be seen as soon as possible and the same 
assessments should be performed as described in Section 7.1.4 for a discontinued or withdrawn 
participant. 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 
and/or ECs of the early termination of the trial. 
5 
Population 
5.1 
Study population 
For the Phase Ib and the Phase II Group 1 (EGFRmut, any T790M, any MET, 2/4L 
antineoplastic, EGFR TKI resistant), Group 3 (EGFRmut, T790M negative, any MET, 1L 
antineoplastic), and Group 4 (EGFRmut, any T790M, any MET, 1L (treatment naïve) 2-3L 
antineoplastic), adult participants with advanced or metastatic EGFR mutant L858R and/or 
ex19del NSCLC will be eligible (or other rare activating mutations that confer sensitivity to 
first and second generation EGFR inhibitors (e.g. L861Q, G719X, S768I)), whereas for Phase 
II Group 2 participants harboring a de novo EGFRT790M mutation will be eligible to participate 
in this study. 
During the Phase Ib dose escalation part, participants who have progressed on first or second 
generation EGFR TKI treatment (e.g. gefitinib, erlotinib or afatinib) will be enrolled. 
The Phase II Group 1 (EGFRmut, any T790M, any MET, 2/4L antineoplastic, EGFR TKI 
resistant) will enroll participants who had a clinical benefit (complete response (CR)/PR any 
duration or stable disease (SD) for at least 6 months) on first or second generation EGFR TKI 
and subsequently progressed on this first or second generation EGFR TKI treatment. 
Participants should not have received more than one prior line of EGFR TKI and no more than 
three prior lines (including the EGFR TKI) of antineoplastic therapy for NSCLC. Participants 
in the Phase II part Group 1 (EGFRmut, any T790M, any MET, 2/4L antineoplastic, EGFR TKI 
resistant) will be assigned according to their acquired resistance mechanism to four sub-groups: 
a. sub-group 1a : EGFRmutL858R/ex19del NSCLC with acquired mutation T790M (T790M+, 
MET dysregulation-) 
b. sub-group 1b : EGFRmutL858R/ex19del NSCLC with demonstrated MET dysregulation 
(T790M-, MET dysregulation+). MET dysregulation is defined as either MET gene copy 
number ≥ 4 by FISH and/or IHC 3+ (defined as ≥50% of cells staining with high intensity). 


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c. sub-group 1c: EGFRmutL858R/ex19del NSCLC with evidence of both acquired T790M and 
MET dysregulation (T790M+, MET dysregulation+) 
d. sub-group 1d: EGFRmutL858R/ex19del NSCLC with MET below the levels for sub-group b 
(T790M-, MET dysregulation-). 
In the Phase II part Group 2 (EGFRmut, de novo T790M, any MET, 1/3L antineoplastic, EGFR 
TKI naïve), participants should not have received prior EGFR inhibitor treatment and no more 
than two prior lines of antineoplastic therapy for NSCLC. 
In the Phase II Group 3 (EGFRmut, T790M negative, any MET, 1L antineoplastic), participants 
should not have received any prior line of systemic antineoplastic therapy in the advanced 
setting (NSCLC stage IIIB or IV). However, participants who have received no more than 1 
cycle of systemic antineoplastic therapy in the advanced setting are allowed. 
In the Phase II Group 4 (EGFRmut, any T790M, any MET, 1L (treatment naïve) 2-3L 
antineoplastic) participants, with documented EGFRmut NSCLC, who have never received any 
systemic antineoplastic therapy or have failed (defined as intolerance to treatment or 
documented disease progression) a maximum of 2 lines of antineoplastic therapies for advanced 
disease will be enrolled. Group 4 participants will take study drugs with food (unrestricted meal 
type). 
In the Phase II Group 5 (EGFRmut, T790M-, MET GCN ≥ 5, 2L, EGFR TKI resistant), 
previously documented EGFR activating mutation (e.g., L858R and/or ex19del), T790M 
negative, MET amplified who have progressed on one prior line of therapy EGFR TKI for 
advanced/metastatic NSCLC disease will be given capmatinib monotherapy followed by 
capmatinib in combination with nazartinib. 
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. 
5.2 
Inclusion criteria 
Participants eligible for inclusion in this study have to meet all of the following criteria: 
1. Written informed consent must be obtained prior to any screening procedures. 
2. Participants (male or female) ≥ 18 years of age. 
3. Participants in Phase Ib and Phase II Groups 1 to 4 with histologically documented, locally 
advanced or recurrent (stage IIIB who are not eligible for combined modality treatment) or 
metastatic (Stage IV) non-small cell lung cancer. 
Participants in Phase II Group 5 must have stage IIIB/IIIC (not amenable to curative surgery, 
chemoradiation or radiation) or stage IV NSCLC at the time of study entry according to 
AJCC version 8. 
4. Participants in Phase Ib and Phase II Groups 1 to 4 must have advanced NSCLC with locally 
documented EGFRL858R mutation and/or ex19del (or other rare activating mutations that 
confer sensitivity to first and second generation EGFR inhibitors (e.g. L861Q, G719X, 
S768I), or a characterized de novo EGFRT790M mutation). 
Biomarker requirements for participants in Phase II Group 5 are detailed in Inclusion criteria 
15. 
5. Presence of at least one measurable lesion according to RECIST 1.1 as per Appendix 1. 


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6. ECOG performance status ≤1 
7. Participants must be screened for HBV. Participants who are either HBsAg positive or 
HBV-DNA positive must be willing and able to take antiviral therapy 1-2 weeks prior to 
first dose of study treatment (capmatinib+nazartinib) and continue on antiviral therapy for 
at least 4 weeks after the last dose of study treatment. Additional management of the 
participants would be provided by a physician with expertise in management of HBV, if 
needed. 
8. Participants must be screened for HCV. Participants must have negative hepatitis C 
antibody (HCV Ab) or are HCV Ab positive but with an undetectable level of HCV-RNA. 
Note: participants with detectable HCV-RNA are not eligible for the study. 
9. For Phase Ib, participants must have either an acceptable local result detailing their MET 
and EGFRT790M status in a biopsy collected at or post progression on the previous EGFR 
TKI therapy, or sufficient tumor material available from a biopsy collected at or post 
progression on prior EGFR TKI for central assessment of MET and EGFRT790M. For Phase 
II, participants must have sufficient material available for results from central assessment 
of MET and EGFRT790M. The biopsy must be collected at or post progression on last EGFR 
TKI treatment line for Group 1 (EGFRmut, any T790M, any MET, 2/4L antineoplastic, 
EGFR TKI resistant) and Group 5 (EGFRmut, T790M-, MET GCN≥5, 2L, EGFR TKI 
resistant), at any time for Group 2 (EGFRmut, de novo T790M, any MET, 1/3L 
antineoplastic, EGFR TKI naïve), Group 3 (EGFRmut, T790M negative, any MET, 1L 
antineoplastic) and Group 4 (EGFRmut, any T790M, any MET, 1L (treatment naïve) 2-3L 
antineoplastic). 
10. Phase Ib only: documented progression of disease according to RECIST 1.1 while on 
continuous treatment with EGFR TKI (e.g. erlotinib, gefitinib or afatinib). 
11. Phase II Group 1 (EGFRmut, any T790M, any MET, 2/4L antineoplastic, EGFR TKI 
resistant) only: Participants demonstrated a documented clinical benefit (CR (any duration), 
PR (any duration), or SD for at least 6 months) on prior EGFR TKI (e.g. erlotinib, gefitinib 
or afatinib) and subsequently demonstrated progression according to RECIST 1.1. 
12. Phase II Group 2 (EGFRmut, de novo T790M, any MET, 1/3L antineoplastic, EGFR 
TKI naïve) only: Participants must have advanced NSCLC with a “de novo” T790M EGFR 
mutation: 
a. Participants must have NSCLC harboring a documented EGFRT790M mutation 
identified by the Novartis designated central laboratory. An archival or newly obtained 
tumor sample must be available for molecular pre-screening. 
b. For purposes of this protocol “de novo” T790M will be defined as the presence of 
EGFRT790M in NSCLC participants who have NOT been previously treated with any 
therapy known to inhibit EGFR. 
13. Phase II Group 3 (EGFRmut, T790M negative, any MET, 1L antineoplastic) only: 
participants must harbor an EGFR activating mutation and must be naïve from any line of 
systemic antineoplastic therapy in the advanced setting. 
14. Phase II Group 4 (EGFRmut, any T790M, any MET, 1L (treatment naïve) 2-3L 
antineoplastic) only: All participants must harbor an EGFR activating mutation and 2/3L 
participants must have failed (defined as intolerance to treatment or documented disease 
progression) a maximum of 2 prior lines of antineoplastic therapy in the advanced setting. 


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15. Phase II Group 5 (EGFRmut, T790M-, MET GCN≥5, 2L, EGFR TKI resistant) only:  
• Histologically or cytologically confirmed diagnosis of NSCLC (excluding squamous 
cell carcinoma) with all the following: 
• EGFR mutations known to be associated with EGFR TKI sensitivity. This must 
be assessed as part of the participant standard of care by a validated test for 
EGFR mutations, as per local regulations. Exon 19 del, L858R, either alone or 
in combination with other EGFR sensitivity mutation assessed by a CLIA-
certified USA laboratory or an accredited local laboratory outside the USA must 
be documented in the participant source documents before the participant can 
be consented for pre-screening for MET amplification status. 
• EGFR T790M negative status for participants who have progressed on first or 
second generation EGFR TKI, or third generation EGFR TKI other than 
osimertinib, as per tissue-based result from a CLIA-certified USA laboratory or 
an accredited local laboratory outside of the USA, by a validated test according 
to local regulations. Results must be documented in the participant source 
documents before the participant can be consented for pre-screening for MET 
amplification. If a local T790M result is not available, T790M status in tissue 
per central Novartis-desginated laboratory result is required.  
• MET gene amplification defined as: Gene copy number (GCN) ≥ 5 per tissue-
based result from a CLIA-certified USA laboratory or an accredited local 
laboratory outside of the USA by a test that is validated according to local 
regulations with results documented in the participant source documents. An 
adequate amount of tumor tissue (archived or if not available, newly obtained 
biopsy sample) must be available at the time of enrollment for central 
assessment of MET gene amplification status. If a local result is not available, 
a tumor tissue sample must be submitted and determined as MET amplified 
(GCN ≥ 5) per central Novartis-designated laboratory. 
• Histological transformation from NSCLC into small cell lung cancer (SCLC) 
following previous EGFR TKI treatment are excluded. 
• Participants must have progressed on one prior line of therapy either to first/second 
generation EGFR TKIs, osimertinib or other third generation EGFR TKIs for 
advanced/metastatic disease (stage IIIB/IIIC [not amenable to curative surgery, 
chemoradiation or radiation or stage IV NSCLC). Acquired resistance to EGFR TKI 
treatment is defined as documented clinical benefit (CR [any duration], PR [any 
duration], or SD for at least 6 months) on prior first/ second EGFR TKIs (e.g., erlotinib, 
gefitinib, afatinib, dacomitinib), osimertinib or other third generation EGFR TKI (such 
as almonertinib and furmonertinib) and subsequently demonstrated radiological disease 
progression. 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 systemic 
chemotherapies will count as one prior line of treatment if relapse occurred within 12 
months from the end of the neo-adjuvant or adjuvant systemic therapy. Adjuvant 
osimertinib therapy will count as prior line of EGFR TKI treatment if relapse occurs 
during the adjuvant osimertinib therapy. 


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16. Participants must have a life expectancy of at least 3 months. 
17. Willing and able to comply with scheduled visits, treatment plan and laboratory tests. 
5.3 
Exclusion criteria 
Participants eligible for this study must not meet any of the following criteria: 
1. Phase Ib: 
• More than one previous treatment line with erlotinib, gefitinib or afatinib 
• Previous treatment with any investigational agent known to inhibit EGFR (mutant or 
wild-type) 
• Participants who have received more than three prior lines of antineoplastic therapies 
(including EGFR TKI) in advanced setting. 
2. Phase II: 
• Group 1 (EGFRmut, any T790M, any MET, 2/4L antineoplastic, EGFR TKI resistant): 
• More than three prior lines of systemic antineoplastic therapies (including EGFR 
TKI) in the advanced setting 
• More than one previous treatment line with first or second generation EGFR TKI 
(e.g. erlotinib, gefitinib, afatinib) in the advanced setting 
• Previous treatment with an investigational or marketed third generation EGFR TKI 
(e.g. osimertinib, CO-1686, nazartinib) 
• Previous treatment with other investigational or marketed agent known to inhibit 
EGFR (e.g. EGF monoclonal antibody therapy, dual TKI inhibitor) 
• Group 2 (EGFRmut, de novo T790M, any MET, 1/3L antineoplastic, EGFR TKI naïve): 
• More than two previous treatment lines of systemic antineoplastic therapies in the 
advanced setting. 
• Previous treatment with an investigational or marketed agent that inhibits EGFR. 
EGFR inhibitors include (but not limited to) all generations of EGFR TKI (e.g. 
erlotinib, gefitinib, afatinib, osimertinib, CO-1686, nazartinib) or other anti-EGFR 
or EGFR monoclonal antibody therapy or dual TKI inhibitors. 
• Group 3 (EGFRmut, T790M negative, any MET, 1L antineoplastic): 
• De novo EGFR T790M mutation identified by central assessment 
• Previous treatment with any systemic antineoplastic therapy in the advanced 
setting (NSCLC stage IIIB or IV). Participants who received only one cycle of 
systemic antineoplastic therapy in the advanced setting are allowed. 
• Group 4 (EGFRmut, any T790M, any MET, 1L (treatment naïve) 2-3L antineoplastic): 
• More than two prior lines of systemic antineoplastic therapies in the advanced 
setting 
• Previous treatment with an investigational or marketed third generation EGFR TKI 
(e.g. osimertinib, CO-1686, nazartinib) 
• Previous treatment with an investigational or marketed agent that inhibits EGFR 
(e.g.: EGF monoclonal antibody therapy or dual TKI inhibitors). 


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For participants in Group 1 to 4, systemic antineoplastic therapy administered as adjuvant or 
neo-adjuvant treatment more than six months prior to study enrollment is not considered a prior 
line of therapy for purpose of this study. For participants in Group 5, please refer to inclusion 
criteria 15. 
3. Previous treatment with a MET inhibitor or HGF-targeting therapy. 
4. 
Participants with symptomatic brain metastases. However, participants with 
asymptomatic/controlled brain metastases may participate in the trial. If treatment is required, 
these participants must have completed any planned radiation therapy and/or surgery > 2 weeks 
prior to the first dose of study treatment and remain asymptomatic. Participants must be 
neurologically stable, having no new neurologic deficits on clinical examination, and no new 
findings on central nervous system imaging. Participants taking steroids must have been on a 
stable dose for two weeks prior to the first dose of study treatment. 
For Group 5: Participants with symptomatic 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. 
5. Any medical condition that would, in the investigator’s judgment, prevent the participant’s 
participation in the clinical study due to safety concerns or compliance with clinical study 
procedures (e.g., active infection, inflammation, intestinal obstruction, unable to swallow 
medication, social/psychological issues, etc.). Any severe, acute, or chronic medical or 
psychiatric condition or laboratory abnormality or substance abuse that may increase the 
risk associated with study participation or study treatment administration or that may 
interfere with the interpretation of study results and, in the judgment of the investigator, 
would make the participant inappropriate for the study. 
6. Presence or history of another malignancy. 
Exception: Participants who have been disease-free for 3 years, or participants with a history of 
adequately treated in-situ carcinoma of the uterine cervix, completely resected basal or 
squamous cell carcinoma, non-melanomatous cancer of skin, history of stage IA melanoma that 
has been cured, are eligible. 
For Group 5: 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. 
7. Undergone a bone marrow or solid organ transplant. 
8. Known history of human immunodeficiency virus (HIV) seropositivity (HIV testing is not 
mandatory). 
For Group 5: Participants with known history of testing positive for human immunodeficiency 
virus (HIV) infection, and with a history of acquired immunodeficiency syndrome (AIDS)-
defining 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. HIV participants coinfected with hepatitis virus must also be 
excluded. To ensure that effective anti retroviral treatment (ART) is tolerated and that toxicities 


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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. 
9. Participants receiving concomitant immunosuppressive agents or chronic corticosteroids 
use at the time of study entry except for control of brain metastases, topical applications, 
inhaled sprays, eye drops or local injections. 
10. Participants with clinically significant, uncontrolled cardiovascular disease, such as: 
• Unstable angina within 6 months prior to screening 
• Myocardial infarction within 6 months prior to screening 
• Participants with a history of documented congestive heart failure (New York Heart 
Association functional classification III-IV) 
• Participants with uncontrolled hypertension defined as a Systolic Blood Pressure (SBP) 
≥ 160 mm Hg and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without 
anti-hypertensive 
medication. 
Initiation 
or 
adjustment 
of 
antihypertensive 
medication(s) is allowed prior to screening 
• Ventricular arrhythmias 
• Supraventricular and nodal arrhythmias not controlled with medication 
• Other cardiac arrhythmia not controlled with medication 
• Participants with corrected QT (QTc) ≥470 ms using Fridericia correction (QTcF) on 
the screening ECG (using the average QTcF of the triplicate ECGs) 
11. 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). 
12. Unable or unwilling to swallow tablets or capsules. 
13. Participants have received anti-cancer therapies within the following time frames prior to 
the first dose of study treatment: 
• Conventional cytotoxic chemotherapy: ≤4 weeks (≤6 weeks for nitrosoureas and 
mitomycin-C) 
• Biologic therapy (e.g., antibodies): ≤4 weeks 
• Non-cytotoxic small molecule therapeutics: ≤5 half-lives (if half-life known) or ≤2 
weeks 
• Other investigational agents: ≤4 weeks 
• For Group 5: Previous anti-cancer and investigational agents within 4 weeks or ≤ 5 x 
half-life of the agent (whichever is shorter) before first dose of capmatinib. 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. 
• For Group 5: Treatment with a prior first or second generation EGFR TKIs (e.g., 
erlotinib, gefitinib, afatinib, dacomitinib), osimertinib or another third generation 
EGFR TKIs within 14 days or approximately 5x half-life, whichever is shorter, of the 
first dose of study treatment (if sufficient washout time has not occurred due to schedule 
or PK properties, an alternative appropriate washout time based on known duration and 


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time to reversibility of drug related adverse events could be agreed upon by Novartis 
and the Investigator).  
14. Participants who have received thoracic radiotherapy to lung fields ≤ 4 weeks prior to 
starting the study treatment 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 starting the study treatment or participants who 
have not recovered from radiotherapy-related toxicities. Palliative radiotherapy for bone 
lesions ≤ 2 weeks prior to starting study treatment. 
15. Major surgery: ≤2 weeks. 
For Group 5: Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 
weeks prior (2 weeks for resection of brain metastases) to starting capmatinib or who have 
not recovered from side effects of such procedure. Video-assisted thoracic surgery (VATS) 
and mediastinoscopy will not be counted as major surgery and participants can be enrolled 
in the study ≥ 1 week after the procedure. 
16. Participants (except those in Phase II Group 5) have not recovered from all toxicities related 
to prior anticancer therapies to grade ≤1 (CTCAE v 4.03). Participants in Phase II Group 5 
will use version 5.0. Participants with any grade of alopecia are allowed to enter the study. 
17. Participants in Phase Ib and Phase II Groups 1 to 4 have out of range laboratory values 
defined as: 
• Absolute Neutrophil Count (ANC) <1.5 x 109/L (1.5 x 103/µL) 
• Hemoglobin (Hgb) <9 g/dL (90 g/L) 
• Platelets (PLT) <75 x 109/L (75 x 103/µL) 
• Total bilirubin >1.5 x upper limit of normal (ULN) 
• AST and/or ALT >3 x ULN, except for participants with liver metastasis who may not 
be included if AST and/or ALT >5 x ULN 
• Alkaline phosphatase (ALP) >5 xULN 
• Calculated creatinine clearance < 45mL/min (0.75 mL/sec) using Cockcroft-Gault 
formula 
• Asymptomatic serum amylase or lipase > Grade 2 
• Serum amylase or serum lipase CTCAE grade ≥ 1 with signs and/or symptoms 
suggesting pancreatitis or pancreatic injury (e.g. elevated P-amylase, abnormal imaging 
findings of pancreas, etc.) 
Participants in Phase II Group 5 have out of range laboratory values defined as: 
• 
Absolute Neutrophil Count (ANC) <1.5 x 109/L (1.5 x 103/µL) without growth factor 
support 
• 
Hemoglobin (Hgb) <9 g/dL (90 g/L) 
• 
Platelets (PLT) <100 x 109/L (100 x 103/µL) 
• 
Total bilirubin >1.5 x upper limit of normal (ULN) 
• 
AST and/or ALT > 2.5 x ULN except for participants with liver metastasis, who may 
not be included if AST and/or ALT > 5 x ULN 
• 
Alkaline phosphatase (ALP) >5 xULN 


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• 
Calculated creatinine clearance (using Cockcroft-Gault formula) < 50 mL/min 
• 
Asymptomatic serum amylase increase grade 1 and 2 are allowed if at the beginning of 
the study is 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 
18. Participants have the following laboratory values outside of the laboratory normal limits or 
cannot be corrected to within normal limits with supplements during screening: 
• Potassium 
• Magnesium 
• Phosphorus 
• Total calcium (corrected for serum albumin) 
19. Participants receiving treatment with medications that are known to be: 
• strong inhibitors or inducers of CYP3A4/5, 
• or CYP3A4/5, CYP1A2, CYP2C8, CYP2C9, CYP2C19, and/or CYP2D6 substrates 
with narrow therapeutic index, 
• or at risk for QT interval prolongation and/or Torsades de Pointe (long QT syndrome, 
family history of idiopathic sudden death or congenital long QT syndrome), 
• and cannot be discontinued or replaced by safe alternative medication within 5 half-
lives or 7 days prior (whichever is longer) to the start of study treatment and for the 
duration of the study. 
• For Phase II Group 5 (capmatinib monotherapy): strong inducers of CYP3A that cannot 
be discontinued at least 1 week prior to the start of treatment with capmatinib and for 
the duration of the study. 
• Please refer to Appendix 4 for a list of prohibited concomitant medications. 
20. Participants who have impairment of GI function or GI disease that may significantly alter 
the absorption of study treatment (e.g., ulcerative diseases, uncontrolled nausea, vomiting, 
diarrhea, or malabsorption syndrome) 
21. Pregnant or nursing (lactating) women. 
22. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
dosing and for 3 months after stopping the study treatments. 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 sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before 
taking study treatment. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment. 
• Male partner: 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. 


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• Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception. 
• In case of use of oral contraception women should have been stable on the same pill for 
a minimum of 3 months before taking study treatment. 
• Women are considered post-menopausal 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 childbearing 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 
ago. In the case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow up hormone level assessment is she considered 
not of childbearing potential. 
23. Sexually active males unwilling to use a condom during intercourse while taking drug and 
for 3 months after stopping investigational medications. 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. 
24. Participants with known hypersensitivity or contraindications to capmatinib or nazartinib, 
or any excipient of these agents. 
25. For Group 5: Carcinomatous meningitis. 
26. For Group 5: Known EGFR T790M positive, Known C797S positive, known druggable 
molecular alterations (such as ROS1, BRAF, KRAS etc.) who might be candidates for 
alternative targeted therapies as applicable per local regulations and treatment guidelines. 
27. 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 
The investigational drugs to be used in this study are nazartinib and capmatinib. 
The study treatment is the combination of nazartinib (once a day) and capmatinib (twice a day). 
In Phase II Group 5, the participants will start with capmatinib monotherapy (twice a day) and 
then will have the opportunity to continue with the combination of nazartinib (once a day) and 
capmatinib (twice a day) based on radiological disease progression evaluation based on 
investigator’s assessment per RECIST 1.1. 


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6.1.1 
Dosing regimen 
Table 6-1 
Dose and treatment schedule 
Study treatments 
Pharmaceutical form and 
route of administration* 
Dose strengths* 
Frequency and/or 
Regimen 
Nazartinib 
Capsule for oral use 
25 mg, 50 mg, 100 mg 
Daily 
Nazartinib 
Tablet for oral use 
25 mg, 50 mg, 200 mg 
Daily 
Capmatinib 
Tablet for oral use 
100 mg, 150 mg, 200 mg 
Twice daily 
* For participants in Phase II Group 5, nazartinib will only be available in capsule for oral use with the dose 
strengths of 25 mg and 50 mg. Capmatinib will only be available in tablet for oral use with the dose strengths of 
150 mg and 200 mg. 
In the Phase Ib part of the study, the starting dose for the first cohort of participants will be 
50 mg q.d. for nazartinib and 200 mg b.i.d. for capmatinib. 
Note: on 23-Feb-2016, RP2D was declared during the 5th dose-escalation teleconference during 
the Phase Ib part of the study. In the Phase II for Groups 1 to 4, all participants will receive the 
RP2D, i.e. capmatinib 400 mg b.i.d. + nazartinib 100 mg q.d. 
In the Phase II part of the study, participants of Group 5 will start with capmatinib 400 mg b.i.d 
monotherapy. Upon radiological disease progression based on investigator’s assessment per 
RECIST 1.1, Nazartinib 100 mg q.d. will be administered in the combination therapy together 
with capmatinib administered at the same dose with given during the monotherapy period.  
Capmatinib and nazartinib will be supplied as open label participant specific supply. 
Participants will be instructed to take the daily doses of capmatinib and nazartinib concurrently 
in the early morning, at approximately the same time each day. The second (evening) dose of 
capmatinib should be taken 12 ±2 hours apart from first dose (morning) of capmatinib. 
Unless otherwise instructed, each dose of capmatinib and nazartinib shall be taken in the fasted 
state, at least one hour before or two hours after a meal (except Phase II Group 4 and Group 5). 
Participants will self-administer the study medication with a glass of water (approximately 
250 mL) at about the same time every day. Nazartinib capsules should not be opened and study 
medication (nazartinib and capmatinib) should be swallowed whole and not chewed. During 
the fasting period, participants are free to drink water. On the days when PK blood samples are 
to be collected (Section 7.2.3), participants will be instructed to hold their dose of study drugs 
and the administration of study drugs will be supervised by the study personnel. 
For participants in Phase II Group 4, each dose of capmatinib and nazartinib should be taken 
within 30 minutes following a meal (unrestricted meal type). On the days when PK blood 
samples are to be collected, participants will be instructed to hold their dose of study drugs and 
come to the clinic fasting. The study drugs will be administered within 30 minutes following 
the meal with the supervision by the study personnel. 
For participants in Phase II Group 5, each dose of capmatinib monotherapy or capmatinib plus 
nazartinib 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). 
Capmatinib and capmatinib plus nazartinib can be administered with or without food. 
Participants must be instructed to swallow the tablets whole and not to chew or crush them or 
dissolve them in water. Participants should take the recommended dose of capmatinib tablets 


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twice daily (b.i.d.) at approximately the same time each day starting at Cycle 1 Day 1. The 
morning and the evening doses should be taken 12 (± 4) hours apart, although a 12-hour interval 
is highly recommended. 
On the days when samples for full PK profiles are taken (C1D1, C1D15 and C2D1 for all 
participants in Phase Ib and, C1D1 and C2D1 for the ten first participants in Phase II Group 3 
and approximately twenty participants in phase II Group 4 as described in Section 7.2.3), the 
time of the meal before and after the dose needs to be recorded on the eCRF. 
Participants must avoid consumption of Seville orange (and juice), grapefruit or grapefruit juice, 
grapefruit hybrids, pummelos, pomegranate (and juice) and star citrus fruits at least 7 days prior 
to the first dose of study treatment and during the entire study treatment period due to potential 
CYP3A interaction. Regular orange juice is allowed. 
Participants should be instructed not to make up missed doses. A missed dose is defined as any 
time point when a participant forgets to take capmatinib or nazartinib within 4 hours of the 
planned time of dosing, or if a participant forgets to take his/her dose for that day. In such cases, 
the dose should be omitted and the participant should continue treatment with the next 
scheduled dose. 
If vomiting occurs, no attempt should be made to replace the vomited dose. If any episodes of 
vomiting occurred within the first 4 hours of capmatinib and nazartinib dosing on post dose PK 
sampling days, it must be noted in the Adverse Events CRF and the exact time of vomiting 
should be recorded on the appropriate Dosage Administration Record eCRF. 
During the whole duration of the treatment with capmatinib in combination with nazartinib, the 
participant is recommended to use precautionary measures against ultraviolet exposure (refer 
to Section 6.3.3, Table 6-13). 
6.1.2 
Treatment duration 
Participant may continue treatment with the study treatment until participant experiences 
unacceptable toxicity, disease progression and/or treatment is discontinued at the discretion of 
the investigator or withdrawal of consent/opposition to use data/biological samples. Refer to 
Section 7.1.3, Section 7.1.4 and Section 7.1.5. 
Note: the study treatment may be continued beyond RECIST 1.1 defined progressive disease 
and until the end of the study as defined in Section 4.3 if, in the judgment of the investigator, 
there is evidence of clinical benefit and the participant wishes to continue with the study 
treatment. The judgment of the investigator should be documented in the Case Report Form and 
the continued evidence of clinical benefit should be updated on a regular basis. These 
participants will continue assessments as outlined in the assessments section and will complete 
the EOT visit only after permanent discontinuation from study treatment. 
For Phase II Group 5: The treatment duration consists of a capmatininb monotherapy stage and 
an extension stage which is a combination treatment by adding nazartinib onto capmatinib. 
When participants progress on the capmatinib monotherapy, they will have the opportunity to 
enter the extension stage or persue alternative treatment which is in the best interest of 
participants. 






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Table 6-3 
Provisional dose levels for capmatinib 
Dose level 
Capmatinib 
proposed dose* 
Increment from previous dose 
-1** 
100 mg b.i.d. 
- 
1 (starting dose with nazartinib capsules) 
200 mg b.i.d. 
- 
2 
400 mg b.i.d. 
100% 
3 
600 mg b.i.d. 
50% 
*It is possible for additional and/or intermediate dose levels to be added during the course of the study. Cohorts 
may be added at any time during dose escalation and at any dose level below either the estimated MTD or the 
RP2D for which safety data exists in order to better understand safety or PK. 
**Dose level −1 represents a treatment dose for participants requiring a dose reduction from the starting dose 
level in combination with nazartinib capsules. 
6.2.3 
Guidelines for dose escalation and determination of MTD/RP2D 
6.2.3.1 
MTD definition 
The MTD is defined as the highest combination drug doses expected to cause DLT in less than 
35% of the treated participants in the first cycle of treatment during the escalation part of the 
study. AEs and laboratory abnormalities considered to be DLTs are defined in  
Table 6-4. Since several combinations may correspond to this definition, more than one MTD 
may be identified with different doses of the study drugs. One of these MTDs or a lower dose 
combination will then be selected as the RP2D. 
The applied adaptive Bayesian methodology provides an estimate of the combinations of 
nazartinib and capmatinib not exceeding the MTD. Typically the MTD is a tested combination 
with maximum probability of targeted toxicity (DLT rate between 16% and <35%). The use of 
the EWOC principle limits the risk that a potential next dose will exceed the MTD  
(Section 10.4.2). 
6.2.3.2 
Dose cohort modification 
For the purposes of dose escalation decisions, each cohort will consist of 3 to 6 newly enrolled 
participants who will be treated at the specified dose level. The first cohort will be treated with 
the starting dose of nazartinib 50 mg q.d. in combination with capmatinib at the starting dose 
of 200 mg b.i.d. 
Participants must complete a minimum of one cycle of treatment with the minimum safety 
evaluation and drug exposure or have had a DLT within the first cycle of treatment to be 
considered evaluable for dose escalation decisions (Section 10.1.4). Dose escalation decisions 
will occur when the cohort of participants has met these criteria. Dose escalation decisions will 
be made by Investigators and Novartis study personnel. Decisions will be based on a synthesis 
of all relevant data available from all dose levels evaluated in the ongoing study including safety 
information, DLTs, all CTCAE Grade ≥ 2 toxicity data during Cycle 1 and PK data from 
evaluable participants. The recommended dose for the next cohort of participants will be guided 
by the Bayesian logistic regression model (BLRM) with EWOC principle (Section 2.2). The 
adaptive Bayesian methodology provides an estimate of all dose levels of nazartinib and 
capmatinib that do not exceed the MTD and incorporates all DLT information at all dose levels 
for this estimation. In general, the next dose will have the highest chance that the DLT rate will 


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fall in the target interval [16-35%) and will always satisfy the EWOC principle. In all cases, the 
dose for the next cohort will not exceed a 100% increase from the previous dose. Smaller 
increases in dose may be recommended by the Investigators and Sponsor upon consideration of 
all of the available clinical data. Any dose escalation decisions made by investigators and 
Novartis personnel will not exceed the dose level recommended by the BLRM using the EWOC 
principle. If needed to better define the dose-toxicity relationship additional participants may 
be enrolled to the current dose level, to a preceding dose level, or to an intermediate dose level 
before proceeding with further dose escalation. 
If two participants in a previously untested dose level experience a DLT, enrollment to that 
cohort will stop, the BLRM will be updated and the next cohort will be opened at the next lower 
dose level or an intermediate dose level that satisfies the EWOC principle (Table 14-11, 
Appendix 2). However, if two participants in a new cohort at a previously tested dose level 
experience a DLT (e.g., a total of eight participants are treated on this dose level with two DLTs 
observed), further enrollment to that cohort will stop, the BLRM will be updated with this new 
information and re-evaluation of the available safety and PK data will occur. By incorporating 
information gained at the preceding dose cohorts, additional participants may be enrolled into 
the current dose cohort only if the combination still meets the EWOC principle and as agreed 
by Investigators and Novartis personnel. Alternatively, if recruitment to the same cohort may 
not resume, a new cohort of participants may be recruited to a lower dose level as agreed by 
Investigators and Novartis personnel and if the BLRM predicts that the risk for this lower dose 
level to exceed the MTD remains below 25% (EWOC). Re-escalation may then occur if data in 
subsequent cohorts supports this (EWOC principle is satisfied) and Investigators and Novartis 
personnel agree. 
Dose escalation will continue until identification of the MTD or a suitable lower dose for the 
Phase II part. This will occur when the following conditions are met: 
• at least six participants have been treated at this dose 
• this dose satisfies one of the following conditions: 
• the posterior probability of targeted toxicity at this dose exceeds 50% and is the highest 
among potential doses, or 
• minimum of 18 participants have already been treated on the trial. 
• it is the dose recommended for participants, either per the model or by review of all clinical 
data by Novartis and Investigators in a dose-escalation teleconference, see Section 6.2.3.1. 
To better understand the safety, tolerability and PK of nazartinib in combination with 
capmatinib, additional cohorts of participants may be enrolled at preceding dose levels, or to 
intermediate dose levels before or while proceeding with further dose escalation. 
If a decision is made to escalate to a higher dose level but one or more additional participant(s) 
treated at the preceding dose level experiences a DLT during the first cycle of treatment, then 
the BLRM will be updated with this new information before any additional participants are 
enrolled at that higher dose level. Participants ongoing will continue treatment at their assigned 
dose levels. 


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Change of drug formulation for nazartinib: 
For the first cohort with nazartinib tablets, data from all the previous cohorts will be down 
weighted (see Appendix 2, Section 14.2.3) and the BLRM will be run to get the starting dose 
for the new drug variant. Whatever the recommendation from the model is, this starting dose 
should never be higher than the doses that have already been used. 
In the scenario when the MTD/RP2D is already declared for the dose combination with 
nazartinib capsules at the time of introduction of nazartinib tablets, the nazartinib tablet will be 
introduced at a dose level which was previously tested in the current study, which satisfies the 
EWOC criterion when the BLRM is run for tablet formulation and which is considered to be a 
safe dose to start with after reviewing all available safety and pharmacokinetic data from the 
current study as well as the single agent studies involving these two compounds. In this case 
there are two possibilities. The starting dose for the first cohort with nazartinib tablets will be 
either the MTD/RP2D for the capsule formulation or a lower dose level as described in 
Section 6.2.1. 
6.2.3.3 
Implementation of dose escalation decisions 
To implement dose escalation decisions, the available toxicity information (including adverse 
events and laboratory abnormalities that are not DLTs), the recommendations from the BLRM, 
and the available PK information will all be evaluated by the Investigators and Novartis study 
personnel (including the study physician and statistician) during a dose decision meeting by 
teleconference. Drug administration at the next higher dose level may not proceed until the 
investigator receives written confirmation from Novartis indicating that the results of the 
previous dose level were evaluated and that it is permissible to proceed to a higher dose level. 
6.2.3.4 
Intra-participant dose escalation 
Intra-participant dose escalation is not permitted at any time within the first four cycles of 
treatment. After the forth cycle is completed, individual participants may be considered for 
treatment at a dose of nazartinib or capmatinib higher than the dose to which they were initially 
assigned. Only one of the investigational study drugs will be escalated at any one time. In order 
for a participant to be treated at a higher dose of nazartinib or capmatinib, he or she must have 
tolerated the lower dose for at least four cycles of therapy (i.e. he or she must not have 
experienced at the lower dose originally assigned a toxicity of CTCAE grade ≥ 2 for which the 
relationship to study treatment cannot be ruled out). Moreover, the new, higher dose with which 
the participant is to be treated must be a dose pair that has completed evaluation in a dose-
escalation meeting and has not exceeded the MTD estimated by the Bayesian model given all 
available data. 
There is no limit to the number of times a participant may have his or her dose of either 
nazartinib or capmatinib increased. In any further escalation, again only one study drug will be 
increased at any time. Any further increases after the initial intra-participant dose escalation are 
participant to the same rules as for the initial intra-participant escalation. Consultation and 
agreement with Novartis must occur prior to any intra-participant dose escalation occurring. 
These changes must be recorded on the Dosage Administration Record eCRF. 


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6.2.4 
Definitions of dose limiting toxicities 
A DLT is defined as an AE or abnormal laboratory value assessed as unrelated to disease, 
disease progression, inter-current illness, or concomitant medications that occurs within the first 
28 days of treatment with nazartinib in combination with capmatinib during the escalation part 
of the study and meets any of the criteria included in Table 6-4. National Cancer Institute (NCI) 
CTCAE version 5.0 will be used for all grading. For the purpose of dose-escalation decisions, 
DLTs will be considered and included in the BLRM. 
The investigator must notify the Sponsor immediately of any unexpected CTCAE grade ≥ 3 
adverse events or laboratory abnormalities. Prior to enrolling participants into a higher dose 
level, CTCAE grade ≥ 2 adverse events will be reviewed for all participants at the current dose 
level. 
Table 6-4 
Criteria for defining dose-limiting toxicities in the Phase Ib part 
Toxicity 
Any of the following criteria: 
Hematology 
Any hematologic toxicity = grade 3, lasting for > 7 consecutive days 
Any hematologic toxicity ≥ grade 4 (of any duration) 
Febrile neutropenia (ANC < 1.0 x 109/L or 1000/mm3 with a single temperature 
of >38.3 °C (101 °F) or a sustained temperature of ≥38 °C (100.4 °F) for more than 
one hour. 
Renal 
Serum creatinine ≥ grade 3 (≥ 3.0 x baseline or > 3.0 - 6.0 x ULN) 
Hepatic 
Total bilirubin ≥ grade 3 (> 3 x ULN) 
AST or ALT = grade 3 (>5.0-20.0 x ULN) for >7 consecutive days 
AST or ALT = grade 4 (>20.0 x ULN) 
For participants with normal baseline AST and ALT and total bilirubin value: 
AST or ALT >3.0xULN combined* with total bilirubin >2.0 x ULN without evidence 
of cholestasis** 
OR 
For participants with abnormal baseline AST or ALT or total bilirubin value: 
[AST or ALT>2x baseline AND > 3.0 xULN] OR [AST or ALT > 8.0 xULN], whichever 
is lower, combined with [total bilirubin > 2 x baseline AND > 2.0 x ULN] 
Pancreas 
Asymptomatic serum amylase or lipase grade 3 (>2.0 – 5.0 × ULN) occurring for > 
14 consecutive days 
Asymptomatic serum amylase or lipase grade 4 (>5.0 x ULN) of any duration 
Symptomatic serum amylase or lipase elevation, medical intervention required 
Neurologic 
Any neurological abnormality or toxicity ≥ grade 2 
Diarrhea 
≥ grade 3 despite optimal treatment 
Skin and subcutaneous 
tissue disorders 
≥ grade 3 despite 7 consecutive days of optimal treatment 
Respiratory 
≥ grade 2 pneumonitis or interstitial lung disease (ILD) without infection etiology 
Other adverse events 
Any adverse event ≥ grade 3 
Single event or multiple occurrences of the same event that lead to a dosing 
interruption of > 7 days in Cycle 1, may be considered to be DLTs by the 
Investigators and Novartis, even if not CTCAE grade 3 or higher 


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Toxicity 
Any of the following criteria: 
* “Combined” defined as: total bilirubin increase to the defined threshold concurrently with ALT/AST increase to 
the defined threshold 
** “Cholestasis” defined as: ALP elevation >2xULN and R value (ALT/ALP in x ULN) < 2] in participants without 
bone metastasis, or elevation of ALP liver fraction in participants with bone metastasis) 
CTCAE version 4.03 will be used for all grading. 
Participants may receive supportive care (e.g. transfusion of red blood cells) as per local institutional guidelines. 
6.3 
Dose modifications for toxicities 
6.3.1 
Dose modification and dose interruption 
For participants who do not tolerate the protocol-specified dosing schedule due to drug related 
toxicities, dose interruptions and/or reductions are recommended in order to allow participants 
to continue the study treatment. For the dose escalation part of the study, dose reductions during 
cycle 1 are only allowed if a DLT is observed and recorded. 
Table 6-7 provides recommendations for dose modification and dose interruption (i.e., 
interruption and re-initiation criteria for nazartinib and capmatinib treatment). 
Refer to Table 6-5 and Table 6-6 for recommended dose reduction steps for the Phase II part of 
the study. 
If, due to study drug related toxicity, a participant requires a dose interruption of >21 days from 
the intended day of the next scheduled dose, then the participant must be discontinued from the 
study treatment unless described otherwise. 
Each participant is only allowed two dose reductions on each drug. In addition, a participant 
must discontinue treatment with nazartinib and capmatinib if, after treatment is resumed at a 
lower dose, the toxicity recurs with the same or worse severity. 
Exceptions on dose interruptions and modifications can be made on a case by case basis after 
discussion with Novartis and Investigator. 
In exceptional cases, after discussion with Novartis, participants may be allowed to continue 
treatment or resume treatment with only one of the investigational drugs. 
All dose interruptions or modifications must be recorded on the Dosage Administration Record 
CRF. 
In case of study treatment interruption, visit schedule should still be followed and assessments 
performed as per Table 7-1 and Table 7-2. 
After dose modification, re-escalation to a previous dose level is not permitted apart from the 
exceptional cases described in Table 6-14 and Table 6-15. 
Events not included in the study protocol or the reference guidance documents should be 
managed according to local practices. 


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Table 6-5 
Dose reduction steps for capmatinib 
Dose level 
Proposed daily dose of capmatinib 
0  
capmatinib 400 mg b.i.d. 
-1 
capmatinib 300 mg b.i.d. 
-2 
capmatinib 200 mg b.i.d. 
Table 6-6 
Dose Reduction steps for nazartinib 
Dose level 
Proposed daily dose of nazartinib 
0 
nazartinib 100 mg q.d. 
-1 
nazartinib 75 mg q.d. 
-2 
nazartinib 50 mg q.d. 
Note: dose reduction should be based on the worst toxicity demonstrated at the last dose 


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Table 6-7 
Criteria for dose reduction, interruption and re-initiation of nazartinib 
and capmatinib for adverse drug reaction 
Worst toxicity 
CTCAEa Grade (value) 
Recommendation 
HEMATOLOGICAL 
Neutrophil count decreased (ANC) Neutropenia  
Grade 1 (ANC < LLN - 
1500/mm3; < LLN - 1.5 x 
109/L) 
Maintain dose levels of nazartinib and capmatinib 
Grade 2 (ANC < 1500 - 
1000/mm3; < 1.5 - 1.0 x 
109/L) 
Maintain dose levels of nazartinib and capmatinib 
Grade 3 (ANC <1000 – 
500/mm3) 
Omit study treatment until resolved to ≤ grade 2, then resume nazartinib at the same 
dose level: 
• 
If fully resolved in ≤ 7 days, then resume capmatinib at same dose level 
• 
If fully resolved in > 7 days, then resume capmatinib at ↓ 1 dose level 
• If recurrence of grade 3 toxicity on maintained dose of nazartinib and ↓ 1 dose 
level of capmatinib, omit study treatment until resolved to ≤ grade 2, then resume 
nazartinib at↓ 1 dose level and the same dose level of capmatinib (i.e., both study 
drugs ↓ 1 dose level from dose levels at initial occurrence of grade 3 AE) 
• If recurrence of grade 3 during nazartinib monotherapy, omit study treatment until 
resolved to ≤ grade 2, then resume nazartinib at↓ 1 dose level 
• If no recurrence of grade 3 toxicity after 7 days of nazartinib monotherapy at ↓ 1 
dose level, resume capmatinib at same dose level 
Grade 4 (ANC 
< 500/mm3) 
Omit study treatment until resolved, then resume nazartinib at the same dose level 
• If no recurrence of grade 3 or higher toxicity after 7 days of nazartinib 
monotherapy, resume capmatinib at ↓ 1 dose level 
• If recurrence of grade 3 or higher toxicity on maintained dose level of nazartinib 
and ↓ 1 dose level of capmatinib, omit study treatment until resolved to ≤ grade 2, 
then resume nazartinib at↓ 1 dose level and capmatinib at the same dose level 
(i.e., both study drugs ↓ 1 dose level from levels at initial occurrence of grade 4 
AE) 
• If recurrence of grade 3 or higher toxicity during nazartinib monotherapy, omit 
study treatment until resolved to ≤ grade 2, then resume nazartinib at↓ 1 dose level 
• If no recurrence of grade 4 toxicity after 7 days of nazartinib monotherapy at↓ 1 
dose level, resume capmatinib at the same dose level 
Febrile Neutropenia  
ANC < 1000/mm3 and a 
single 
temperature 
of >38.3°C (101°F) or a 
sustained temperature 
of >=38°C (100.4°F) for 
more than one hour 
Omit study treatment until resolved, then resume nazartinib at the same dose level: 
• 
If resolved in ≤ 7 days, resume capmatinib treatment at ↓ 1 dose level 
• 
If resolved in > 7 days, permanently discontinue capmatinib treatment 
• 
If recurrence during nazartinib monotherapy, omit nazartinib until resolved, then 
resume nazartinib ↓ 1 dose level and capmatinib at ↓ 1 dose level 
Platelet count decreased (Thrombocytopenia)  
Grade 1 (PLT < LLN - 
75,000/mm3; < LLN - 
75 x 109/L) 
Maintain dose levels of nazartinib and capmatinib 
Grade 2 (PLT < 75,000 - 
50,000/mm3; < 75 - 50 x 
109/L) 
Maintain dose levels of nazartinib and capmatinib 
Grade 3 (PLT < 50,000 - 
25,000/mm3) 
Omit study treatment until resolved to ≤ grade 2, then resume nazartinib at the same 
dose level: 


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Worst toxicity 
CTCAEa Grade (value) 
Recommendation 
• 
If fully resolved in ≤ 7 days, then resume capmatinib at same dose level 
• 
If fully resolved in > 7 days, then resume capmatinib ↓ 1 dose level 
• If recurrence of grade 3 toxicity during nazartinib monotherapy, omit study 
treatment until resolved to ≤ grade 2, then resume nazartinib ↓ 1 dose level, 
resume capmatinib at same dose level 
Grade 4 (PLT 
< 25,000/mm3) 
Omit study treatment until resolved to ≤ grade 2, then resume nazartinib at the same 
dose level: 
• If no recurrence of grade 3 or higher toxicity after 7 days of nazartinib 
monotherapy, resume capmatinib at ↓ 1 dose level 
• If recurrence of grade 3 or higher toxicity on maintained dose of nazartinib and ↓ 
1 dose level of capmatinib, omit study treatment until resolved to ≤ grade 2, then 
↓ 1 dose level of nazartinib and maintain dose level of capmatinib (i.e., both study 
drugs ↓ 1 dose level from dose levels at initial occurrence of grade 4 AE) 
• If recurrence of grade 3 or higher toxicity during nazartinib monotherapy, omit 
study treatment until resolved to ≤ grade 2, then resume nazartinib ↓ 1 dose level 
• If no recurrence of grade 3 or higher toxicity after 7 days of nazartinib monotherapy 
at ↓ 1 dose level, resume capmatinib at ↓ 1 dose level 
Hemoglobin decreased (Anemia) 
Grade 1 (Hgb < LLN - 
10.0 g/dL; < LLN - 6.2 
mmol/L; < LLN - 100 
g/L) 
Maintain dose levels of nazartinib and capmatinib 
Grade 2 (Hgb < 10.0 - 
8.0 g/dL; < 6.2 – 4.9 
mmol/L; < 100 - 80 g/L) 
Maintain dose level of nazartinib and capmatinib 
Grade 3 (Hgb < 8 g/dL) 
Omit study treatment until resolved to ≤ grade 2, then resume at same dose levels of 
nazartinib: 
• 
If fully resolved in ≤ 7 days, then resume capmatinib at same dose level 
• 
If fully resolved in > 7 days, then resume capmatinib at ↓ 1 dose level 
• If recurrence of grade 3 toxicity during nazartanib monotherapy, omit study 
treatment until resolved to ≤ grade 2, then resume nazartinib ↓ 1 dose level and 
resume capmatinib at same dose level 
Grade 4 (life-
threatening 
consequences; urgent 
intervention indicated 
Omit study treatment until resolved to ≤ grade 2, then resume same dose level of 
nazartinib and re-evaluate in 7 days, or sooner if clinically indicated 
• If no recurrence of grade 3 or higher toxicity after 7 days of nazartinib 
monotherapy, resume capmatinib at ↓ 1 dose level 
• If recurrence of grade 3 or higher toxicity during nazartinib monotherapy, omit 
study treatment until resolved to ≤ grade 2, then resume at ↓ 1 dose level of 
nazartinib.  
• If no recurrence of grade 3 or higher toxicity after 7 days of nazartinib monotherapy 
at ↓ 1 dose level, resume capmatinib at ↓ 1 dose level 
RENAL 
Serum creatinine 
Grade 1 (> ULN - 1.5 x 
ULN)  
Maintain dose levels of nazartinib and capmatinib 
Grade 2 (> 1.5 and ≤ 3.0 
x baseline; or > 1.5 and 
≤ 3 × ULN) 
Omit study treatment until resolved to ≤ grade 1 or baseline, then resume treatment 
at the same dose level of nazartinib and capmatinib 
Grade 
3 
(> 3.0 
x 
baseline; or > 3.0 and ≤ 
6.0 × ULN) 
Omit study treatment until resolved to ≤ grade 1, then resume nazartinib at the same 
dose level: 


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Worst toxicity 
CTCAEa Grade (value) 
Recommendation 
• If no recurrence of grade 3 toxicity after 7 days of nazartinib monotherapy, resume 
capmatinib at ↓ 1 dose level 
• If recurrence of grade 3 toxicity on maintained dose of nazartinib and ↓ 1 dose 
level of capmatinib, omit study treatment until resolved to ≤ grade 1, then resume 
nazartinib at same dose level and Capmatinib ↓ 1 dose level  
• If recurrence of grade 3 toxicity during nazartinib monotherapy, omit study 
treatment until resolved to ≤ grade 1 or baseline, then resume nazartinib ↓ 1 dose 
level 
• If no recurrence of grade 3 toxicity after 7 days of nazartinib monotherapy at ↓ 1 
dose level, resume capmatinib at ↓ 1 dose level 
Grade 4 (> 6.0 × ULN) 
Discontinue capmatinib permanently and omit nazartinib until resolved to ≤ grade 1 
or baseline, then resume nazartinib at same dose level. 
HEPATICb 
Isolated Total Bilirubin elevation 
(for participants with Gilbert Syndrome these dose modifications apply to changes in direct [conjugated] bilirubin 
only) 
Grade 1 (> ULN – 1.5 x 
ULN) 
Maintain nazartinib and capmatinib dose level 
Grade 2 (> 1.5 and ≤ 3.0 
× ULN)  
Omit study treatmentMonitor LFTsc weekly, or more frequently if clinically indicated 
until resolved to ≤ grade 1, then resume nazartinib and capmatinib at the same dose 
level. 
Grade 3 (> 3.0 and 
≤10.0 × ULN)g 
Omit study treatment. Monitor LFTsc weekly, or more frequently if clinically indicated 
until resolved to ≤ grade 1, then resume nazartinib at the same dose level.  
• 
If no recurrence of grade 3 toxicity after 7 days of nazartinib monotherapy, resume 
capmatinib at ↓ 1 dose level  
• 
If recurrence of grade 3 toxicity on maintained dose level of nazartinib and ↓ 1 
dose level of capmatinib, omit study treatment until resolved to ≤ grade 1, then 
resume nazartinib at same dose level and Capmatinib ↓ 1 dose level   
• 
If recurrence of grade 3 toxicity during nazartinib monotherapy, omit study 
treatment until resolved to ≤ grade 1, then resume nazartinib at ↓ 1 dose level 
• 
If no recurrence of grade 3 toxicity after 7 days of nazartinib monotherapy at ↓ 1 
dose level, resume capmatinib at ↓ 1 dose level 
Grade 4 (> 10.0 × ULN)g 
Discontinue participant permanently from capmatinib and nazartinib. 
The participant should be monitored weekly (including LFTsc), or more frequently if 
clinically indicated, until total bilirubin has resolved to baseline or stabilization over 4 
weeks. 
Isolated AST or ALT elevation 
Grade 2 (> 3.0 and ≤5.0 
× ULN)  
Maintain dose level of both drugs with LFTsc monitored per protocol. 
Repeat LFTsc as soon as possible, preferably within 48-72 hours from awareness of 
the abnormal results; if abnormal lab values are confirmed upon the repeat test, then 
monitor LFTsc weekly, or more frequently if clinically indicated, until resolved to ≤ 
grade 1. 
Grade 3 (> 5.0 - 20.0 × 
ULN)  
Omit study treatment. Monitor LFTsc weekly, or more frequently if clinically indicated 
until resolved to ≤ grade 1, then resume nazartinib at the same dose level: 
● If resolved in ≤ 7 days, then resume capmatinib at same dose level 
● If resolved in > 7 days, then resume capmatinib at ↓ 1 dose level 
● If recurrence during nazartinib monotherapy, omit study treatment until resolved to 
≤ grade 1, then resume nazartinib at ↓ 1 dose level  
● If no recurrence after 7 days of nazartinib monotherapy at ↓ 1 dose level, then 
resume capmatinib at ↓ 1 dose level   
Grade 4 (> 20.0 x ULN) 
Mandatory: Permanently discontinue both study drugs. 


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Recommendation 
Repeat LFTsc as soon as possible, preferably within 48-72 hours from awareness of 
the abnormal results; monitor LFTsc weekly, or more frequently if clinically indicated, 
until resolved to baseline or stabilization over 4 weeks. 
Combinedd elevations of AST or ALT and concurrent Total bilirubinf 
For 
participants 
with 
normal baseline ALT 
and 
AST 
and 
total 
bilirubin value: AST or 
ALT 
> 3.0 
× 
ULN 
combined 
with 
total 
bilirubin > 2.0 × ULN 
without 
evidence 
of 
cholestasise  
or  
For 
participants 
with 
elevated baseline AST 
or ALT or total bilirubin 
value: [AST or ALT> 3x 
baseline or [AST or 
ALT > 8.0 × ULN], 
whichever 
is 
lower, 
combined 
with 
[total 
bilirubin >2x baseline 
AND >2.0 × ULN] 
Permanently discontinue nazartinib and capmatinib in the absence of signs of 
cholestasis, hemolysis, and if alternative causes of the liver injury have been excluded 
(e.g., concomitant use of hepatotoxic drug(s), alcoholic hepatitis, viral hepatitis etc.) 
Repeat LFTsc as soon as possible, preferably within 48 hours from awareness of the 
abnormal results, then with weekly monitoring of LFTsb, or more frequently if clinically 
indicated, until AST, ALT, or bilirubin have resolved to baseline or stabilized over 4 
weeks. 
METABOLICh 
Amylase and/or lipase elevation 
Grade 3 (>2.0 - 5.0 x 
ULN with signs or 
symptoms; >5.0 x ULN 
and asymptomatic) 
Omit study treatment until resolved to ≤ grade 1, then resume nazartinib at the same 
dose level: 
• If resolved in ≤ 14 days, resume capmatinib at the same dose level 
• If resolved in > 14 days, resume capmatinib at↓ 1 dose level 
• If recurrence of grade 3 toxicity during nazartinib monotherapy, omit study 
treatment until resolved to ≤ grade 2, then ↓ 1 dose level nazartinib 
• If no recurrence of grade 3 toxicity after 7 days of nazartinib monotherapy at ↓ 1 
dose level, resume capmatinib at ↓ 1 dose level 
Grade 4 (>5.0 x ULN 
and 
with 
signs 
or 
symptoms) 
Permanently discontinue capmatinib and omit nazartinib until resolved to grade ≤ 2, 
then maintain dose level of nazartinib. Monitor for recurrence of grade 3 toxicity after 
7 days or sooner if clinically indicated 
Note: Perform diagnostic procedures (e.g., abdominal CT scan or ultrasound) to exclude pancreatic pathology. 
Withhold study treatment for acute onset of new or progressive unexplained abdominal symptoms, such as 
severe pain or vomiting; if diagnosed with pancreatitis ≥ grade 3 permanently discontinue from capmatinib 
treatment. 
HBV and HCV reactivation 
Refer to Table 6-10, Table 6-11 and Table 6-12, and Section 6.3.2 for details. 
CARDIAC 
Electrocardiogram QT corrected (QTc) interval prolonged 
Grade 3 (QTc ≥ 501 ms 
on at least two separate 
ECGs) 
Omit study treatment until resolved to ≤ grade 1then: 
• If resolved in ≤ 7 days, resume capmatinib at same dose level and nazartinib at ↓ 
1 dose level  
• 
If resolved in > 7 days, resume capmatinib and nazartinib at ↓ 1 dose level  
Grade 4 ([QT/QTc ≥ 
501 or > 60 ms change 
Permanently discontinue nazartinib and capmatinib. 


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CTCAEa Grade (value) 
Recommendation 
from baseline] and 
[Torsades de pointes or 
polymorphic ventricular 
tachycardia, or 
signs/symptoms of 
serious arrhythmia]) 
Obtain local cardiologist (or qualified specialist) consultation and repeat cardiac 
monitoring as indicated until the QTcF returns to <481 ms. 
VASCULAR DISORDERS 
Hypertension 
CTCAE 
grade 3 for at least 7 
days, despite treatment 
Omit nazartinib dose until resolved ≤ grade 1, then maintain dose level of capmatinib 
and re-evaluate after 7 days, or sooner if clinically indicated 
• 
If no recurrence of grade 3 toxicity after 7 days of capmatinib monotherapy, 
resume nazartinib at ↓ 1 dose level 
• If recurrence of grade 3 toxicity during capmatinib monotherapy, omit study 
treatment until resolved to ≤ grade 1, then resume capmatinib ↓ 1 dose level 
• If no recurrence of grade 3 toxicity after 7 days of capmatinib monotherapy at ↓ 1 
dose level, resume nazartinib at ↓ 1 dose level 
CTCAE grade 4 
Discontinue capmatinib and nazartinib 
GASTROINTESTINAL 
Diarrheae 
Grade 1 
Maintain dose levels of both study drugs but institute anti-diarrheal treatment 
Grade 
2 
(despite 
maximal 
anti-diarrheal 
medication) 
Omit dose until resolved to ≤ grade 1, then maintain dose levels of both study drugs.   
Grade 
≥3 
(despite 
maximal 
anti-diarrheal 
medication) 
Omit study treatment until resolved to ≤ grade 1, then resume capmatinib at same 
dose level  
• If no recurrence of grade 3 toxicity after 7 days of capmatinib monotherapy, 
resume nazartinib at ↓ 1 dose level 
• If recurrence of grade 3 toxicity during capmatinib monotherapy, omit study 
treatment until resolved to ≤ grade 1, then resume capmatinib ↓ 1 dose level 
• If no recurrence of grade 3 toxicity after 7 days of capmatinib monotherapy at ↓ 1 
dose level, resume nazartinib at same dose level 
Dose modifications apply to participants who experience diarrhea despite appropriate anti-diarrheal medication. 
This medication should be started at the first sign of diarrhea. 
Nausea 
Grade 1 or 2 
Maintain dose levels of both study drugs but adjust anti-emetic treatment 
Grade ≥3 (despite 
standard anti-emetics) 
Omit study treatment until resolved to ≤ grade 1, then resume nazartinib at 
samedose level  
• If no recurrence of grade 3 toxicity after 7 days of nazartinib monotherapy, resume 
capmatinib at ↓ 1 dose level 
• If recurrence of grade 3 toxicity during nazartinib monotherapy, omit study 
treatment until resolved to ≤ grade 1, then ↓ 1 dose level capmatinib 
• If no recurrence of grade 3 toxicity after 7 days of capmatinib monotherapy at ↓ 1 
dose level, resume nazartinib at same dose level  
Vomiting 
Grade 1 
Maintain dose levels of both study drugs but adjust anti-emetic treatment 
Grade 2 (despite 
standard anti-emetics) 
Omit study treatment until resolved to ≤ grade 1, then maintain dose levels of both 
drugs. 
Grade 
≥3 
(despite 
standard anti-emetics) 
Omit study treatment until resolved to ≤ grade 1, then resume nazartinib at same dose 
level  


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CTCAEa Grade (value) 
Recommendation 
• If no recurrence of grade 3 toxicity after 7 days of nazartinib monotherapy, resume 
capmatinib at ↓ 1 dose level 
• If recurrence of grade 3 toxicity during nazartinib monotherapy, omit study 
treatment until resolved to ≤ grade 1, then ↓ 1 dose level capmatinib 
• If no recurrence of grade 3 toxicity after 7 days of capmatinib monotherapy at ↓ 1 
dose level, resume nazartinib at same dose level 
Grade 4 (despite 
standard anti-emetics) 
Discontinue study treatment 
Dose modifications apply to participants who experience nausea and/or vomiting despite appropriate antiemetic 
medication. This medication should be started at the first sign of nausea and/or vomiting. 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS   
Stevens-Johnson 
Syndrome (SJS) or Lyell 
syndrome/Toxic 
Epidermal 
Necrolysis 
(TEN) 
Permanently discontinue study treatment and manage per institutional guidelines. 
Rashj 
Grade 1 
Macules/papules 
covering <10% BSA 
(Body Surface Area) 
Maintain dose levels of nazartinib and capmatinib 
Grade 2 
Macules/papules 
covering 10 - 30% BSA 
Maintain dose levels of nazartinib and capmatinib 
Grade 3 
Macules/papules 
covering >30% BSA 
Omit study treatment until resolved to ≤grade 1, then resume capmatinib at the same 
dose level. 
• If no recurrence of grade 3 toxicity after 7 days of capmatinib monotherapy, 
resume nazartinib at ↓ 1 dose level 
• If recurrence of grade 3 toxicity during capmatinib monotherapy, omit study 
treatment until resolved to ≤ grade 1, then resume capmatinib↓ 1 dose level 
• If no recurrence of grade 3 toxicity after 7 days of capmatinib monotherapy at ↓ 1 
dose level, resume nazartinib at same dose level 
Grade 4 
Permanently discontinue study treatment 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
Pneumonitis/Interstitial lung disease 
Grade 1 
Interrupt study treatment 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 and nazartinib.  
Only in the absence of a diagnosis of ILD/Pneumonitis, capmatinib and nazartinib 
may be resumed at the same dose. 
If it recurs after resumption of study drug, permanently discontinue capmatinib and 
nazartinib. 
Grade 2 
Mandatory: Omit capmatinib and nazartinib during diagnostic workup for 
ILD/pneumonitis until improvement to ≤ Grade 1. Exclude infections and other 
etiologies. 
In presence of diagnosis of ILD/Pneumonitis after diagnostic workup, it is mandatory 
to permanently discontinue capmatinib and nazartinib. 
Only in the absence of a diagnosis of ILD/Pneumonitis, capmatinib and nazartinib 
may be resumed following these guidelines: 
• 
If resolves to ≤ Grade 1 in ≤ 7 days capmatinib and nazartinib at ↓1 dose level  


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CTCAEa Grade (value) 
Recommendation 
• If fails to resolve to ≤ Grade 1 within 7 days or recurs after resumption of 
capmatinib and nazartinib at ↓1 dose level , permanently 
discontinue capmatinib and nazartinib. 
Grade 3 OR Grade 4 
Permanently discontinue study treatment. 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Fatigue/ Asthenia  
Grade 1 or 2 
Maintain dose levels of nazartinib and capmatinib 
Grade 3 
Omit study treatment until resolved to ≤ grade 1, then resume nazartinib at 
the same dose level: 
• If resolved in ≤ 7 days, then resume capmatinib at same dose level 
• If resolved in > 7 days, then resume capmatinib↓ 1 dose level 
• If recurrence of grade 3 toxicity during nazartinib monotherapy, omit 
study treatment until resolved to ≤ grade 1, then resume nazartinib at↓ 
1 dose level  
• 
If no recurrence of grade 3 toxicity after 7 days of nazartinib 
monotherapy at ↓ 1 dose level, resume capmatinib at same dose level 
Peripheral edema  
Grade 1 or 2 
Maintain dose levels of nazartinib and capmatinib 
Grade 3 
Omit study treatment until resolved to ≤ grade 1, then resume nazartinib at same dose 
level and re-evaluate after 7 days, or sooner if clinically indicated 
• If no recurrence of grade 3 toxicity after 7 days of nazartinib monotherapy, resume 
capmatinib at ↓ 1 dose level 
• If recurrence of grade 3 toxicity on maintained dose of nazartinib and ↓ 1 dose 
level of capmatinib, omit study treatment until resolved to ≤ grade 1, then resume 
capmatinib at↓ 1 dose level and maintain dose level of nazartinib 
• If recurrence of grade 3 toxicity during nazartinib monotherapy, omit study 
treatment until resolved to ≤ grade 1, then resume nazartinib at↓ 1 dose level 
• If no recurrence of grade 3 toxicity after 7 days of nazartinib monotherapy at ↓ 1 
dose level, resume capmatinib at ↓ 1 dose level 
Grade 4 
Permanently discontinue capmatinib and omit dose of nazartinib until resolved to ≤ 
grade 1, then continue nazartinib monotherapy 
Eye Disorders (Results and images of ophthalmic examinations should be made available upon request) 
Grade 1 or 2 
Uveitis/Retinopathy 
Maintain dose level of both study drugs, and refer to an ophthalmologist for 
ophthalmic monitoring at least every 14 days. 
Grade 3 
Uveitis/Retinopathy 
Omit study treatment until resolved to ≤ grade 1, and refer to an ophthalmologist for 
ophthalmic monitoring at least once a week, then: 
• 
If resolved in ≤ 14 days, then resume capmatinib at same dose level and 
nazartinib at↓ 1 dose level  
• If resolved in > 14 days, then permanently discontinue participant from nazartinib 
and resume capmatinib at same dose level 
Grade 4 
Uveitis/Retinopathy 
Permanently discontinue nazartinib and refer the participant to an ophthalmologist for 
monitoring. Resumption of nazartinib following resolution to ≤ grade 1 may be 
considered if approved by ophthalmologist and after documented discussion with 
Novartis. 
Resume capmatinib at same dose level upon resolution to ≤ grade 1. 
Retinal vein occlusion of 
any Grade 
Permanently discontinue nazartinib and refer the participant to an ophthalmologist 
immediately for monitoring. Resumption of nazartinib following resolution to ≤ grade 


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Recommendation 
1 may be considered may be considered if approved by ophthalmologist and after 
documented discussion with Novartis. 
Resume capmatinib at same dose level upon resolution to ≤ grade 1. 
Other ocular/visual toxicity 
Grade 1 or 2 
Maintain dose levels of both drugs, and within one week refer to an ophthalmologist 
for ophthalmic monitoring at least every 14 days. 
Grade 3 
Omit study treatments until resolved to ≤ grade 1, and within one week refer to an 
ophthalmologist for ophthalmic monitoring at least once a week, then: 
• 
If resolved in ≤ 14 days, then resume capmatinib at same dose level and 
nazartinib at↓ 1 dose level  
• If resolved in > 14 days, then discontinue participant from nazartinib and resume 
capmatinib ↓ 1 dose level 
Grade 4 
Permanently discontinue nazartinib, omit capmatinib and refer the participant to an 
ophthalmologist immediately for monitoring. Resumption of nazartinib at ↓ 1 dose 
level following resolution to ≤ grade 1 may be considered if approved by 
ophthalmologist and after documented discussion with Novartis. 
Resume capmatinib at same dose level upon resolution to ≤ grade 1. 
Other adverse events 
Grade 1 or 2 
Maintain dose levels of nazartinib and capmatinib 
Grade ≥3 
Omit study treatment until resolved to ≤ grade 1, then resume nazartinib at same dose 
level of and re-evaluate after 7 days, or sooner if clinically indicated 
• If no recurrence of grade 3 toxicity after 7 days of nazartinib monotherapy, resume 
capmatinib at ↓ 1 dose level 
• If recurrence of grade 3 toxicity on maintained dose level of nazartinib and ↓ 1 
dose level of capmatinib, omit study treatment until resolved to ≤ grade 1, then 
resume nazartinib at↓ 1 dose level and maintain dose level of capmatinib (i.e., 
both study drugs ↓ 1 dose level from levels at initial occurrence of grade 3 AE) 
• If recurrence of grade 3 toxicity during nazartinib monotherapy, omit study 
treatment until resolved to ≤ grade 1, then nazartinib at↓ 1 dose level  
• If no recurrence of grade 3 toxicity after 7 days of nazartinib monotherapy at ↓ 1 
dose level, resume capmatinib at ↓ 1 dose level 
All dose modifications should be based on the worst preceding toxicity. 
a Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
b If grade 3 or 4 hyper-bilirubinemia 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. 
c LFTs include albumin, ALT, AST, total bilirubin (fractionated if total bilirubin > 2.0 × ULN), alkaline phosphatase 
(fractionated if alkaline phosphatase > 2.0 × ULN) and gamma-glutamyl transpeptidase (GGT). For isolated 
elevations of any grade of alkaline phosphatase and/or GGT, maintain dose level. 
d “Combined” defined as: total bilirubin increases to the defined threshold concurrently with ALT/AST increase to 
the defined threshold 
e “Cholestasis” defined as: ALP elevation (> 2 × ULN and R value< 2) in participants without bone metastasis, or 
elevation of ALP liver fraction in participants with bone metastasis Note: The R value is calculated by dividing 
the ALT by the ALP, using multiples of the ULN for both values. It denotes the relative pattern of ALT and/or ALP 
elevation is due to cholestatic or hepatocellular liver injury 
f 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 


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g Note: If total bilirubin > 3.0 × ULN is due to the indirect (non-conjugated) component only, and hemolysis as 
the etiology has been ruled out as per institutional guidelines (e.g., review of peripheral blood smear and 
haptoglobin determination), then ↓ 1 dose level and continue treatment at the discretion of the investigator. 
h A CT scan or other imaging study to assess the pancreas, liver, and gallbladder must be performed within 
1 week of the first occurrence of any ≥ grade 3 of amylase and/or lipase. If asymptomatic grade 2 elevations of 
lipase and/or amylase occur again at the reduced dose, participants will be discontinued permanently from study 
treatment. 
i Antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools or overt diarrhea. 
j 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).  
Table 6-8 
Dose modifications for capmatinib monotherapy (or if nazartinib 
permanently discontinued and capmatinib continued as monotherapy) 
Worst toxicity CTCAE Gradea during a cycle 
of therapy 
Recommendation 
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 fully resolved in ≤ 7 days, resume treatment at the 
same dose level 
• If fully resolved in > 7 days, then resume at↓ 1 dose level 
Grade 4 (ANC < 500/mm3; < 0.5 x 109/L) 
Omit dose until resolved to ≤ grade 2 and then resume at ↓ 
1 dose level 
Platelet count decreased (Thrombocytopenia) 
Grade 1 (PLT < LLN - 75,000/mm3; < LLN - 75 x 
109/L) 
Maintain dose level 
Grade 2 (PLT < 75,000 - 50,000/mm3; < 75 - 50 x 
109/L) 
Maintain dose level 
Grade 3 (PLT < 50,000 - 25,000/mm3; < 50 - 25 x 
109/L) 
Omit dose until resolved to ≤ grade 2, then: 
• 
If fully resolved in ≤ 7 days, then resume at same dose 
level 
• 
If resolved in > 7 days, then resume at ↓ 1 dose level 
Grade 4 (PLT < 25,000/mm3; < 25 x 109/L) 
Omit dose until resolved to ≤ grade 2, then resume at ↓ 1 
dose level 
Febrile Neutropenia 
ANC <1000/mm3 and a single temperature 
of >38.3°C (101°F) or a sustained temperature 
of >=38°C (100.4°F) for more than one hour 
Omit dose, then: 
• If resolved in ≤ 7 days, resume treatment at resume at ↓ 
1 dose level 
• If resolved in > 7 days, permanently discontinue 
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 


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of therapy 
Recommendation 
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 fully resolved in ≤ 7 days, resume at the same dose 
level 
• If fully resolved in > 7 days, then resume at↓ 1 dose level 
Grade 4 (Life-threatening consequences; urgent 
intervention indicated) 
Omit dose until resolved to ≤ grade 2 and then resume at↓ 
1 dose level 
If grade 4 toxicity recurs, permanently discontinue 
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 at the same dose level. 
Grade 3 (> 3.0 - 6.0 x ULN) 
Omit dose until resolved to ≤ grade 1 or baseline, then 
resume at ↓ 1 dose level. 
Grade 4 (> 6.0 x ULN) 
Permanently discontinue 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 fully resolved in ≤ 7 days, resume at same dose level. 
• 
If resolved in > 7 days, resume at↓1 dose level 
Grade 3 (> 3.0 - 10.0 x ULN) 
Omit dose until resolved to ≤ grade 1, then 
• 
If fully resolved in ≤ 7 days, resume at↓ 1 dose level 
• 
If fully resolved in > 7 days, permanently discontinue 
capmatinib treatment 
Grade 4 (> 10.0 x ULN) 
Mandatory: Permanently discontinue 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 elevation at baseline) then 
• 
If fully resolved in ≤ 7 days, then resume at the same 
dose level 
• 
If fully resolved in > 7 days, resume at ↓ 1 dose level 
Grade 4 (> 20.0 x ULN) 
Mandatory: Permanently discontinue 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: 
Mandatory: Permanently discontinue capmatinib treatment 


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of therapy 
Recommendation 
[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 
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 1, then 
• If fully resolved in ≤ 14 days, resume at the same dose 
level 
• If fully resolved in > 14 days, then resume  at↓ 1 dose 
level 
Grade 4 (> 5.0 x ULN with signs or symptoms) 
Permanently discontinue capmatinib treatment 
CARDIAC 
Electrocardiogram QT corrected (QTc) interval prolonged 
Grade 1 (QTcF 450-480 ms) 
Grade 2 (QTcF 481-500 ms) 
Maintain dose level 
Grade 3 (QTcF ≥ 501 ms on at least two separate 
ECGs) 
Omit dose until resolved to ≤ grade 1, then: 
• If fully resolved in ≤ 7 days, resume at the same dose 
level 
• If resolved in > 7 days, then resume at↓ 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 capmatinib treatment 
GASTROINTESTINAL 
Pancreatitis 
Grade 2 
Maintain dose level 
Grade ≥ 3 
Mandatory: Permanently discontinue capmatinib treatment 
Diarrhea** 
Grade 1 (despite appropriate anti-diarrheal 
medication) 
Maintain dose level 
Grade 
2 
(despite 
maximal 
anti-diarrheal 
medication) 
Omit dose until resolved to ≤ grade 1, then resume at same 
dose level. 
If diarrhea returns as ≥ grade 2, then omit dose until 
resolved to ≤ grade 1, then resume at ↓ 1 dose level 
Grade 3 or 4 (despite appropriate anti-diarrheal 
medication) 
Omit dose until resolved to ≤ grade 1, then resume 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 resume at same 
dose level. 
If vomiting returns as ≥ grade 2, then omit dose until 
resolved to ≤ grade 1, then resume at↓ 1 dose level. 
Grade 3 (despite appropriate anti-emetics) 
Omit dose until resolved to ≤ grade 1, then resume at ↓ 1 
dose level 


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Worst toxicity CTCAE Gradea during a cycle 
of therapy 
Recommendation 
Grade 4 (despite appropriate anti-emetics) 
Omit dose until resolved to ≤ grade 1, then resume at ↓ 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 resume at ↓ 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 fully resolved in ≤ 7 days, then resume at ↓ 1 dose 
level 
• 
If fully resolved in > 7 days (despite appropriate skin 
toxicity 
therapy), 
then 
permanently 
discontinue 
capmatinib treatment 
Grade 4, despite skin toxicity therapy 
Omit dose and permanently discontinue 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 resumed at the same dose. 
If it recurs after resumption of capmatinib, 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 resumedfollowing these guidelines: 
• If resolves to ≤ Grade 1 in ≤ 7 days reduce study drug by 
1 dose level 
• If fails to resolve to ≤ Grade 1 within 7 days or recur after 
resumption 
of 
capmatinib 
at 
decreased 
dose, 
permanently discontinue capmatinib 
Grade 3 and Grade 4 
Mandatory: Permanently discontinue capmatinib. 
Treat with i.v. steroids as clinically indicated. Oxygen 
therapy as indicated 


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Worst toxicity CTCAE Gradea during a cycle 
of therapy 
Recommendation 
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 fully resolved in ≤ 7 days, resume at same dose level 
• 
If fully resolved in > 7 days, resume at ↓ 1 dose level 
Grade 4 
Permanently discontinue capmatinib 
Peripheral edema  
Grade 1 or 2 
Maintain dose level. 
Grade 3 
Omit dose until resolved to ≤ Grade 1, then resume at↓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 
activities of daily living), consider omitting the dose until 
resolved to ≤ grade 1, then resume either at same dose or 
↓ 1 dose level. 
Grade 3 
Omit dose until resolved to ≤ grade 1, then resume at↓ 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 metastasis, or elevation of ALP liver fraction in participants with bone metastasis 
d If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please follow the 
instructions for isolated elevation of total bilirubin and isolated elevation of AST/ALT, and take a conservative 
action based on the degree of the elevations (e.g. discontinue treatment at the situation when omit dose is 
needed for one parameter and discontinue treatment is required for another parameter). After all elevations 
resolve to the defined thresholds that allow treatment re-initiation, re-start the treatment either at the same dose 
or at one dose lower if meeting a criterion for dose reduction 
* Note: If total bilirubin > 3.0 x ULN is due to the indirect (non-conjugated) component only, and hemolysis as the 
etiology has been ruled out as per institutional guidelines (e.g., review of peripheral blood smear and haptoglobin 
determination), then ↓ 1 dose level and continue treatment at the discretion of the investigator 
** Note: antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools or overt 
diarrhea 
*** During the whole duration of treatment with 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) 


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Table 6-9 
Dose modifications for nazartinib (if capmatinib permanently 
discontinued and nazartinib continued as monotherapy) 
Worst toxicity CTCAEa Grade (value) during a 
cycle of therapy 
Recommendations 
HEMATOLOGICAL 
Neutrophil count decreased (ANC) Neutropenia 
Grade 1 (ANC <LLN - 1500/mm3) 
Maintain dose level  
Grade 2 (ANC <1500 - 1000/mm3) 
Maintain dose level 
Grade 3 (ANC <1000 - 500/mm3) 
Omit dose until resolved ≤ Grade 2, then maintain dose level  
Grade 4 (ANC <500/mm3) 
Recommendation: omit dose until resolved to ≤ Grade 2, 
then resume at↓ 1 dose level 
Febrile Neutropenia 
(ANC <1.0 x 109/L, fever ≥ 38.5°C) 
Recommendation: omit dose until resolved, then resume at 
↓ 1 dose level 
Thrombocytopenia 
Grade 1 (PLT <LLN - 75,000/mm3) 
May maintain dose level 
Grade 2 (PLT <75,000 - 50,000/mm3) 
May maintain dose level 
Grade 3 (PLT <50,000 - 25,000/mm3) 
• 
Recommendation: omit dose until resolved to ≤ Grade 1, 
then: 
• 
If fully resolved in ≤ 7 days, then resume at same dose 
level 
• 
If fully resolved in >7 days, then resume at ↓ 1 dose level  
Grade 4 (PLT <25,000/mm3) 
Recommendation: omit dose until resolved to ≤ Grade 1, 
then resume at ↓ 1 dose level 
RENAL 
Serum creatinine 
Grade 1 (>ULN - 1.5 x ULN)- 
May maintain dose level 
Grade 2 (>1.5 – 3,.0 x ULN) 
Recommendation: omit dose until resolved to ≤ Grade 1 or 
baseline, then resume at same dose level 
Grade 3 (>3.0 – 6.0 x ULN  
Recommendation: omit dose and discontinue nazartinib 
Grade 4 (>6.0 x ULN) 
Recommendation: omit dose and discontinue nazartinib 
HEPATICb 
Isolated Total Bilirubin 
(for participant s with Gilbert Syndrome these dose modifications apply to changes in direct [conjugated] 
bilirubin only) 
Grade 1 (>ULN -1.5 x ULN) 
Recommendation: maintain dose level  
Grade 2 (>1.5 - 3.0 x ULN) 
Recommendation: omit dose. Monitor LFTsc weekly, or 
more frequently if clinically indicated until resolved to ≤ 1.5 
x ULN, then: 
• 
If fully resolved in ≤14 days, then resume at same dose 
level 
• 
If fully resolved in >14 days, then resume at↓1 dose level 
Grade 3 (>3.0 - 10.0 x ULNg) 
Recommendation: omit dose. Monitor LFTsc weekly, or 
more frequently if clinically indicated until resolved to ≤ 1.5 
x ULN, then: 
• 
If fully resolved in ≤14 days, then resume at↓1 dose level 


N o v arti s  
C o nfi d e nti al  
P a g e 1 3 1  
A m e n d e d Pr ot o c ol V er si o n 0 7 ( Cl e a n ) 
 
Pr ot o c ol N o. CI N C 2 8 0 X 2 1 0 5 C  
 
 
W or st t o xi cit y C T C A E
a  Gr a d e  ( v al u e) d uri n g a 
c y cl e of t h er a p y  
R e c o m m e n d ati o n s  
•  
If f ull y r e s ol v e d i n 1 4 d a y s, t h e n di s c o nti n u e n a z arti ni b. 
T h e p arti ci p a nt s h o ul d b e m o nit or e d w e e kl y (i n cl u di n g 
L F T s b ), or m or e fr e q u e ntl y if cli ni c all y i n di c at e d, u ntil t ot al 
bilir u bi n h a s r e s ol v e d t o b a s eli n e or st a bili z ati o n o v er 4 
w e e k s.  
Gr a d e 4 ( > 1 0. 0 x U L N g ) 
M a n d at or y: P er m a n e ntl y di s c o nti n u e n a z arti ni b  
T h e  p arti ci p a nt  s h o ul d  b e  m o nit or e d  w e e kl y  (i n cl u di n g  
L F T s b ), or m or e fr e q u e ntl y if cli ni c all y i n di c at e d, u ntil t ot al 
bilir u bi n h a s r e s ol v e d t o b a s eli n e or st a bili z e d o v er 4 w e e k s.  
I s ol at e d A S T or A L T 
Gr a d e 1: > U L N - 3. 0 x U L N  
R e c o m m e n d ati o n:  m ai nt ai n d o s e l e v el  
Gr a d e 2: > 3. 0 - 5. 0 x U L N  
A N D  
F or p arti ci p a nt s wit h b a s eli n e v al u e ≤ 3. 0 x U L N  
R e c o m m e n d ati o n:  m ai nt ai n d o s e l e v el.   R e p e at  L F T s b  a s 
s o o n  a s  p o s si bl e,  pr ef er a bl y  wit hi n  4 8 - 7 2  h o ur s  fr o m  
a w ar e n e s s of t h e a b n or m al r e s ult s; if a b n or m al l a b v al u e s 
ar e  c o nfir m e d  u p o n  t h e  r e p e at  t e st,  t h e n  m o nit or  L F T s b 
w e e kl y,  or  m or e  fr e q u e ntl y  if  cli ni c all y  i n di c at e d,  u ntil  
r e s ol v e d t o ≤ 3. 0 x U L N 
Gr a d e 2: > 3. 0 - 5. 0 x U L N  
A N D  
F or p arti ci p a nt s wit h b a s eli n e v al u e > 3. 0 -5. 0 x 
U L N  
M ai nt ai n d o s e l e v el  
Gr a d e 3: > 5. 0 - 1 0. 0 x U L N  
A N D  
F or p arti ci p a nt s wit h b a s eli n e v al u e ≤ 3. 0 x U L N  
R e c o m m e n d ati o n:  o mit  d o s e.  R e p e at  L F T s b  a s  s o o n  a s  
p o s si bl e, pr ef er a bl y wit hi n 4 8 -7 2 h o ur s fr o m a w ar e n e s s of 
t h e  a b n or m al  r e s ult s;  m o nit or  L F T sb  w e e kl y,  or  m or e  
fr e q u e ntl y if cli ni c all y i n di c at e d, u ntil r e s ol v e d t o ≤ 3. 0 x U L N 
T h e n  
•  
If f ull y r e s ol v e d i n ≤ 1 4 d a y s, r e s u m e at s a m e d o s e l e v el  
•  
If r e s ol v e d i n > 1 4 d a y s, r e s u m e at ↓ 1 d o s e l e v el  
Gr a d e 3: > 5. 0 - 1 0. 0 x U L N  
A N D  
F or p arti ci p a nt s wit h b a s eli n e v al u e > 3. 0 -5. 0 x 
U L N  
M ai nt ai n  d o s e  l e v el.  R e p e at  L F T s
b  a s  s o o n  a s  p o s si bl e,  
pr ef er a bl y  wit hi n  4 8 -7 2  h o ur s  fr o m  a w ar e n e s s  of  t h e  
a b n or m al r e s ult s; if a b n or m al l a b v al u e s ar e c o nfir m e d u p o n 
t h e  r e p e at  t e st,  t h e n  m o nit or  L F T sb ,  w e e kl y,  or  m or e  
fr e q u e ntl y if cli ni c all y i n di c at e d, u ntil r e s ol v e d t o ≤ 5. 0 x U L N  
G r a d e 3: > 5. 0 - 1 0. 0 x U L N  
A N D  
If  A S T  or  A L T  >  5  x  U L N  i n  p arti ci p a nt s  wit h  
b a s eli n e  A S T  or  A L T  ≤  3  x  U L N,  or  if  A S T  or 
A L T > 8 x U L N i n p arti ci p a nt s wit h b a s eli n e A S T 
or A L T > 3 x U L N b ut ≤ 5 x U L N  
M a n d at or y: I m m e di at e t e sti n g f or vir al h e p atiti s i nf e cti o n or 
r e a cti v ati o n  s h o ul d  b e  p erf or m e d,  s e e  S e cti o n  6. 3. 2 . 
P arti ci p a nt s w h o h a v e H B V -D N A or H C V -R N A m o nit ori n g 
d ur i n g t h e st u d y s h o ul d b e r e-t e st e d i m m e di at el y 
Gr a d e 3: > 5. 0 - 1 0. 0 x U L N  
A N D  
> 1 0. 0 - 2 0. 0 x U L N  
M a n d at or y: O mit d o s e. R e p e at L F T s
b  a s s o o n a s p o s si bl e, 
pr ef er a bl y  wit hi n  4 8 -7 2  h o ur s  fr o m  a w ar e n e s s  of  t h e  
a b n or m al r e s ult s; m o nit or L F T s b  w e e kl y, or m or e f r e q u e ntl y 
if  cli ni c all y  i n di c at e d,  u ntil  r e s ol v e d  t o  ≤  Gr a d e  1  ( or  t o 
b a s eli n e), t h e n r e s u m e at ↓ 1 d o s e l e v el.  
Gr a d e 4: > 2 0. 0 x U L N  
F or  p arti ci p a nt s  d eri vi n g  cli ni c al  b e n efit  u p o n  
i n v e sti g at or’ s j u d g e m e nt  
M a n d at or y: O mit d o s e. R e p e at L F T s
b a s s o o n a s p o s si bl e, 
pr ef er a bl y  wit hi n  4 8 -7 2  h o ur s  fr o m  a w ar e n e s s  of  t h e  
a b n or m al r e s ult s; m o nit or L F T s b  w e e kl y, or m or e fr e q u e ntl y 
if  cli ni c all y  i n di c at e d,  u ntil  r e s ol v e d  t o  ≤  3  x  U L N  ( or  ≤  5  x 
U L N f or p arti ci p a nt s wit h b a s eli n e v al u e > 3. 0 -5. 0 x U L N), 


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Worst toxicity CTCAEa Grade (value) during a 
cycle of therapy 
Recommendations 
then resume at ↓ 1 dose level. Only 1 dose reduction is 
allowed; if reoccurs at > 5 x ULN, discontinue nazartinib 
For all other participants: 
Mandatory: Permanently discontinue participant from study 
drug treatment  
Repeat LFTsb as soon as possible, preferably within 48-72 
hours from awareness of the abnormal results; monitor 
LFTsb weekly, or more frequently if clinically indicated, until 
resolved to baseline or stabilization over 4 weeks. 
Combinedd elevation of AST or ALT and concurrent Total bilirubinf 
For participants with normal baseline ALT,  AST 
and  total bilirubin value: 
AST or ALT >3.0 x ULN combined with total 
bilirubin >2.0 x ULN without evidence of 
cholestasise  
OR  
For participants with elevated baseline AST or 
ALT or total bilirubin value: 
[AST or ALT>2x baseline AND > 3.0 x ULN] OR 
[AST or ALT > 8.0 x ULN], whichever is lower, 
combined with [total bilirubin >2x baseline 
AND >2.0 x ULN] 
Mandatory: Permanently discontinue nazartinib.  
Repeat as soon as possible, preferably within 48 hours from 
awareness of the abnormal results, then with weekly 
monitoring of LFTsb), or more frequently if clinically 
indicated, until AST, ALT, or bilirubin have resolved to 
baseline or stabilization over 4 weeks.  
METABOLICh 
Asymptomatic amylase and/or lipase elevation 
Grade 1 (>ULN - 1.5 x ULN) 
May maintain dose level 
Grade 2 (>1.5 - 2.0 x ULN) 
May maintain dose level 
Grade 3 (>2.0 - 5.0 x ULN) 
Recommendation: omit dose until resolved to Grade ≤ 2, 
then: 
If fully resolved in ≤ 14 days, then resume at same dose 
level 
If fully resolved in >14 days, then resume at↓ 1 dose level 
Grade 4 (>5.0 x ULN) 
Recommendation: Omit dose and discontinue nazartinib 
Note: withhold nazartinib for acute onset of new or progressive unexplained abdominal symptoms, such as 
severe pain or vomiting; perform diagnostic procedures (e.g., abdominal CT scan or ultrasound) to exclude 
pancreatic pathology. 
HBV and HCV reactivation 
Refer to Table 6-10, Table 6-11 and Table 6-12, and Section 6.3.2 for details. 
CARDIAC 
Electrocardiogram QT corrected (QTc) interval prolonged 
Grade 1 (QTc 450-480 ms) 
May maintain dose level 
Grade 2 (QTc 481-500 ms) 
May maintain dose level 
Grade 3 (QTc ≥ 501 ms on at least two separate 
ECGs) 
Recommendation: omit dose until QTc is less than 481 ms 
and then resume at↓ 1 dose level 
• Perform an analysis of serum potassium, and if below 
lower limit of normal, correct with supplements to within 
normal limits. Repeat ECG in 24 hours, or less, as 
clinically indicated; continue monitoring as clinically 
indicated until QTc <481 ms 


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Worst toxicity CTCAEa Grade (value) during a 
cycle of therapy 
Recommendations 
• 
Repeat ECGs 7 days after dose resumption for all 
participants who had therapy interrupted due to QTc ≥ 
501 ms. 
Grade 4 (QTcF ≥ 501 or > 60 ms change from 
baseline and Torsades de pointes or polymorphic 
ventricular tachycardia or signs/symptoms of 
serious arrhythmia) 
Recommendation: discontinue nazartinib 
Bradycardia 
Grade 1 or 2 
Recommendation: omit dose until recovery to asymptomatic 
bradycardia or to a heart rate ≥ 60 bpm 
Evaluate 
concomitant 
medications 
known 
to 
cause 
bradycardia and adjust the dose of nazartinib  
Grade 3 
Recommendation: omit dose until recovery to asymptomatic 
bradycardia or to a heart rate ≥ 60 bpm 
Grade 4 (in participants taking a concomitant 
medication also known to cause bradycardia or a 
medication known to cause hypotension) 
If the concomitant medication can be adjusted or 
discontinued, resume nazartinib at ↓ 1 dose level with 
frequent monitoring 
Grade 4 (in participants who are not taking a 
concomitant medication also known to cause 
bradycardia or known to cause hypotension) 
Recommendation: permanently discontinue nazartinib 
Vascular disorders 
Hypertension 
Grade 3 
Recommendation: omit dose until resolved ≤ Grade 1, then 
resume at↓ 1 dose level 
Grade 4 
Recommendation: omit dose and discontinue nazartinib 
GASTROINTESTINAL 
Diarrheai 
Grade 
1 
(despite 
maximal 
anti-diarrheal 
medication) 
Recommendation: maintain dose level but adjust anti-
diarrhea treatment 
Grade 
2 
(despite 
maximal 
anti-diarrheal 
medication) 
Recommendation: omit dose until resolved to ≤ Grade 1, 
then resume at same dose level. 
If diarrhea returns as ≥ Grade 2, then omit dose until 
resolved to ≤ Grade 1, then resume at↓ 1 dose level 
Grade 
3 
(despite 
maximal 
anti-diarrheal 
medication) 
Recommendation: omit dose until resolved to ≤ Grade 1, 
then resume at ↓ 1 dose level 
Grade 
4 
(despite 
maximal 
anti-diarrheal 
medication) 
Recommendation: omit dose until resolved to ≤ Grade 1, 
then resume at↓ 1 dose level 
Nausea 
Grade 1 or 2 
Recommendation: maintain dose level but adjust anti-emetic 
treatment 
Grade 3 (despite standard anti-emetics) 
Recommendation: omit dose until resolved to ≤ Grade 1, 
then resume at↓ 1 dose level 
Vomiting 
Grade 1 (despite standard anti-emetics)  
Recommendation: maintain dose level but adjust anti-emetic 
treatment 
Grade 2 (despite standard anti-emetics) 
Recommendation: omit dose until resolved to ≤ Grade 1, 
then resume at same dose level. 


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Worst toxicity CTCAEa Grade (value) during a 
cycle of therapy 
Recommendations 
If vomiting returns as ≥ Grade 2, then suspend dose until 
resolved to ≤ Grade 1, then resume at↓ 1 dose level 
Grade 3 (despite standard anti-emetics) 
Recommendation: omit dose until resolved to ≤ Grade 1, 
then resume at↓ 1 dose level 
Grade 4 (despite standard anti-emetics) 
Recommendation: omit dose until resolved to ≤ Grade 1, 
then resume at↓ 1 dose level 
Dose modifications apply to participants who experience nausea and/or vomiting despite appropriate antiemetic 
medication. This medication should be started at the first sign of nausea and/or vomiting. 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Rash/photosensitivity 
Refer to Table 6-13,  Table 6-14 , and Table 6-15 for management and dose modification for rash/skin toxicities 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
Pneumonitis/Interstitial lung disease 
Refer to Table 6-16 for management and dose modification for non-infectious pneumonitis/interstitial lung 
disease 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Fatigue/ Asthenia  
Grade 1 or 2 
May maintain dose level 
Grade 3 
Recommendation: omit dose until resolved to ≤ grade 1, 
then: 
If fully resolved in ≤ 7 days, then reseum at same dose level 
If fully resolved in > 7 days, then resume at↓ 1 dose level 
Metabolic 
Any Grade hypophosphatemia 
Treatment with phosphate supplements as clinically 
indicated and maintain dose level 
Persistent hyperglycemia (glucose > 250 
mg/dL) 
despite 
optimal 
anti-hyperglycemic 
therapy 
Omit dose until hyperglycemia is adequately controlled then 
resume nazartinib at ↓ 1 dose level 
If adequate hyperglycemic control cannot be achieved with 
optimal medical management permanently discontinue 
nazartinib 
Other adverse events 
Grade 1 or 2 
May maintain dose level 
Grade 3 
Recommendation: omit dose until resolved to ≤ grade 1, then 
resume at↓ 1 dose level 
Grade 4 
Recommendation: 
omit 
dose 
and 
then 
discontinue 
nazartinib.  
Note: Omit dose for ≥ grade 3 vomiting or grade 3 nausea 
only if the vomiting or nausea cannot be controlled with 
optimal antiemetic (as per local practice) 
All dose modifications should be based on the worst preceding toxicity. 
a Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
b If Grade 3 or 4 hyper-bilirubinemia 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. 
c LFTs include albumin, ALT, AST, total bilirubin (fractionated if total bilirubin >2.0 x ULN), alkaline phosphatase 
(fractionated if alkaline phosphatase > 2.0 x ULN) and gamma-glutamyl transpeptidase (GGT). For isolated 
elevations of any grade of alkaline phosphatase and/or GGT, maintain dose level. 
d “Combined” defined as: total bilirubin increases to the defined threshold concurrently with ALT/AST increase to 
the defined threshold 


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Worst toxicity CTCAEa Grade (value) during a 
cycle of therapy 
Recommendations 
e “Cholestasis” defined as: ALP elevation (>2xULN and R value< 2) in participants without bone metastasis, or 
elevation of ALP liver fraction in participants with bone metastasis 
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN for both values. It 
denotes the relative pattern of ALT and/or ALP elevation is due to cholestatic or hepatocellular liver injury 
f 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 
g 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. 
h A CT scan or other imaging study to assess the pancreas, liver, and gallbladder must be performed within 1 
week of the first occurrence of any ≥ Grade 3 of amylase and/or lipase. If asymptomatic Grade 2 elevations of 
lipase and/or amylase occur again at the reduced dose, participants will be discontinued permanently from study 
treatment. 
iAntidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools or overt diarrhea.  


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6.3.2 
Guidelines for screening, monitoring and management of HBV / HCV 
reactivation 
HBV screening tests, on study monitoring, and management of HBV 
reactivation 
1. All participants must be screened with HBV serologic markers: HBsAg, HBsAb, and 
HBcAb. 
2. If HBsAg and/or HBcAb are positive, test for HBV-DNA. 
3. Refer to Table 6-10 for actions to be taken based on screening HBV results. 
4. If a participant is HBsAg positive or HBV-DNA positive BUT is not on antiviral therapy: 
a. Consult a physician with expertise in managing HBV 
b. Initiate antiviral therapy with entecavir 0.5 mg q.d. 1-2 weeks prior to first dose of study 
treatment (capmatinib + nazartinib). Note: ongoing participants prior to initiation of 
Amendment 3 follow the Urgent Safety Measure. 
c. If a participant cannot take entecavir or if entecavir is not available at your institution, 
contact Novartis to select an appropriate antiviral therapy. 
d. If antiviral therapy cannot be given, the participant is not eligible for study treatment 
(capmatinib +nazartinib). 
e. During the study, monitor HBV-DNA every 4 weeks (or more frequently if clinically 
indicated). (Refer to Table 6-11 if there is evidence of viral reactivation on study) 
f. Antiviral therapy should continue for at least 4 weeks after the last dose of study 
treatment (capmatinib + nazartinib). 
5. Participants who are HBsAg positive or HBV-DNA positive at screening and already have 
been receiving antiviral therapy are eligible provided the participant remains on antiviral 
treatment. 
a. Identify a consulting physician with expertise in managing HBV who can provide 
treatment guidance, if required, while the participant is on study. 
b. HBV-DNA should be monitored every 4 weeks (or more frequently if clinically 
indicated). 
c. Antiviral therapy should continue for at least 4 weeks after the last dose of study 
treatment (capmatinib +nazartinib). 
6. Refer to Table 6-11 for guidelines of management for HBV reactivation. 


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Table 6-10 
Actions to be taken based on hepatitis B results screening 
Test 
Result 
Result 
Result 
Result 
Result 
HBV-DNA 
+ 
+ or - 
- 
- 
- 
HBsAg 
+ or - 
+ 
- 
- 
- 
HBsAb 
+ or - 
+ or - 
+ 
and no prior 
HBV 
vaccination 
- 
or 
+ 
with 
prior 
HBV 
vaccination 
- 
or 
+ 
with 
prior 
HBV 
vaccination 
HBcAb 
+ or - 
+ or - 
+ or - 
+ 
- 
Required 
actions 
* Consult a physician with expertise in managing 
HBV. 
After the consultation, antiviral therapy should be 
started 1-2 weeks prior to first dose of study 
treatment (capmatinib + nazartinib). 
Recommended antiviral therapy is entecavir 0.5 
mg q.d. Contact Novartis if a participant cannot 
take entecavir or if entecavir is not available at your 
institution. 
Monitor HBV-DNA every 4 weeks (or more 
frequently if clinically indicated). 
Antiviral therapy should continue for at least 4 
weeks after the last dose of study treatment 
(capmatinib + nazartinib). 
No antiviral therapy. 
 
Monitor HBV-DNA every 4 
weeks. 
No antiviral 
therapy. 
HBV-DNA 
screening 
not required 
unless 
if 
HBsAg 
and/or 
HBcAb 
are 
positive 
*Recommended antiviral therapy is entecavir 0.5 mg q.d. Contact Novartis if a participant cannot take entecavir 
or if entecavir is not available at your institution. Antiviral therapy should continue for at least 4 weeks after the 
last dose of study treatment (capmatinib + nazartinib). 
Table 6-11 
Guidelines for management of HBV reactivation 
HBV reactivation (with or without clinical signs and symptoms)* 
Screening 
test results 
Monitoring test 
results that define 
HBV reactivation 
Actions to be taken 
Positive 
HBV-DNA 
OR 
Positive 
HBsAg 
Increase of 1 log in 
HBV-DNA relative to 
screening 
HBV-DNA 
value 
OR 
new appearance of 
measurable HBV-DNA 
Interrupt study treatment (capmatinib + nazartinib). Assess participant 
compliance with antiviral therapy. Consult a physician with expertise in 
managing HBV and consider changing antiviral therapy. 
While participant is on antiviral therapy, continue interruption of study 
treatment (capmatinib + nazartinib) administration until resolution to: 
• 
≤ screening HBV-DNA levels and 
• 
≤ grade 1 ALT (or baseline ALT, if > grade 1) if ALT elevation was 
observed 
If resolution occurs within ≤ 21 days study treatment (capmatinib + 
nazartinib) should be re-started at the same dose level unless dose 
reduction/interruption is indicated due to any other reason. Antiviral 
therapy should continue for at least 4 weeks after the last dose of study 
treatment (capmatinib + nazartinib). 
If resolution occurs > 21 days Contact Novartis for approval of restarting 
of study treatment (capmatinib + nazartinib). 
• 
If restarting of study treatment (capmatinib + nazartinib) is 
approved: follow the same guidelines as above. 


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HBV reactivation (with or without clinical signs and symptoms)* 
Screening 
test results 
Monitoring test 
results that define 
HBV reactivation 
Actions to be taken 
• 
If restarting of study treatment (capmatinib + nazartinib) is NOT 
approved: discontinue study treatment (capmatinib + nazartinib). 
Continue antiviral therapy for at least 4 weeks after the last dose 
of study treatment (capmatinib + nazartinib). 
Monitor HBV-DNA every 4 weeks (or more frequently if clinically 
indicated). 
Negative 
HBV-DNA 
AND 
Negative 
HBsAg 
New appearance of 
measurable HBV-DNA 
Interrupt study treatment (capmatinib + nazartinib). Consult a physician 
with expertise in managing HBV. After the consultation, start antiviral 
therapy. 
While participant is on antiviral therapy, continue interruption of study 
treatment (capmatinib + nazartinib) administration until resolution to: 
• 
≤ baseline HBV-DNA levels and 
• 
≤ grade 1 ALT (or baseline ALT, if > grade 1) if ALT elevation was 
observed 
If resolution occurs within ≤ 21 days study treatment (capmatinib + 
nazartinib) should be re-started at the same dose level unless dose 
reduction/interruption is indicated due to any other reason. Antiviral 
therapy should continue for at least 4 weeks after the last dose of study 
treatment (capmatinib + nazartinib). 
If resolution occurs > 21 days Contact Novartis for approval of 
restarting of study treatment (capmatinib + nazartinib). 
• 
If restarting of study treatment (capmatinib + nazartinib) is 
approved: follow the same guidelines as above. 
• 
If restarting of study treatment (capmatinib + nazartinib) is NOT 
approved: discontinue study treatment (capmatinib + nazartinib). 
Continue antiviral therapy for at least 4 weeks after the last dose 
of study treatment (capmatinib + nazartinib). 
Monitor HBV-DNA every 4 weeks (or more frequently if clinically 
indicated). 
* All reactivations of HBV are to be recorded as serious adverse event (SAE). Date of viral reactivation is the 
date on which the defined lab results for reactivation were met (e.g. for a participant who was HBV-DNA positive 
on 01-JAN-15 and whose ALT reached > 5 × ULN on 01-APR-15, the date of viral reactivation is 01-APR-15). 
HCV screening tests, on study monitoring, and management of HCV 
reactivation 
1. Screen all new participants for HCV Ab. If HCV Ab is detected then check HCV-RNA. 
2. Only participants with negative HCV Ab or with positive HCV Ab but undetectable level 
of HCV-RNA are eligible to be dosed with study treatment (capmatinib + nazartinib) 
(assuming all other eligibility criteria are met). Participants with detectable HCV-RNA are 
not eligible to be enrolled in the study. 
3. The following two categories of participants should be monitored every 8 weeks (or more 
frequently if clinically indicated) with HCV RNA-PCR for HCV reactivation: 
a. Participants with detectable HCV-RNA at screening and were treated until HCV-RNA 
becomes undetectable (only applicable to participants enrolled prior to Amendment 3) 
b. Participants with known history of HCV infection and undetectable HCV-RNA at 
screening 
4. Refer to Table 6-12 for definition of HCV reactivation and the management guidelines. 


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Table 6-12 
Guidelines for management of HCV reactivation 
HCV reactivation (with or without clinical signs and symptoms)1 
Screening test results 
Monitoring test 
results that define 
HCV reactivation 
Action to be taken 
Knowledge 
of 
past 
hepatitis C infection with 
no detectable HCV-RNA 
OR 
Detectable HCV-RNA at 
screening 
and 
was 
treated until HCV-RNA 
becomes undetectable2 
New 
appearance 
of 
detectable HCV-RNA 
Interrupt study treatment (capmatinib + nazartinib). 
Consult a physician with expertise in managing HCV. After 
the consultation, start antiviral therapy. 
While participant on antiviral therapy, continue interruption 
of study treatment (capmatinib + nazartinib) administration 
until resolution to: 
• 
no detectable HCV-RNA and 
• 
≤ grade 1 ALT (or baseline ALT, if > grade 1) if ALT 
elevation was observed. 
If resolution occurs within ≤ 21 days study treatment 
(capmatinib + nazartinib) should be re-started at the same 
dose level unless dose reduction/interruption is indicated 
due to any other reason. 
If resolution occurs > 21 days Contact Novartis for 
approval of restarting of study treatment (capmatinib + 
nazartinib). 
• 
If restarting of study treatment (capmatinib + 
nazartinib) is approved: follow the same guidelines as 
above. 
• 
If restarting of study treatment (capmatinib + 
nazartinib) is NOT approved: permanently discontinue 
the participant from study treatment (capmatinib + 
nazartinib). 
Monitor HCV-RNA every 4 weeks (or more frequently if 
clinically indicated) 
1 All reactivations of HCV are to be recorded as serious adverse event (SAE). Date of viral reactivation is the 
date on which the defined lab results for reactivation were met (e.g., for a participant whose HCV-RNA was 
detectable on 01-JAN-15 and ALT reached > 5 x ULN on 22-JAN-15, the date of viral reactivation is 22-JAN-15). 
2 Applicable to ongoing participants only 
On study monitoring of liver function test (LFT) for all participants 
LFTs should be monitored for all participants as per protocol, or more frequently if clinically 
indicated. 
At any time during the study, if ALT > 5 x ULN in participants with baseline ALT ≤ 3 x ULN, 
or if ALT > 8 x ULN in participants with baseline ALT > 3 x ULN but ≤ 5 x ULN: immediately 
1. Perform test(s) for viral hepatitis infection or reactivation: all participants should be 
screened with viral hepatitis panel (HA Ab-IgM, HBsAg, HBcAb-IgM, and HC Ab). In 
addition 
a. Participants who have HBV-DNA monitoring during the study should be re-tested for 
HBV-DNA immediately; refer to Table 6-11 for definition and management of HBV 
reactivation. 
b. Participants who have HCV-RNA monitoring during the study should be re-tested for 
HCV-RNA immediately; refer to Table 6-12 for definition and management of HCV 
reactivation. 
2. If any of the above tests indicate: 


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a. HBV reactivation: refer to Table 6-11 for management guidelines. 
b. HCV reactivation: refer to Table 6-12 for management guidelines. 
c. New viral infection: immediately interrupt study treatment (capmatinib + nazartinib), 
consult a physician with expertise in managing viral hepatitis and contact Novartis for 
further discussion. 
3. Perform other relevant tests/procedures as clinically indicated. 
4. Follow the dosing modification for ALT elevation according to guidelines in Table 6-7. 
6.3.3 
Guidelines for the management and dose modification of skin-related 
toxicities 
Rash, particularly maculopapular rash or rash pruritic, is an adverse event frequently observed 
following treatment with nazartinib. Participants must be closely monitored for any 
signs/symptoms related to rash/skin toxicities. Recommended guidelines for management and 
dose modification of rash/skin toxicities are provided in Table 6-13, Table 6-14, and  
Table 6-15. 
Recommended dose modifications apply to both nazartinib and capmatinib. 
Table 6-13 
Guidelines for prevention and symptomatic care of rash/skin toxicities   
Type of care 
Action 
Prevention/Prophylaxis 
Starting from Day 1 for all 
participants 
• 
Avoid unnecessary exposure to sunlight/ultraviolet 
• 
Apply broad-spectrum sunscreen with SPF≥15 at least twice daily 
• 
Use thick, alcohol-free emollient cream (e.g. glycerine and cetomacrogol 
cream) on dry areas of the body at least twice daily 
Symptomatic care* 
• 
Pruritic lesions: cool compresses and oral antihistamine therapies 
• 
Desquamation: thick, alcohol-free emollient cream and mild soap 
• 
Paronychia: antiseptic bath and topical antibiotics; if no improvement, consult 
dermatologist 
• 
Infected lesions: appropriate topical or systemic antibiotics 
*Participants who develop rash/skin toxicities should be evaluated by a qualified physician and receive 
symptomatic and supportive care management. 
Table 6-14 
Management and dose modification for maculopapular rash1, 2 
Initial 
CTCAE 
Grade 
Adverse Event Management 
Action and Dose Modification 
Grade 1 
• 
Initiate appropriate symptomatic care (Refer 
to Table 6-13) 
• 
Use mild-strength topical steroid (e.g. 1% 
hydrocortisone cream) on affected areas 
• 
Re-assess every week 
Continue nazartinib and capmatinib at same 
dose level 
Grade 2 
• 
Initiate appropriate symptomatic care (Refer 
to Table 6-13) 
• 
Use moderate-strength topical steroid (e.g. 
2.5% hydrocortisone cream or 0.5% 
fluticasone cream) on affected areas PLUS 
low-dose oral steroid (e.g. 5 mg-10 mg PO 
q.d. for 1 week) with taper 
Continue nazartinib and capmatinib at same 
dose level 
• 
If no recovery or worsened within 1 
week, interrupt nazartinib and 
capmatinib until recover to ≤ Grade 1. 
Once rash has recovered to ≤ Grade 1, 
restart nazartinib and capmatinib at one 


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Initial 
CTCAE 
Grade 
Adverse Event Management 
Action and Dose Modification 
• 
Re-assess every week 
level reduced from the previous dose 
level3 
Grade ≥3 
• 
Initiate appropriate symptomatic care (Refer 
to Table 6-13) 
• 
Use moderate-strength topical steroid on 
affected areas PLUS mid-dose oral steroid 
(e.g. 20-40 mg PO q.d. for 1 week) with 
taper over 1-2 weeks or i.v. steroid (e.g. 
methylprednisolone 20-30 mg i.v. b.i.d. for 3 
days) if clinically indicated 
• 
Consult dermatologist 
• 
Reassess every week 
• 
Interrupt nazartinib and capmatinib until 
rash recovers to ≤ Grade 1. Once 
recovers to ≤ Grade 1, restart study drug 
at one level reduced from the previous 
dose level2. 
• 
Oral antihistamine therapies (e.g. 
levocetirizine 5 mg q.d., desloratadine 5 
mg q.d., or fexofenadine 180 mg q.d.) 
should be given concurrently with study 
drug for 4 weeks when restarting 
treatment. 
• 
If no recovery to ≤ Grade 2 within 3 
weeks, permanently discontinue study 
drug 
• 
Participants who develop more than 1 
episode of Grade ≥ 3 rash will be 
permanently discontinued from study 
drug 
1 Maculopapular rash includes macular rash, papular rash, and maculopapular rash. 
2 For all grades of maculopapular rash, consider skin biopsy for pathologic evaluation. Study drugs may be 
resumed although steroids are still ongoing or being tapered. 
3 A maximum of 2 dose reductions is allowed. Participants, who require further dose decrease after 2 dose 
reductions, should be discontinued from study drug. Escalation by one level to previous dose level may be 
considered if no rash is evident after 4 weeks of uninterrupted study drug at the reduced dose level. Re-
escalation can only be done once. 


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Table 6-15 
Management and dose modification for other rashes including 
acneiform rash 
Initial 
CTCAE 
Grade 
Adverse Event Management 
Action and Dose Modification 
Grade 1 
• 
Monitor for change in severity and consider 
symptomatic and/or topical treatment (Refer 
to Table 6-13) 
• 
Re-assess every 2 week 
Continue study drug at same dose level 
Grade 2 
• 
Initiate appropriate symptomatic care (Refer 
to Table 6-13) 
• 
Depending on the type of rash, a variety of 
agents can be used including mild to 
moderate strength steroid creams, topical 
or systemic antibiotics, topical or systemic 
antihistamines, and retinoid creams. 
• 
Re-assess every 2 week 
Continue study drug at same dose level 
• 
If no recovery or worsened within 2 weeks, 
interrupt study drug until rash recovers to ≤ 
Grade 1 
• 
Once rash recovers to ≤ Grade 1, then 
restart study drug at one reduced dose 
level* 
Grade ≥3 
• 
Initiate appropriate symptomatic care (Refer 
to Table 6-13) 
• 
Depending on the type of rash, a variety of 
agents can be used including mild to 
moderate strength steroid creams, low-
dose oral steroids, etopical or systemic 
antibiotics, topical or systemic 
antihistamines, and retinoid creams. 
• 
Consult dermatologist 
• 
Reassess every 2 week 
Interrupt study drug until rash recovers to ≤ 
Grade 1. 
-Once rash recovers to ≤ Grade 1, restart study 
drug at one reduced dose level* 
• 
If no recovery to ≤ Grade 2 within 3 weeks, 
permanently discontinue study drug 
• 
Participants who develop more than 1 
episode of Grade ≥3 rash will be 
permanently discontinued from study 
treatment 
*A maximum of 2 dose reductions is allowed. Participants, who require further dose decrease after 2 dose 
reductions, should be discontinued from study drug. Escalation by one level to previous dose level may be 
considered if no rash is evident after 4 weeks of uninterrupted study drug at the reduced dose. Re-escalation 
can only be done once. 
6.3.4 
Follow-up for toxicities 
Participants whose treatment is interrupted or permanently discontinued due to an adverse event 
or clinically significant laboratory value, must be followed up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts should be consulted as deemed necessary. 
All participants must be followed up for adverse events and serious adverse events for 30 days 
following the last doses of nazartinib and capmatinib. 
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. 


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Table 6-16 
Toxicity follow-up evaluation 
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 
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: 


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TOXICITY 
FOLLOW-UP EVALUATION 
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. 
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: 
Call the study’s central ECG review laboratory immediately and 
request an immediate manual read of the ECG. 
Perform an analysis of serum potassium, calcium, phosphorus, and 
magnesium, and if below lower limit of normal, correct with 
supplements to within normal limits. 
Review concomitant medication usage for the potential to 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. 
If the central ECG report shows a QTcF ≥ 501 msec (not previously 
documented on the site machine), contact the participant and 
instruct him/her to suspend capmatinib and return for a repeat ECG 
as soon as possible. The central ECG reader should be called for a 
manual read of the repeat ECG immediately, and the above 
guidance followed. 
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). 


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TOXICITY 
FOLLOW-UP EVALUATION 
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/h 
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). 
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 ≤ 1 
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 


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TOXICITY 
FOLLOW-UP EVALUATION 
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 Bronchoalveolar Lavage (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 i.v. steroids (methylprednisolone 125 mg) as indicated. 
When symptoms improve to ≤ Grade 1, a high dose oral steroid 
(prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg 
every 4 hr)b 
If i.v. steroids followed by high dose oral steroids does not reduce 
initial symptoms within 48 to 72 hours, consider non-corticosteroid 
immunosuppressive medication 
a Pulmonary function tests (PFTs) to include: diffusing capacity of the lungs for carbon monoxide corrected for 
hemoglobin (DLCO); spirometry; resting oxygen saturation. 
Guideline for significant deterioration in lung function: 
a 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. 
6.3.4.1 
Follow up on potential QTcF prolongation 
In case of QTcF >500 ms, (or QTcF prolongation >60 ms from baseline) 
• Assess the quality of the ECG recording and the QT value and repeat if needed 
• Interrupt study treatment (capmatinib + nazartinib) 
• Determine the serum electrolyte levels (in particular hypokalemia, hypomagnesemia). 
If abnormal, correct abnormalities before resuming study drug treatment (capmatinib + 
nazartinib). 
• Review concomitant medication use for other causes for QT prolongation, and for drugs 
with the potential to increase the risk of drug exposure related QT prolongation 
• Check study drug dosing schedule and study treatment compliance 
• Consider collecting a time-matched PK sample, and record time and date of last study 
drugs intake. 
• Perform a repeat ECG within one hour of the first QTcF of >500 ms. 


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After confirming ECG reading at site, if QTcF > 500 ms 
• Interrupt study treatment (capmatinib + nazartinib) 
• Repeat ECG and confirm ECG diagnosis by a cardiologist or central ECG lab 
• If QTcF confirmed > 500 ms: 
• Correct electrolytes, eliminate culprit concomitant treatments, and identify clinical 
conditions that could potentially prolong the QT 
• Consult with a cardiologist (or qualified specialist) 
• Increase cardiac monitoring as clinically indicated, until the QTcF returns to ≤ 480 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 >500 ms. 
• After resolution to ≤ 480 ms, consider re-introducing study treatment (capmatinib + 
nazartinib) at reduced dose, and increase ECG monitoring: 
• If QTcF remains ≤ 500 ms after dose reduction, continue planned ECG monitoring 
during subsequent study treatment 
• If QTcF recurs > 500 ms after dose reduction, discontinue participant from trial. 
6.3.4.2 
Follow up on potential drug-induced liver injury (DILI) cases 
Participants with transaminase increase combined with total bilirubin increase may be 
indicative of potential DILI, these cases should be considered as clinically important events and 
assessed appropriately to establish the diagnosis. The required clinical information, as detailed 
below, should be sought to obtain the medical diagnosis of the most likely cause of the observed 
laboratory abnormalities. 
The threshold for potential DILI may depend on the participant’s baseline AST/ALT and 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 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] 
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before DILI is assumed as the cause of liver injury.   
• Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, Glutamate dehydrogenase (GLDH), prothrombin time 
(PT)/INR and alkaline phosphatase. 
• A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected. 
• Evaluate status of liver metastases (new or exacerbation) or vascular occlusion – e.g., using 
CT, MRI, or duplex sonography. 


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• 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 
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 6-17 provides guidance on specific clinical and diagnostic assessments which can be 
performed to rule out possible alternative causes of observed LFT abnormalities. Guidance 
on specific clinical and diagnostic assessments which can be performed to rule out possible 
alternative causes of observed LFT abnormalities. 
Table 6-17 
Guidance to rule out other alternative causes of observed LFT 
abnormalities 
Disease 
Assesment 
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 
Cytomegalovirus (CMV), Herpes Simplex 
Virus (HSV), Epstein-Barr Virus (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, Mean Corpuscular Volume (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) 
Caeruloplasmin 
Hemochromatosis 
Ferritin, transferrin 
Alpha-1-antitrypsin deficiency 
Alpha-1-antitrypsin 
• Obtain PK sample, as close as possible to last dose of study drug,  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 


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significant”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the term 
“potential drug-induced liver injury”. All events should be followed up with the outcome clearly 
documented. 
6.3.5 
Anticipated risks and safety concerns of the study drug 
Appropriate eligibility criteria and specific DLT definitions, as well as specific dose 
modification and stopping rules are included in this protocol. Prophylactic or supportive 
treatment for expected toxicities, including management of study-drug induced adverse events 
will be as per institutional guidelines. 
Refer to preclinical toxicity 
 and clinical data found in the [nazartinib and 
capmatinib Investigator’s Brochure]. 
6.4 
Concomitant medications 
6.4.1 
Permitted concomitant therapy 
In general, concomitant medications and therapies deemed necessary for the supportive care 
(e.g. such as anti-emetics, anti-diarrhea) and safety of the participant are allowed, except when 
specifically prohibited (see Section 6.4.3). 
The participant must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug) and significant 
non-drug therapies (including physical therapy, herbal/natural medications and blood 
transfusions) administered during the study must be listed on the Concomitant Medications or 
the Surgical and Medical Procedures CRF. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
enrolling a participant or allowing a new medication to be started. If the participant is already 
enrolled, contact Novartis to determine if the participant should continue participation in the 
study. 
6.4.1.1 
Permitted concomitant therapy of capmatinib in combination with 
nazartinib 
Anticoagulation treatment is also allowed if INR has been established within the therapeutic 
range prior to study entry. PT and PTT ≥ 1.5x ULN are permitted in these cases. 
After discussion with Novartis, participants who develop progressive disease limited to the bone 
or CNS may undergo radiotherapy to the bone or CNS, and surgical resection of CNS 
metastases, and remain on study. Nazartinib and capmatinib should be held for at least 5 days 
prior to radiotherapy or surgery. Nazartinib and capmatinib may be resumed > 3 days after 
completing radiotherapy or surgery if all procedure-related toxicities have resolved to ≤ Grade 
1. 
The exception to this is palliative bone radiation, which is permitted throughout the study. 
However, study treatment should be interrupted on the day of radiotherapy. 










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6.5 
Participant numbering, treatment assignment 
This is a non-randomized trial and Integrated Response Technology (IRT) will only be used for 
distribution of study medication in the Phase II part. 
6.5.1 
Participant numbering 
Each participant is identified in the study by a participant Number (Participant No.), that is 
assigned when the participant is first enrolled for molecular pre-screening and is retained as the 
primary identifier for the participant throughout his/her entire participation in the trial. The 
participant No. consists of the Center Number (Center No.) (as assigned by Novartis to the 
investigative site) with a sequential participant number suffixed to it, so that each participant is 
numbered uniquely across the entire database. Upon signing the molecular pre-screening or 
screening informed consent form, the participant is assigned to the next sequential participant 
No. available to the investigator through the EDCinterface. 
For Phase II participants, the investigator or designated staff will contact the IRT at the 
molecular pre-screening visit and at the screening visit to provide the requested identifying 
information for participant registration into the IRT. 
Once assigned, the participant No. must not be reused for any other participant and the 
participant No. for that individual must not be changed, even if the participant is re-screened. If 
the participant fails to be assigned to treatment or start treatment for any reason, the reason will 
be entered into the Screening Disposition page. 
IRT must be notified within 2 days that the participant was not enrolled. 
6.5.2 
Treatment assignment 
The assignment of a participant to a particular cohort will be coordinated by the sponsor during 
the Phase Ib part of the study. 
For the Phase II part, an IRT will be used to track participant enrollment, document key 
eligibility criteria, allocate participants into 5 different groups based on their characteristics at 
study entry, and track individual assignment of capmatinib monotherapy or capmatinib in 
combination with nazartinib drug supplies. The IRT will dispense the selected capmatinib 
monotherapy or capmatinib in combination withand nazartinib dose to each participant 
participating in this trial. 
For each allocated participant, and prior to dosing, all participants who fulfill all 
inclusion/exclusion criteria will be assigned to one of the groups of interest during the Phase II 
part, and information will be collected via IRT: 
• Group 1 (first or second generation TKI resistant): EGFRmutL858R/ex19del NSCLC 
participants developing resistance to EGFR-TKI: 
• sub-group 1a: EGFRmutL858R/ex19del NSCLC with acquired mutation T790M (T790M+, 
MET dysregulation-). 
• sub-group 1b: EGFRmutL858R/ex19del NSCLC with demonstrated MET dysregulation 
(T790M-, MET dysregulation+). 
MET dysregulation is defined as either gene copy number ≥ 4 and/or IHC 3+ (defined 
as ≥50% of cells staining with high intensity) 


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• sub-group 1c: EGFRmutL858R/ex19del NSCLC with either evidence of both acquired 
T790M and MET dysregulation (T790M+, MET dysregulation+) 
• sub-group 1d: EGFRmutL858R/ex19del NSCLC with MET dysregulation below the levels 
for sub-group b (T790M-, MET dysregulation-). 
• Group 2 (EGFRmut, de novo T790M, any MET, 1/3L antineoplastic, EGFR TKI naïve): 
EGFR-TKI naïve NSCLC participants with T790M de novo mutation. 
• Group 3 (EGFRmut, T790M negative, any MET, 1L antineoplastic): EGFRmutL858R/ex19del 
NSCLC participants, treatment naïve. 
• Group 4 (EGFRmut, any T790M, any MET, 1L (treatment naïve) 2-3L antineoplastic: 
EGFRmut NSCLC who failed (defined as intolerance to treatment or documented disease 
progression) maximum 2 prior lines of systemic antineoplastic therapy 
• Group 5 (EGFRmut, T790M-, MET GCN≥5, 2L, EGFR TKI resistant): previously 
documented EGFR activating mutation (e.g., L858R and/or ex19del), T790M negative, 
MET amplified who have progressed on one prior line of therapy (either to first/second 
generation EGFR TKIs, osimertinib or other third generation EGFR TKIs) for 
advanced/metastatic NSCLC disease. 
Participants in Phase Ib, Phase II Groups 1, 2 and 3 will take the combination therapy in fasting 
conditions whilst participants in Phase II Group 4 will take the study treatment with food. 
For the purpose of this study, common EGFR activating/sensitizing mutations are L858R point 
mutation and exon 19 deletions which account for approximately 90% of the cases. Other rare 
EGFR mutations such as L861Q, G719X, and S768I are also considered activating/sensitizing 
mutations for enrollment onto the Phase II Group 1, Group 3 and Group 4. 
The IRT will also specify medication number of the bottles of capmatinib monotherapy or 
capmatinib in combination with nazartinib study drug to be dispensed to the participant. 
6.6 
Study drug preparation and dispensation 
The investigator or responsible site personnel must instruct the participant or caregiver to take 
the study drugs as per protocol. Study drug(s) will be dispensed to the participant by authorized 
site 
personnel 
only. 
Dose 
strength 
and 
treatment 
schedule 
are 
described 
in  
Table 6-1. All dosages prescribed to the participant and all dose changes during the study must 
be recorded on the Dosage Administration Record CRF. 
As per Section 2.7, 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 
of IMP directly to a participant’s home may be permitted (if allowed by local or regional health 
authorities and ethics committees as appropriate) 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 IMP from the site to the participant’s home remains under the 
accountability of the Investigator. Each shipment/provisioning will be for a maximum of 3 
months supply. In this case, regular phone calls or virtual contacts (every 4 weeks (+/- 1 week) 
or more frequently if needed) will occur between the site and the participant for instructional 
purposes, safety monitoring, drug accountability, investigation of any adverse events, ensuring 


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participants continue to benefit from treatment and discussion of the participant´s health status 
until the participants can resume visits at the study site. 
6.6.1 
Study drug packaging and labeling 
The study medication packaging has a 2-part label. 
In Phase Ib responsible site personnel will add the participant number on the label. 
In Phase II, a unique medication number will also be printed on each part of this label which 
corresponds to one of the treatment arms and a specific visit or dose/dose level. Responsible 
site personnel will identify the study treatment package(s) to dispense to the participant by using 
the IRT and obtaining the medication number(s). Site personnel will add the participant number 
on the label. 
Immediately before dispensing the package to the participant, site personnel will detach the 
outer part of the label from the packaging and affix it to the source document (Drug Label Form) 
for that participant’s unique participant number. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the drug but no information about the 
participant. Additionally in Phase II, labels will include the unique medication number. 
Nazartinib and capmatinib will be supplied by -Novartis Global Clinical Supply. Nazartinib 
25 mg, 50 mg and 100 mg capsules, and 25 mg, 50 mg and 200 mg tablets will be packaged in 
high-density polyethylene (HDPE) bottles. Capmatinib 100 mg, 150 mg and 200 mg tablets will 
be packaged in HDPE bottles. 
For participants in Phase II Group 5, nazartinib and capmatinib will be supplied by Novartis 
Global Clinical Supply. Nazartinib 25 mg, 50 mg capsules will be packaged in HDPE bottles. 
Capmatinib 150 mg and 200 mg tablets will be packaged in HDPE bottles. 
6.6.2 
Drug supply and storage 
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, the study treatment should be stored according to the 
instructions specified on the drug labels and in the [capmatinib Investigator’s Brochure] and 
[nazartinib Investigator’s Brochure] . 
6.6.3 
Study drug compliance and accountability 
6.6.3.1 
Study drug compliance 
Compliance will be assessed by the investigator and/or study personnel at each participant visit 
and information provided by the participant and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each 
participant visit. 


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6.6.3.2 
Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Participants will be asked to return 
all unused study treatment and packaging on a regular basis, at the end of the study or at the 
time of study treatment discontinuation. 
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 
6.6.4 
Disposal and destruction 
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate. 
Study treatment destruction at the investigational site will only be permitted if authorized by 
Novartis in a prior agreement and permitted by local regulations. 
7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
Table 7-1 and Table 7-2 lists all of the assessments and indicates with an “X”, the visits when 
they are performed. All data obtained from these assessments must be supported in the 
participant’s source documentation. 
No CRF will be used as a source document. 
Screening/baseline evaluations (including baseline radiological assessments) must be 
performed ≤ 28 days of Cycle 1 Day 1. Laboratory assessments performed as part of the 
screening evaluations and within 72 hours of the first dose of study treatment, are not required 
to be repeated on the first dosing day. 
During the course of the study visits, test and/or procedures should occur on schedule whenever 
possible. During the Phase Ib part of the study, for C2D1, a visit window of +3 days is permitted 
to ensure minimal follow-up of 28 days during cycle 1. For all other visits, a visit window of 
+/- 3 days is allowed. HBV/HCV results should be available prior to first dose of study 
treatment (capmatinib + nazartinib). On PK collection days of Cycle 1, the window is only +/- 
1 day. PK samples of Cycle 1 Day 1 must be collected at the same day of first dose. 
Radiological assessments must be performed +/-7 days of the scheduled date of the assessment. 


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As per Section 2.7, during a public health emergency as declared by local or regional authorities 
i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by the investigator as 
the situation dictates. If allowed by local health authority and depending on operational 
capabilities, phone calls, 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 7-1 
Visit evaluation schedule for Phase Ib and Phase II Groups 1 to 4 
 
 
 
Screening Phase 
Treatment Phase 
Follow-Up 
 
Category 
Protocol 
Section 
Molecular 
Pre-
screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent 
cycles 
EoT 
30-day 
Safety F/U 
Disease 
progression 
F/U
Survival 
F/U 
every 3 months
Day of Cycle 
 
 
 
-28 to 1 
1 
2 
8 
15 16 22 1 2 
8 
15 22 1 
15 
 
 
 
 
Obtain Molecular Pre-
screening Informed Consent 
D 
7.1.1. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Obtain Main Informed Consent D 
7.1.2. 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRT Registration (Phase II) 
 
6.5.1. 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Participant history 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
D 
7.1.2.2. 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
D 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Current medical conditions 
D 
7.1.2.2. 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis and extent of 
cancer 
D 
7.1.2.2. 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior antineoplastic therapies 
D 
7.1.2.2. 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking history 
D 
7.1.2.2. 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
D 
7.1.2.2. 
 
 
Continuously 
X 
 
 
Antineoplastic therapies since 
discontinuation of study 
treatment 
D 
7.1.2.2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Physical examination 
S 
7.2.2.1. 
 
X 
X  
X X 
 
X 
X  
X X 
X 
X 
 
X 
 
 
 
Vital signs 
D 
7.2.2.2. 
 
X 
X  
X X 
 
X 
X  
X X 
X 
X 
 
X 
 
 
 
Height 
D 
7.2.2.3. 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
D 
7.2.2.3. 
 
X 
X  
 
 
 
 
X  
 
 
 
X 
 
X 
 
 
 
Performance status 
D 
7.2.2.4. 
 
X 
X  
 
 
 
 
X  
 
 
 
X 
 
X 
 
 
 


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Screening Phase 
Treatment Phase 
Follow-Up 
 
Category 
Protocol 
Section 
Molecular 
Pre-
screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent 
cycles 
EoT 
30-day 
Safety F/U 
Disease 
progression 
F/U
Survival 
F/U 
every 3 months
Day of Cycle 
 
 
 
-28 to 1 
1 
2 
8 
15 16 22 1 2 
8 
15 22 1 
15 
 
 
 
 
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
D 
7.2.2.5.1.  
X 
X  
X X 
 
X 
X  
X X 
X 
X 
X 
up to 
Cycle 6 
only 
X 
 
 
 
Chemistry 
D 
7.2.2.5.2.  
X 
X  
X X 
 
X 
X  
X X 
X 
X 
X 
up to 
Cycle 6 
only 
X 
 
 
 
Coagulation 
D 
7.2.2.5.3.  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
D 
7.2.2.5.4.  
X 
X  
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
HBV testing 
D 
6.3.2. 
7.2.2.5.5. 
 
X 
In cases of positive HBV testing, monitor HBV-DNA every 4 
weeks or every 12 weeks, per Table 6-10 and Table 6-11 (or 
more frequently if clinically indicated). 
 
 
 
 
HCV testing 
D 
6.3.2. 
7.2.2.5.5. 
 
X 
In cases of positive HCV-Ab, monitor HCV-RNA every 8 
weeks, per Table 6-12 (or more frequently if clinically 
indicated). 
 
 
 
 
Pregnancy test 
D 
7.2.2.5.6.  
X 
X  
 
 
 
 
X  
 
 
 
X 
 
X 
 
 
 


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Screening Phase 
Treatment Phase 
Follow-Up 
 
Category 
Protocol 
Section 
Molecular 
Pre-
screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent 
cycles 
EoT 
30-day 
Safety F/U 
Disease 
progression 
F/U
Survival 
F/U 
every 3 months
Day of Cycle 
 
 
 
-28 to 1 
1 
2 
8 
15 16 22 1 2 
8 
15 22 1 
15 
 
 
 
 
Imaging 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor evaluation as per 
RECIST 1.1 CT/MRI: 
- Mandatory at each 
evaluation: chest, abdomen 
- Mandatory if lesions at 
baseline: brain, skin 
- If clinically indicated: bone, 
other tumor sites 
D 
7.2.1. 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Every 8 
wks (12 
wks 
from 
C13D1) 
 
X (if not 
conducted 
within 30 
days of 
EOT) 
 
X 
every 
8 wks 
 
ECG (triplicate) 
D 
7.2.2.6.1.  
X 
X  
 
 
 
 
X  
 
 
 
X 
 
X 
 
 
 
Safety 
 
 
 
 
 
 
 
AEs 
D 
8. 
X 
Procedural 
SAE only 
X 
Continuously 
 
 
Biomarkers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Molecular Pre-Screening 
(Tumor sample archival or 
newly obtained) 
 
7.1.1. 
7.2.4. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole Blood sample for 
determination of MET and 
EGFR status in cfDNA 
 
7.2.4. 
 
X* 
 
X C3 
and 
every 
third 
cycle 
 
X 
 
 
 


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Screening Phase 
Treatment Phase 
Follow-Up 
 
Category 
Protocol 
Section 
Molecular 
Pre-
screening 
Screening 
Cycle 1 
Cycle 2 
Subsequent 
cycles 
EoT 
30-day 
Safety F/U 
Disease 
progression 
F/U
Survival 
F/U 
every 3 months
Day of Cycle 
 
 
 
-28 to 1 
1 
2 
8 
15 16 22 1 2 
8 
15 22 1 
15 
 
 
 
 
Study Drug administration 
D 
6.1.1. 
 
 
Continuously 
 
 
 
 
PK sampling 
(Phase Ib part) 
D 
7.2.3.2. 
 
 
X X X X 
X 
 
X X  
 
 
X 
C3 and 
4 only 
 
 
 
 
 
PK sampling 
(Phase II part) 
D 
7.2.3.3. 
 
 
X X X  
 
 
X X  
 
 
X 
C3 and 
4 only 
 
 
 
 
 
Meal Recorded 
(Full PK participants) 
 
6.1.1. 
 
 
X  
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
Survival contact 
(telephone call) 
 
7.1.6. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
* Collect during screening phase or at C1D1 before the first dose of study drugs is administered. 
 


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Table 7-2 
Visit evaluation schedule for Phase II Group 5 
Period 
Category 
Protocol 
Section 
Screening 
Treatment – Capmatinib 
Monotherapy 
Extension Treatment (ET) – 
Capmatinib + Nazartinib 
combination therapy 
Follow-up 
Visit Name 
 
 
Molecular 
pre-
screening 
Screening 
Cycle 
1 
Cycle 2 
and 
beyond 
EOT 
ET-
Cycle 
1 
ET-
Cycle 2 
and 
beyond 
ET-EOT 
30-day 
Safety 
F/U 
Post-
treatment 
F/U 
Day of cycle 
 
 
- 
-28 to -1 
1 
1 
- 
1 
1 
- 
- 
- 
Obtain Molecular Pre-
screening informed 
consent 
D 
7.1.1. 
X 
 
 
 
 
 
 
 
 
 
Newly obtained tumor 
biopsy (preferred) or 
archival tumor sample 
for central assessment 
of MET amplification 
status 
 
7.1.1. 
7.2.4. 
X1 
 
 
 
 
 
 
 
 
 
Information on prior 
local testing for MET 
amplification status 
 
7.2.4. 
X 
X (only if 
not 
provided 
at pre-
screening) 
 
 
 
 
 
 
 
 
Collection of local 
EGFR T790M status 
 
7.2.4. 
X 
 
 
 
 
 
 
 
 
 
Diagnosis and extent of 
cancer 
D 
7.1.2.2. 
X 
 
 
 
 
 
 
 
 
 
Demography 
D 
7.1.2.2. 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
D 
5.2 
5.3 
X 
X 
 
 
 
 
 
 
 
 


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Period 
Category 
Protocol 
Section 
Screening 
Treatment – Capmatinib 
Monotherapy 
Extension Treatment (ET) – 
Capmatinib + Nazartinib 
combination therapy 
Follow-up 
Visit Name 
 
 
Molecular 
pre-
screening 
Screening 
Cycle 
1 
Cycle 2 
and 
beyond 
EOT 
ET-
Cycle 
1 
ET-
Cycle 2 
and 
beyond 
ET-EOT 
30-day 
Safety 
F/U 
Post-
treatment 
F/U 
Day of cycle 
 
 
- 
-28 to -1 
1 
1 
- 
1 
1 
- 
- 
- 
Obtain Main informed 
consent(s) 
D 
7.1.2. 
 
X 
 
 
 
X2 
 
 
 
 
IRT eligibility check 
S 
6.5.1. 
 
X 
 
 
 
 
 
 
 
 
IRT Registration 
 
6.5.1. 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Relevant medical 
history/current medical 
history 
D 
7.1.2.2. 
 
X 
 
 
 
 
 
 
 
 
Prior/Concomitant 
Medications 
D 
7.1.2.2. 
 
Continuously from 28 days prior to first dose 
until 30 days after last dose of study treatment 
X 
 
Prior antineoplastic 
therapies 
D 
7.1.2.2. 
 
X 
 
 
 
 
 
 
 
 
Smoking history 
D 
7.1.2.2. 
 
X 
 
 
 
 
 
 
 
 
Targeted Physical Exam 
S 
7.2.2.1. 
 
 
X 
X 
X 
X 
X 
X 
 
 
Physical examination, 
including neurological 
exams 
S 
7.2.2.1. 
 
X 
As clinically indicated 
 
 
Height 
D 
7.2.2.3. 
 
X 
 
 
 
 
 
 
 
 
Weight 
D 
7.2.2.3. 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital Signs 
D 
7.2.2.2. 
 
X 
X 
X 
X 
X 
X 
X 
 
 
HIV history (HIV testing 
where locally required) 
S 
5.3 
 
X 
 
 
 
 
 
 
 
 


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Period 
Category 
Protocol 
Section 
Screening 
Treatment – Capmatinib 
Monotherapy 
Extension Treatment (ET) – 
Capmatinib + Nazartinib 
combination therapy 
Follow-up 
Visit Name 
 
 
Molecular 
pre-
screening 
Screening 
Cycle 
1 
Cycle 2 
and 
beyond 
EOT 
ET-
Cycle 
1 
ET-
Cycle 2 
and 
beyond 
ET-EOT 
30-day 
Safety 
F/U 
Post-
treatment 
F/U 
Day of cycle 
 
 
- 
-28 to -1 
1 
1 
- 
1 
1 
- 
- 
- 
Performance Status 
(ECOG) 
D 
7.2.2.4. 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology 
D 
7.2.2.5.1 
 
X 
X 
X 
up to 
Cycle 6 
only 
X 
X 
X 
up to 
ET-
Cycle 6 
only 
X 
 
 
Chemistry 
D 
7.2.2.5.2. 
 
X 
X 
X 
up to 
Cycle 6 
only 
X 
X 
X 
up to 
ET-
Cycle 6 
only 
X 
 
 
Coagulation 
D 
7.2.2.5.3. 
 
X (≤72 hr 
before 
C1D1) 
As clinically indicated 
 
 
Urinalysis (dipstick) 
D 
7.2.2.5.4. 
 
X 
As clinically indicated 
 
 
HBV testing 
D 
6.3.2. 
7.2.2.5.5. 
 
X 
 
 
 
In cases of 
positive HBV 
testing, monitor 
HBV-DNA every 4 
weeks, per  
Table 6-10 and 
Table 6-11 (or 
more frequently if 
 
 
 


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Period 
Category 
Protocol 
Section 
Screening 
Treatment – Capmatinib 
Monotherapy 
Extension Treatment (ET) – 
Capmatinib + Nazartinib 
combination therapy 
Follow-up 
Visit Name 
 
 
Molecular 
pre-
screening 
Screening 
Cycle 
1 
Cycle 2 
and 
beyond 
EOT 
ET-
Cycle 
1 
ET-
Cycle 2 
and 
beyond 
ET-EOT 
30-day 
Safety 
F/U 
Post-
treatment 
F/U 
Day of cycle 
 
 
- 
-28 to -1 
1 
1 
- 
1 
1 
- 
- 
- 
clinically 
indicated). 
HCV testing 
 
6.3.2. 
7.2.2.5.5. 
 
X 
 
 
 
In cases of 
positive HCV-Ab, 
monitor HCV-
RNA every 4 
weeks, per  
Table 6-12 (or 
more frequently if 
clinically 
indicated). 
 
 
 
Pregnancy Test 
(Serum) 
D 
7.2.2.5.6. 
 
X (≤72 hr 
before 
C1D1) 
 
 
X 
 
 
X 
 
 
Pregnancy Test (Urine) 
D 
7.2.2.5.6. 
 
 
 
X 
 
 
X 
 
 
 
Tumor evaluation 
D 
7.2.1. 
 
X 
 
Cycle 3 
then 
every 8 
weeks 
(from 
cycle 13 
every 12 
weeks) 
X (Not 
required if 
previous 
assessment 
was 
performed 
≤28 days) 
X3 
ET-
Cycle 3 
then 
every 8 
weeks 
(from 
cycle 
13 
every 
X (Not 
required if 
previous 
assessment 
was 
performed 
≤28 days) 
 
 
X every 8 
weeks 
 


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Period 
Category 
Protocol 
Section 
Screening 
Treatment – Capmatinib 
Monotherapy 
Extension Treatment (ET) – 
Capmatinib + Nazartinib 
combination therapy 
Follow-up 
Visit Name 
 
 
Molecular 
pre-
screening 
Screening 
Cycle 
1 
Cycle 2 
and 
beyond 
EOT 
ET-
Cycle 
1 
ET-
Cycle 2 
and 
beyond 
ET-EOT 
30-day 
Safety 
F/U 
Post-
treatment 
F/U 
Day of cycle 
 
 
- 
-28 to -1 
1 
1 
- 
1 
1 
- 
- 
- 
12 
weeks) 
ECG (triplicate) 
D 
7.2.2.6.1. 
 
X 
X 
As 
clinically 
indicated 
X 
X 
X 
 
 
Adverse Events 
D 
8. 
Continuously from signing of main ICF until 30 days after last dose of study treatment 
 
 
Serious Adverse Events 
D 
8. 
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 
Capmatinib drug 
administration 
 
6.1 
 
 
Continuously twice daily dosing [b.i.d] 
 
 
Nazartinib drug 
administration 
 
6.1 
 
 
 
 
 
Continuously once daily [q.d.] 
 
 
Antineoplastic therapies 
since discontinuation 
from study treatment 
D 
7.1.2.2. 
 
 
 
 
 
 
 
 
X 
X 


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Period 
Category 
Protocol 
Section 
Screening 
Treatment – Capmatinib 
Monotherapy 
Extension Treatment (ET) – 
Capmatinib + Nazartinib 
combination therapy 
Follow-up 
Visit Name 
 
 
Molecular 
pre-
screening 
Screening 
Cycle 
1 
Cycle 2 
and 
beyond 
EOT 
ET-
Cycle 
1 
ET-
Cycle 2 
and 
beyond 
ET-EOT 
30-day 
Safety 
F/U 
Post-
treatment 
F/U 
Day of cycle 
 
 
- 
-28 to -1 
1 
1 
- 
1 
1 
- 
- 
- 
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 Can be collected up to C1D1 
2 Each participant must sign separate combination treatment ICF prior to any assessments of the Extension Treatment period or first dose with combination therapy 
3 Not required if the EOT scan is within 28 days of ET-C1D1, then the EOT scan can be defined as re-baseline of extension. Otherwise, a re-baseline scan should be 
arranged 28 days prior to ET-C1D1. In case exceed 28 days of C1D1 and no re-scan was done, the EOT scan can be used as re-baseline for efficacy assessment 


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7.1.1 
Molecular pre-screening 
All participants entering the pre-screening phase must sign the molecular pre-screening 
informed consent form (ICF). 
Activating mutations L858R and ex19del 
For participants in Phase Ib part and Phase II part Groups 1 3, 4 and 5 local pathology reports 
showing L858R and/or ex19del evidence must be available in medical records prior to sign the 
main ICF. Documented proof of other rare activating mutations that confer sensitivity to first 
and second generation EGFR inhibitors (e.g. L861Q, G719X, S768I) also satisfies eligibility 
criteria. 
For Phase II Group 2 (de novo EGFR T790M mutation), local pathology reports showing the 
activating mutation analysis results must be available in the medical records as well. The 
participants will be enrolled irrespective of the activating mutation status, i.e. may harbor or 
may not harbor an EGFR activating mutation in addition to the EGFR T790M mutation. 
Activating mutation status as per local pathology reports must be recorded in the eCRF for all 
participants. 
Resistance mechanisms EGFRT790M and MET dysregulation: Phase Ib 
In Phase Ib, if mutational status for EGFRT790M and MET pathway dysregulation are unknown 
following treatment with EGRF-TKI, a newly obtained tumor sample (preferred) or an archival 
tumor sample collected at or following progression on prior EGFR TKI therapy, should be 
provided to Novartis designated central laboratory for EGFR mutation and MET dysregulation 
testing. 
In Phase Ib, acceptable local test results for EGFRT790M should be assessed using: 
• In the United States with QIAGEN Therascreen EGFR test, 
• In the other countries with either Roche COBAS or QIAGEN Therascreen EGFR test. 
MET dysregulation should be preferably analyzed by FISH, and if sufficient tumor material is 
available additionally by IHC. 
MET dysregulation is defined as either 
• IHC 3+ (defined as ≥50% of cells staining with high intensity) and/or 
• MET gene copy number ≥ 4 
For Group 5: MET amplified is defined as gene copy number ≥ 5 
For Phase Ib part, the participant will be able to proceed with study specific screening 
procedures if either 
• Activating mutations L858R and/or ex19del are documented locally AND the central 
laboratory confirms that sufficient tumor sample has been received to perform the 
EGFRT790M mutation and/or MET dysregulation testing or 


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• Activating mutations L858R and/or ex19del are documented locally AND EGFRT790M 
mutational and MET statuses have been determined by the appropriate analysis methods at 
the local laboratory. 
Resistance mechanisms EGFRT790M and MET dysregulation: Phase II 
All participants must have sufficient tumor samples (newly obtained or archival) available for 
EGFRT790M and MET statuses determination by Novartis designated central laboratory on a 
biopsy collected: 
• At or any time after progression on prior line of EGFR TKI for Group 1 (EGFRmut, any 
T790M, any MET, 2/4L antineoplastic, EGFR TKI resistant); 
• At any time for Group 2 (EGFRmut, de novo T790M, any MET, 1/3L antineoplastic, EGFR 
TKI naïve) and Group 3 (EGFRmut, T790M negative, any MET, 1L antineoplastic); 
• At any time in treatment-naïve participants or at/or any time after progression on the last 
treatment line for advanced disease for Group 4 (EGFRmut, any T790M, any MET, 1L 
(treatment naïve) 2-3L antineoplastic); if biopsy is not available after last treatment, the 
most recent available archival biopsy should be provided; 
• At or any time after progression on prior line of EGFR TKI for Group 5 (EGFRmut, T790M-, 
MET GCN≥5, 2L, EGFR TKI resistant). 
Participants in Phase II will be able to proceed with main informed consent form signature and 
study specific screening procedures if activating mutations L858R and/or ex19del analysis 
results are documented locally AND sufficient tumor samples have been submitted to the 
central laboratory for EGFRT790M and MET statuses determination. 
In the Phase II, MET dysregulation is defined as either: 
• IHC 3+ (defined as ≥50% of cells staining with high intensity) and/or 
• MET gene copy number ≥ 4 
In Phase II Group 5, MET amplified is defined as MET gene copy number (GCN) ≥ 5. 
Note: Participants with prior documentation of EGFR mutation and/or MET dysregulation 
testing from the Novartis designated central laboratory using the same prescreening tests used 
in this protocol (i.e. being re-prescreened or coming from another Novartis study) are 
potentially eligible. Repeat tumor biopsy or additional archival tumor may not be required for 
these participants provided the central laboratory confirms adequate tumor tissue remains for 
the required study analyses. 
However, if there is not enough residual tissue at the central laboratory to perform all required 
study analyses additional material from an archival tumor biopsy (preferably the same) will be 
requested. 
In Phase II Group 5, MET amplification (GCN≥5) status can be determined per local laboratory 
result (see Section 5.2) as long as an adequate amount of tumor tissue (archived or if not 
available, newly obtained biopsy sample) is available at the time of enrollment for submission 
for retrospective central assessment of MET gene amplification status using a validated FISH 
test at the Novartis-designated laboratory. MET amplification testing by FISH is preferred and 
results from other tissue-based molecular testing methods, such as next generation sequencing 




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All screening evaluations will be performed within 28 days prior to Treatment Day 1. 
HBV/HCV tests will be performed by a local laboratory for the Phase Ib part and by a central 
laboratory for the Phase II part. HBV/HCV test results should be available prior to the first dose 
of study treatment (capmatinib + nazartinib). Participants with positive baseline hepatitis B 
results have to start antiviral treatment 1 to 2 weeks prior to the first dose of study treatment 
(capmatinib + nazartinib) and need to be monitored with HBV-DNA every 4 weeks (or more 
frequently if clinically indicated). Participants with HC Ab positive or history of hepatitis C 
infection should be monitored every 8 weeks (or more frequently if clinically indicated) with 
HCV-RNA. 
Eligibility Check 
For participants enrolled in the Phase II part of the study, once all screening procedures are 
completed, an eligibility checklist must be completed via IRT by the investigator or designee 
prior to receiving the first dose of study treatment. Please refer to and comply with the detailed 
guidelines in the IRT manual. 
After the eligibility has been checked and confirmed that the participant is eligible for the trial, 
then the participant can be enrolled into the study. 
A participant who has a laboratory test result or an ECG finding that does not satisfy the 
entrance criteria may have the test(s) repeated. These test(s) may be repeated as soon as the 
investigator believes the re-test result(s) is/are likely to be within the acceptable range to satisfy 
the entrance criteria. If re-tests are performed during the 28-days screening period, the 
participant will not be required to sign another ICF, and the original participant ID number 
assigned by the investigator will be used. In the event that the laboratory test(s) cannot be 
performed during the original screening period of 28 days, or the re-test(s) do not meet the 
entrance criteria, or other eligibility criteria have changed and are not met anymore, the 
participant is considered a screen failure, and must be discontinued from the study. Participants 
who met all eligibility criteria but fail to be started on treatment as scheduled may also be re-
screened, provided the participant was not registered previously in the CRF as having entered 
the Treatment Period. 
A new ICF will need to be signed if the investigator chooses to re-screen the participant after a 
participant has screen failed. 
All required screening activities must be performed when the participant is re-screened for 
participation in the study. An individual participant may only be re-screened once for the study. 
Once the number of participants screened and enrolled is likely to ensure target enrollment, the 
Sponsor may close the study to further screening. In this case, the participants who screen failed 
will not be permitted to re-screen. 
If a participant fails screening but is re-screened, the participant must be re-screened using the 
same participant number. 
All eligibility criteria must be re-checked, based on the most recent data available, and met prior 
to enrollment of the participant into the study. 


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If the re-screening is successful, the following information should be collected in the CRF: 
• Date the study informed consent was first signed. 
• All assessments done during the first screening period. 
• All assessments repeated during the re-screening period (e.g. ECG, lab). 
• Updated information as per latest status during the re-screening period e.g. Medical history, 
diagnosis and extent of cancer. 
• Adverse events based on the date of re-consent. 
7.1.2.1 
Information to be collected on screening failures 
Participants who sign the molecular pre-screening ICF, or the molecular pre-screening ICF and 
the main ICF, but fail to be started on study treatment for any reason will be considered a screen 
failure. 
The reason for molecular pre-screening failure or screening failure will be entered on the 
Screening Phase Disposition Page. 
For all participants except particpants in Phase II Group 5, the demographic information, 
informed consent, and Inclusion/Exclusion pages must also be completed for Screen Failure 
participants. 
For participants in Phase II Group 5 the following eCRF pages must be completed for screening 
failure participants: 
• EGFR and T790M status as per participant’s record 
• Information on prior local testing for MET amplification status (if available) 
• Tumor samples collection (archival or newly obtained) for central confirmation of MET 
amplification status and T790M status (if local T790M status is not available) 
• NSCLC diagnosis and extent of disease  
• Date of diagnosis and stage of NSCLC 
• Site of active disease 
• Characteristics of disease 
• 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 SAE during the Screening Phase (see Section 8 for SAE 
reporting details). For molecular pre-screening failures, only SAEs possibly related to a study 
procedure will be reported. 


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7.1.2.2 
Participant demographics and other baseline characteristics 
Data to be collected will include general participant demographics, relevant medical history and 
current medical conditions, diagnosis and extent of tumor, details of prior anti-neoplastic 
treatments, HBV and HCV status, and any other assessments that are done for the purpose of 
determining eligibility for inclusion in the study. All medications and significant non-drug 
therapies (including herbal medicines, physical therapy and blood transfusions) taken within 4 
weeks prior to first dose of study drug must be recorded on the eCRF. Smoking history will be 
recorded on the eCRF at screening. 
7.1.3 
Treatment period 
A treatment cycle is defined as 28 days (4 calendar weeks) for the purposes of scheduling 
procedures and evaluations. Please refer to Table 7-1 and Table 7-2 for details of the timing of 
required assessments and Section 7.1 for visit windows. 
Participants will be treated until participant experiences unacceptable toxicity, progressive 
disease and/or treatment is discontinued at the discretion of the investigator or withdrawal of 
consent/opposition 
to 
use 
data/biological 
samples 
as 
described 
in  
Section 7.1.5. 
7.1.4 
Discontinuation from study treatment and from study 
Participants may voluntarily discontinue from the study treatment for any reason at any time. If 
a participant decides to discontinue from the study treatment, the investigator should make a 
reasonable effort (e.g. telephone, e-mail, letter) to understand the primary reason for this 
decision and record this information in the participant’s chart and on the appropriate CRF pages. 
They may be considered withdrawn/opposition to use data/biological samples, if they state an 
intention to withdraw/opposition to use data/biological samples, fail to return for visits, or 
become lost to follow-up for any other reason. 
The investigator must discontinue study treatment for a given participant if he/she believes that 
continuation would be detrimental to the participant’s well-being. 
Discontinuation from study treatment is required under the following circumstances: 
• Adverse events and laboratory abnormalities meeting criteria for study treatment 
discontinuation: refer to Section 6.3. 
• Pregnancy 
• Interruption of one of the study drugs for 21 consecutive days or more, regardless of reason 
for study drug interruption 
• Use of prohibited treatment, refer to Appendix 4. 
• Any other protocol deviation that results in a significant risk to the participant’s safety. 
Participants who discontinue from study treatment agree to return for the end of treatment and 
follow-up visits indicated in the Assessment Schedule (refer Section 7). In addition, before a 
new anti-neoplastic therapy is initiated for a participant, it is strongly recommended to perform 
a tumor assessment. If they fail to return for these assessments for unknown reasons, every 
effort (e.g. telephone, email, letter) should be made to contact them as specified in Section 7.1.7. 


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For Phase II, the investigator must also contact the IRT to register the participant’s 
discontinuation from study treatment. 
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason.  
7.1.4.1 
Replacement policy 
Phase Ib part: 
Participants will not be replaced on study. However, if a participant is considered as non-
evaluable for the Dose Determining Set (DDS), enrollment of a new participant to the current 
cohort will be considered if there is less than the required number of evaluable participants. 
Enrollment of new participants may be considered until at least the minimum number (3) or at 
most the maximum number (6) of evaluable participants is achieved within the cohort. 
Minimum and maximum numbers of evaluable participants per cohort are defined in 
Section 6.2.3. 
Phase II part: 
During the Phase II part no replacements will be needed. 
7.1.5 
Withdrawal of informed consent/Opposition to use data/biological 
samples 
Participants may voluntarily withdraw consent to participate in the study/make opposition to 
use data/biological samples for any reason at any time. 
Withdrawal of consent/opposition to use data/biological samples occurs when a participant: 
• explicitly requests to stop use of their biological samples and/or data (opposition to use 
participant’s data and biological samples) 
and 
• no longer wishes to receive study treatment 
and 
• does not want any further visits or assessments (including further study-related contacts). 
This request should be in writing (depending on local regulations) and recorded in the source 
documentation. 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation, including processing of biological samples that has already 
started at time of consent withdrawal/opposition. No new Personal Data (including biological 
samples) will be collected following consent withdrawal/opposition. If a participant  withdraws 
consent, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) to 
understand the primary reason for this decision and record this information. 
Where consent to the use of Personal and Coded data is not required in a certain country's legal 
framework, the participant therefore cannot withdraw consent. However, they still retain the 
right to object to the further collection or use of their Personal Data. 


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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 
communication or follow up. 
If the participant agrees, a final evaluation at the time of the participant’s consent 
withdrawal/opposition should be made as detailed in the assessment table (refer to Section 7). 
7.1.6 
Follow-up for safety evaluations 
30-day follow-up 
All participants must have safety evaluations for 30 days after the last dose of investigational 
drug(s). At the end of this period, the investigator should assess and discuss with the participant 
any AE observed/concomitant medication taken since discontinuation of study treatment. This 
can be done via a phone contact. 
Data collected should be added to the Adverse Events CRF and the Concomitant Medications 
CRF. Newly introduced antineoplastic therapies will be captured on the 'Antineoplastic 
therapies since discontinuation of study treatment' eCRF page. 
Participants whose treatment is permanently discontinued due to an AE (clinical or based on 
abnormal laboratory value) must be followed until resolution or stabilization of the event, 
whichever comes first. In case of an abnormal laboratory value, blood tests should be repeated 
until resolution or stabilization. 
Post-treatment follow-up 
Any participant who discontinues from study treatment for any reason (except for death, disease 
progression, lost to follow-up, consent withdrawal/opposition or study termination) will 
continue to have tumor assessments performed every 8 weeks in the follow-up period until 
disease progression, death, lost to follow-up, end of study (Last Patient Last Visit, see 
Section 4.3), or withdrawal of consent/opposition to use data/biological samples. 
Antineoplastic therapies since discontinuation of study drug will be collected during this 
follow-up period. 
Survival follow-up 
Upon completion of the 30-day follow-up or disease progression follow-up, all participants 
except those who withdrew consent for follow-up as a result of participant decision, or were 
lost to follow-up, will be followed for survival every 3 months (telephone call) until death or 
until the end of the study (Last Patient Last Visit, see Section 4.3). Participant’s survival status 
may be collected via a phone call. 
This visit does not apply for participants in Phase II Group 5. 
7.1.7 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue from study treatment or discontinue from study or withdraw 


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consent /oppose to the use of their data/biological samples, the investigator should show "due 
diligence" by contacting the participant, family or family physician as agreed in the informed 
consent and 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 lost to 
follow-up until due diligence has been completed. Participants lost to follow-up should be 
recorded as such on the appropriate Disposition eCRF. 
7.2 
Assessment types 
7.2.1 
Efficacy assessments 
Tumor response will be determined locally according to Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 (Appendix 1). 
Tumor response evaluations will be determined by the local investigators, based on RECIST 
1.1. Imaging data will be centrally collected, checked for quality and stored for possible 
independent review by an imaging CRO designated by Novartis. Independent tumor response 
evaluations would then be determined according to the Novartis guideline (Appendix 1), based 
on RECIST 1.1. For Groups 1 to 4, the results of the central BIRC evaluations may be used for 
secondary analyses purposes. 
CT/MRI scans will be performed at baseline within 28 days (preferably 7 days) before start of 
treatment and subsequently every 8 weeks from start of Cycle 3 until progression of disease and 
every 12 weeks from Cycle 13 Day 1 until progression of disease. See Table 7-3 for details. 
CT/MRI scan will be performed at EOT if not conducted within 30 days prior to EOT. Disease 
progression follow-up should be performed as described in Section 7.1.6. Depending on 
regulatory requirements it is allowed to have the EOT scan performed within an extended time 
frame but not later than 8 weeks from the last CT scan. 
For participants in Phase II Group 5 entering the extension treatment period, a new baseline 
assessment should be performed no more than 28 days before the start of combination therapy. 
If the scan confirming disease progrogression on capmatinib monotherapy occurs within 28 
days of the first dose of combination therapy, this scan may be used as the baseline scan for 
combination therapy. 
After baseline, all assessments should be performed within ±7 days of the scheduled day of 
assessment. Imaging evaluations subsequent to an off-schedule confirmatory scan should be 
performed according to the original assessment schedule. The same method of assessment and 
the same technique should be used to characterize each individual and reported lesion at 
baseline and during follow up. 
If at baseline a participant has a medical contraindication to CT i.v. contrast or develops a 
contraindication during the trial, a non-contrast CT of chest plus contrast-enhanced MRI of 
abdomen is acceptable. 
Participants with clinical evidence of bone metastases must have a whole body bone scan at 
baseline per local institutional practice (e.g., Tc99m bone scan, NaF positron emission 
tomography (PET) or whole body bone MRI). Lesions identified on the whole body bone scan 
at baseline, which are not visible on the chest and abdomen CT (or MRI) scan should be imaged 


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at baseline and followed at subsequent scheduled visits using localized CT, MRI or X-ray. After 
baseline, whole body bone scans need not be repeated, unless clinically indicated. 
Skin lesions present at baseline should be documented using color photography, including a 
ruler, so that the size of the lesion(s) can be determined from the photograph. Skin photographs 
should be continued at subsequent tumor assessments for any lesions that were photographed 
at screening. 
Baseline brain CT or MRI will be mandated for all participants prior to study treatment. 
Subsequent brain scans should only be conducted if brain lesions are documented at baseline 
for eligible participants or in participants that develop symptoms indicative of brain metastases. 
All CRs and PRs must be confirmed by a second assessment not earlier than 4 weeks after the 
criteria for response are first met. 
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. 
PET/CT may be used only if the CT is of similar diagnostic quality as a CT performed without 
PET, including the utilization of oral and intravenous contrast media. 
All participants discontinuing from the study for PD must have their disease progression 
documented by radiologic evaluation. In cases of clinically-evident disease progression, all 
efforts should be made to perform a radiologic evaluation. 
Participants with symptoms of rapidly progressing disease without radiological evidence will 
be classified as progression only when clear evidence of clinical deterioration is documented 
and/or participant discontinued due to ‘Disease progression’ or death due to study indication. 
Table 7-3 
Imaging collection plan 
Procedure 
Screening/ Baseline 
During Treatment/Follow-
up 
EoT/ Re-baseline 
CT or MRI 
with contrast 
enhancement 
(Chest and 
Abdomen) 
Mandated 
Mandated, every 8 weeks 
(±7 days) 
Every 12 weeks (±7 days) 
from Cycle 13 Day 1. 
>28 days from last 
assesment 
Whole body bone 
scan 
If clinically indicated 
If clinically indicated 
If bone metastasis is 
clinically suspected 
Brain CT or MRI 
Mandated 
If brain positive at screening 
every 8 weeks (±7 days) 
Every 12 weeks (±7 days) 
from Cycle 13 Day 1. 
If brain negative at 
screening, as clinically 
indicated. 
If brain positive at 
screening 
Or as clinically 
indicated if brain 
negative 
Bone X-ray, CT or 
MRI 
(bone lesions only) 
If lesions on bone scan that 
are not visible on the chest 
and abdomen CT/MRI 
If bone lesions at screening 
every 8 weeks (±7 days) 
Every 12 weeks (±7 days) 
from Cycle 13 Day 1. 
If lesions not visible 
on CT/MRI chest and 
abdomen 


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Procedure 
Screening/ Baseline 
During Treatment/Follow-
up 
EoT/ Re-baseline 
Skin color 
photography (skin 
lesions only) 
Mandated if skin lesions at 
screening 
If skin lesions at screening 
every 8 weeks (±7 days) 
Every 12 weeks (±7 days) 
from Cycle 13 Day 1. 
If skin lesions present 
CT or MRI of other 
tumor sites (e.g., 
pelvis) 
If clinically indicated 
If lesions identified at 
screening 
every 8 weeks (±7 days) 
Every 12 weeks (±7 days) 
from Cycle 13 Day 1. 
If clinically indicated 
As per Section 2.7, 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, changes 
in collection of images (e.g., change of facility or frequency) can be listed as one of the risk 
mitigation procedures. 
7.2.2 
Safety and tolerability assessments 
Safety will be monitored by assessing physical examination, vital signs, height, weight, ECOG 
performance status, laboratory evaluations, 12-lead ECG as well as collecting of the adverse 
events at every visit. For details on AE collection and reporting, refer to Section 8. 
As per Section 2.7, 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 4 weeks (+/- 1 week) 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. 
7.2.2.1 
Physical examination 
A complete physical examination will be performed as per Table 7-1 and Table 7-2 and will 
include the examination of general appearance, skin, neck (including thyroid), eyes, ears, nose, 
throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular and neurological. If 
indicated based on medical history and/or symptoms, rectal, external genitalia, breast, and 
pelvic exams will be performed. Information about the physical examination must be present 
in the source documentation. 
A short physical examination, including examination of general appearance as well as organ or 
complaint-specific, will be performed at all visits starting from Cycle 5 Day 1. 
For participants in Phase II Group 5, a targeted physical examination will be performed at all 
visits as indicated in Table 7-2 and during treatment except where a complete physical 
examination is required (see above). It will include at least the examination of general 
appearance and vital signs (respiratory rate, blood pressure [SBP and DBP] and pulse). If 
indicated based on symptoms, additional examinations 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 metastasis neurological status 
will also be evaluated at the time of radiological assessments. 


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Significant findings that were present prior to the signing of informed consent must be included 
in the Medical History page on the participant’s CRF. Significant new findings that begin or 
worsen after informed consent must be recorded on the Adverse Event page of the participant’s 
CRF. 
7.2.2.2 
Vital signs 
Vital signs (body temperature, pulse rate, blood pressure) must be performed before dosing and 
as indicated in Table 7-1 and Table 7-2 as per institutional standards. 
Vital signs should be assessed on the scheduled day, even if study treatment is being withheld. 
More frequent examinations may be performed at the discretion of the Investigator and if 
medically indicated. 
Unscheduled assessment can be performed if clinically indicated. 
7.2.2.3 
Height and weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, 
but without shoes) will be measured as indicated in Table 7-1 and Table 7-2. 
Height information will be collected at screening only. 
7.2.2.4 
Performance status 
The performance status will be assessed according to the Eastern Cooperative Oncology Group 
(ECOG) Performance Status Scale as specified in Table 7-1, Table 7-2 and Table 7-4. 
Table 7-4 
ECOG performance status 
Grade 
ECOG Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light house work, office work) 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
7.2.2.5 
Laboratory evaluations 
For the Phase Ib part, all laboratory parameters assessed for safety purposes will be evaluated 
locally, at the site. Refer to Table 7-5 for a summary of the parameters to be evaluated according 
to Table 7-1. For Phase II Group 5, all laboratory analysis will be performed locally, inclusive 
of assessment for participants' eligibility. The frequency of the assessments is indicated in 
Table 7-1 for the Phase Ib part and Table 7-2 for Phase II Group5. 
Unscheduled assessment can be performed if clinically indicated. 
For the Phase II part (Groups 1 to 4), central laboratories will be used for the analysis of 
scheduled hematology, biochemistry and other blood specimens collected as part of safety 
monitoring (as detailed in Table 7-5). The frequency of the assesments is indicated for the Phase 
II part (Groups 1 to 4) in Table 7-1. Dipstick urinalysis will be performed locally, except in the 


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case of any significant findings, a urine sample will be sent to central laboratory for further 
microscopic analysis. Laboratory values obtained prior to treatment from central laboratory will 
be used to assess participant’s eligibility. Only laboratory results from the central laboratory 
can be used to determine participant’s eligibility for the study. The time windows granted for 
laboratory evaluations are identical to the corresponding visit time windows for each visit (refer 
to Section 7.1). 
Local laboratory assessments may be performed 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 eCRF as unscheduled visit if the 
following criteria are met: 
• a treatment decision was made based on the local results, or 
• there are no concomitant central results available 
Details on the collection, shipment of samples and reporting of results by the central laboratory 
are provided to investigators in a separate [Laboratory Manual]. 
As per Section 2.7, 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 and 
protocol specified safety laboratories assessments, an alternative laboratory (local) collection 
site may be used. 
Table 7-5 
Central/local clinical laboratory parameters collection plan 
Test Category 
Test Name 
Hematology 
Hematocrit, hemoglobin, platelets, red blood cells (RBC), white blood cells (WBC), WBC 
morphology with differential (basophils, eosinophils, lymphocytes, monocytes, neutrophils) 
Chemistry 
Albumin, alkaline phosphatase, ALT (SGPT), AST (SGOT), amylase, lipase, calcium, 
chloride, magnesium, potassium, creatinine, creatinine clearance, creatine kinase, direct 
bilirubin, indirect bilirubin, total bilirubin, total protein, blood urea nitrogen or urea, uric acid, 
glucose, GGT 
Urinalysis 
Dipstick/bedside measurements for specific gravity, pH, protein, glucose, bilirubin, ketones, 
leukocytes, and blood will be performed. Any clinically significant findings on dipstick will be 
followed up with a microscopic evaluation. 
Coagulation 
Prothrombin time (PT) or international normalized ratio (INR), 
HBV and HCV 
HBsAg, HBsAb, HBcAb, HBV-DNA, HC Ab, HCV-RNA 
7.2.2.5.1 Hematology 
Hematology panel outlined in Table 7-5 will be performed as per the assessment schedule in 
Table 7-1 and Table 7-2. 
7.2.2.5.2 Clinical chemistry 
Clinical chemistry panel outlined in Table 7-5 will be performed as per the assessment schedule 
in Table 7-1 and Table 7-2. 


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7.2.2.5.3 Coagulation 
Coagulation panel outlined in Table 7-5 will be performed as per the assessment schedule in 
Table 7-1 and Table 7-2. 
7.2.2.5.4 Urinalysis 
Urinalysis panel outlined in Table 7-5 will be performed as per the assessment schedule in 
Table 7-1 and Table 7-2. 
7.2.2.5.5 HBV and HCV testing 
HBV tests outlined in Table 7-5 will be performed as per the assessment schedule in Table 7-1 
and Table 7-2. 
HCV tests outlined in Table 7-5 will be performed as per the assessment schedule in Table 7-1 
and Table 7-2. 
7.2.2.5.6 Pregnancy and assessments of fertility 
At screening (and/or Cycle 1 Day 1) a serum pregnancy test should be performed within 72 
hours before the first dose, 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 the Phase II part, serum pregnancy tests will be performed centrally. Urine pregnancy tests 
will be performed locally. 
As per Section 2.7, 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 to have serum pregnancy tests, the supply of 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. If the test result is positive, the participant should stop the intake of study drug 
and inform the investigator. A communication process should be established with the 
participant so that the Site is informed and can verify the pregnancy test results (e.g., following 
Country specific measures). 
7.2.2.6 
Cardiac assessments 
7.2.2.6.1 Electrocardiogram (ECG) 
Standard 12 lead ECGs will be performed as per the assessment schedule in Table 7-1, 
Table 7-2 and Table 7-6. 
Triplicate ECGs will be performed at all time-points during the trial. 






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Dose 
reference ID a 
(capmatinib) 
Dose 
reference ID a 
(nazartinib) 
PK Sample 
number 
(capmatinib) 
PK Sample 
number 
(nazartinib) 
Cycle 
Day 
Scheduled time (hours) 
6 
24 
23 
123 
2 
1 
8 hr (±1 hr) 
6/7 
24 
24 
124 
2 
1 
12 hr (± 1 hr) 
7/103 
24/203 
25 
125 
2 
2 
0 hr / pre-C2D2 dose b 
8 
25 
26 
126 
3 
1 
0 hr / pre-C3D1 dose b 
9 
26 
27 
127 
4 
1 
0 hr / pre-C4D1 dose b 
-- 
 
1001+c 
2001+c 
NA 
NA 
Unscheduled 
a The first dose reference ID is for last dose the participant received prior to the collection of the PK sample, while 
the second dose reference ID is for current dose 
b Take samples immediately prior to the administration of nazartinib and capmatinib 
c Unscheduled blood samples will be uniquely, sequentially numbered 1001, 1002, … or 2001, 2002, … 
7.2.3.3 
Pharmacokinetic sampling during Phase II part 
Full PK blood samples for capmatinib, nazartinib and metabolite LMI258 (nazartinib 
metabolite) will be collected on Days 1, and 2 of Cycle 1 and Cycle 2 during the Phase II part 
for the first 10 participants dosed in Group 3 (first line) and for approximately 20 participants 
in Group 4 (please refer to Table 7-.8). Pre-dose blood PK samples will be collected on Day 8 
of Cycle 1, Day 1 of Cycle 3 and Cycle 4. No PK blood samples will be collected for participants 
in Group 5. 
If a participant experiences an adverse event that fits the criteria of a SAE or DLT as determined 
by the Investigator, an unscheduled PK blood sample should be collected for measurement of 
plasma drug concentrations, unless the event occurs on the day of planned PK profile sampling 
collection. 


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Table 7-8 
Schedule of blood sample collections for capmatinib, nazartinib and 
LMI258 PK assessment during Phase II part (first 10 participants 
dosed in Group 3 and approximately 20 participants in Group 4) 
Dose reference 
ID a 
(capmatinib) 
Dose reference 
ID a 
(nazartinib) 
PK Sample 
number 
(capmatinib
) 
PK Sample 
number 
(nazartinib) 
Cycle 
Day 
Scheduled time (hours) 
11 
31 
201 
301 
1 
1 
0 hr / Pre-dose b 
11 
31 
202 
302 
1 
1 
0.5 hr (±10 minutes) 
11 
31 
203 
303 
1 
1 
1 hr (±10 minutes) 
11 
31 
204 
304 
1 
1 
2 hr (±10 minutes) 
11 
31 
205 
305 
1 
1 
4 hr (±15 minutes) 
11 
31 
207 
307 
1 
1 
8 hr (±1 hr) 
11/12 
31 
207.5 
307.5 
1 
1 
12 hr (±1 hr) 
12/110 
31/210 
208 
308 
1 
2 
0 hr / pre-C1D2 dose b 
113/13 
132/32 
209 
309 
1 
8 
0 hr / pre-C1D8 dose 
114/14 
133/33 
210 
310 
2 
1 
0 hr / pre-C2D1 dose b 
14 
33 
211 
311 
2 
1 
0.5 hr (±10 minutes) 
14 
33 
212 
312 
2 
1 
1 hr (±10 minutes) 
14 
33 
213 
313 
2 
1 
2 hr (±10 minutes) 
14 
33 
214 
314 
2 
1 
4 hr (±15 minutes) 
14 
33 
216 
316 
2 
1 
8 hr (±1 hr) 
14/15 
33 
216.5 
316.5 
2 
1 
12 hr (±1 hr) 
15/120 
33/220 
217 
317 
2 
2 
0 hr / pre-C2D2 dose b 
116/16 
134/34 
218 
318 
3 
1 
0 hr / pre-C3D1 dose b 
117/17 
135/35 
219 
319 
4 
1 
0 hr/ pre-C4D1 dose b 
-- 
 
3001+c 
4001+c 
NA 
NA 
Unscheduled 
a The first dose reference ID is for last dose the participant received prior to the collection of the PK sample, while 
the second dose reference ID is for current dose 
b Take samples immediately prior to the administration of nazartinib and capmatinib 
c Unscheduled blood samples will be uniquely, sequentially numbered 3001, 3002, … or 4001, 4002, … 
Sparse PK samples will be collected from the rest of the participants during Phase II part on 
Days 1, and 2 of Cycle 1 and Cycle 2 to assess single dose and steady-state plasma PK of 
capmatinib, nazartinib and metabolite LMI258. Please refer to Table 7-9 for PK collection 
schedule. The data may be used in conjunction with samples from dose escalation as part of a 
population pharmacokinetic assessment. 








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Table 7-10 
Biomarker sample collection plan in the Phase Ib 
Type of analysis 
Visit 
Mandatory 
/Optional 
Local/ 
Central 
analysis 
Methods 
Material 
Volume 
Active EGFR Mut. 
L858R or ex19Del 
Pre-screening 
Mandatory 
Local 
Any methods 
Biopsy collected at any time 
N/A 
MET 
Pre-screening 
Mandatory 
Local 
FISH or IHC 
Any methods 
Biopsy collected at or any time after progression on first or 
second generation EGFR TKI 
N/A 
 
Central 
FISH and/or-
IHC 
IF NO LOCAL RESULTS AVAILABLE. 
Biopsy collected at or any time after progression on first or 
second generation EGFR TKI 
Either newly obtained formalin-fixed biopsy (preferred) or 
archival tumor block or slides of a formalin fixed paraffin 
embedded (FFPE) 
Block or 5 
slides 
EGFR T790M 
Pre-screening 
Mandatory 
Local 
Qiagen 
therascreen 
OR 
Roche Cobas 
(all countries 
except USA) 
Biopsy collected at or any time after progression on first or 
second generation EGFR TKI 
N/A 
 
Central 
PCR 
IF NO LOCAL RESULTS AVAILABLE. 
Biopsy collected at or any time after progression on first or 
second generation EGFR TKI. Preferably same specimen 
than for MET. 
6 slides 
(unless 
block 
submitted 
for pre-
screening) 


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Type of analysis 
Visit 
Mandatory 
/Optional 
Local/ 
Central 
analysis 
Methods 
Material 
Volume 
cell free DNA 
• 
Screening 
or C1D1 
(pre-dose) 
• 
C3D1 and 
every third 
cycle 
• 
EOT 
Mandatory 
Central 
PCR, NGS 
and/or other 
methods 
Blood sample 
2 x 10 mL 
 
N/A: not applicable 


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Table 7-11 
Biomarker sample collection plan in the Phase II 
Type of analysis 
Visit 
Mandatory 
/Optional 
Local/ 
Central analysis 
Methods 
Material 
Volume 
Activ. EGFR Mut. 
L858R or 
Ex19Del 
Pre-
screening 
Mandatory 
Local 
Any methods 
Biopsy collected at any time 
N/A 
MET 
Pre-
screening 
Mandatory 
Central 
(Group 5: If local 
results available, 
retrospective 
central MET 
confirmation is 
required; if local 
results not 
available, central 
MET testing is 
required) 
FISH and/or IHC 
Group 5: Local 
molecluar test for 
MET 
amplification of 
GCN ≥ 5 (IHC 
not permitted) 
- Group 1: biopsy collected at or any time after progression 
on last EGFR TKI line. 
- Groups 2 and 3: biopsy collected at any time. 
- Group 4: biopsy collected at any time (if treatment-naïve) or 
at/or any time after progression on last antineoplastic 
treatment (if 2/3L participants); if biopsy is not available after 
last treatment, the most recent available archival biopsy 
should be provided. 
Either newly obtained formalin-fixed biopsy (preferred) or 
archival tumor block or slides of a formalin fixed paraffin 
embedded (FFPE) 
Group 5: Biopsy collected at or any time after progression on 
prior line of EGFR TKI 
Block or 5 
slides 
EGFR T790M 
Pre-
screening 
Mandatory 
Central 
(local results 
acceptable in 
Group 5) 
PCR 
- Group 1: biopsy collected at or any time after progression 
on last EGFR TKI line. 
- Groups 2 and 3: biopsy collected at any time. 
- Group 4: biopsy collected at any time (if treatment-naïve) or 
at/or any time after progression on last antineoplastic 
treatment (if 2/3L participants); if biopsy is not available after 
last treatment, the most recent available archival biopsy 
should be provided. 
Preferably same specimen than for MET. 
Group 5: At or any time after progression on prior line of 
EGFR TKI (if local result available, submit at screening or 
C1D1) 
6 slides 
(unless 
block 
submitted 
for pre-
screening) 
Retrospective 
MET  
Screening 
or C1D1 
(pre-dose) 
Mandatory 
Central  
(Group 5 only: if 
local results 
available) 
FISH or other 
methods 
For Group 5 only: IF LOCAL RESULTS AVAILABLE. 
Biopsy collected at or any time after progression on first or 
second generation EGFR TKI.  
Block or 5 
slides 


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Type of analysis 
Visit 
Mandatory 
/Optional 
Local/ 
Central analysis 
Methods 
Material 
Volume 


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Type of analysis 
Visit 
Mandatory 
/Optional 
Local/ 
Central analysis 
Methods 
Material 
Volume 
cell free DNA 
Screening 
or C1D1 
(pre-dose) 
C3D1 and 
every third 
cycle 
EOT 
Mandatory 
Central 
PCR, NGS 
and/or other 
methods 
Blood sample 
Not applicable for Group 5 
2 x 10 mL 
 
N/A: not applicable 


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8 
Safety monitoring, reporting and committees 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An adverse event 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 whose EGFR and/or MET statuses are unknown and who sign the molecular 
pre-screening ICF, AEs which occur after signature of this consent will only be captured if they 
meet the definition of serious as outlined in Section 8.2 and are reported to be causally related 
with study procedures (e.g. an invasive procedure such as biopsy). Once the main study ICF is 
signed, all AEs per the descriptions below will be captured in the Adverse Event CRF. 
Participants whose EGFR mutation and MET statuses are known will sign the main study ICF. 
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s). 
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the participant’s CRF. Adverse event monitoring 
should be continued for at least 30 days (or 5 half-lives, whichever is longer) following the last 
dose of study treatment. Adverse events (including lab abnormalities that constitute AEs) 
should be described using a diagnosis whenever possible, rather than individual underlying 
signs and symptoms. When a clear diagnosis cannot be identified, each sign or symptom should 
be reported as a separate Adverse Event. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0. 
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE Grade 5 (death) will 
not be used in this study (but is collected as a seriousness criterion); rather, information about 
deaths will be collected though a Death form. 
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 


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by the participant (participant) during the screening process or between visits, or through 
physical examination, laboratory test, or other assessments. As far as possible, each adverse 
event must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompagnied by the following information: 
a. The severity grade (CTCAE Grade 1-4) 
b. Its duration (Start and end dates) and the outcome must be reported 
c. Its relationship to the study treatment and other investigational 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. 
d. Action taken with respect to study or investigational treatment (dose not changed, dose 
Reduced/increased, drug interrupted/permanently discontinued) 
e. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
f. Outcome 
(not 
recovered/not 
resolved, 
recovered/resolved, 
recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown) 
g. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1 
and which seriousness criteria have been met. 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the study treatment, the interventions required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors), 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 (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 
Investigator's Brochure (IB). 


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8.1.2 
Laboratory test abnormalities 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events CRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such. 
8.1.3 
Adverse events of special interest 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program. 
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. AESIs are discussed in detail in the [capmatinib Investigator’s Brochure] and [nazartinib 
Investigator’s Brochure]. 
8.2 
Serious adverse events 
8.2.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
Note that hospitalizations for the following reasons should not be reported as serious adverse 
events: 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 


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• Social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given 
above is not a serious adverse event 
8.2.2 
SAE Reporting 
For participants with unknown EGFR and/or MET statuses and who sign the molecular pre-
screening ICF, SAE collection will start upon signing the molecular pre-screening ICF. SAEs 
will only be reported if the event is suspected to be causally related to a study procedure as 
assessed by the investigator (e.g. an invasive procedure such as biopsy). SAEs will be followed 
until resolution or until clinically relevant improvement or stabilization. If the main ICF is not 
signed (molecular screen failure), SAE collection ends 30 days after the last study related 
procedure. 
Serious adverse events considered by the investigator to be possibly related to a biopsy 
procedure will be indicated as such in the AE eCRF. This information will be followed-up for 
30 days after the biopsy procedure. 
For participants with known EGFR and/or MET statuses who sign the main study ICF, SAE 
collection starts at time of main study informed consent whether the participant is a screen 
failure or not. 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days after the participant has stopped study 
treatment must be reported to Novartis safety immediately, without undue delay, but under no 
circumstances later than within 24 hours of obtaining knowledge of the events (Note: if more 
stringent, local regulations regarding reporting timelines prevail). 
Any SAEs experienced after this 30 days period (or 5 half-lives, whichever is longer) should 
only be reported to Novartis safety if the investigator suspects a causal relationship to the study 
treatment, unless otherwise specified by local law/regulations. Recurrent episodes, 
complications, or progression of the initial SAE 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 should be reported 
separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form immediately, without undue delay, but under 
no circumstances later than within 24 hours obtaining knowledge of the events to Novartis 
safety (Note: if more stringent, local regulations regarding reporting timelines prevail). Detailed 
instructions regarding the submission process and requirements for signatures are to be found 
in the investigator folder provided to each site. 


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Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the participant continued or withdrew from study participation. 
If the SAE is not previously documented in the [capmatinib Investigator’s Brochure] and 
[nazartinib Investigator’s Brochure] or Package Insert (new occurrence) and is thought to be 
related to the Novartis study treatment, an oncology Novartis Chief Medical Office and Patient 
Safety (CMO & PS) department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN), to inform all investigators involved in any study with the same drug that this 
SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with Directive 
2001/20/EC or as per national regulatory requirements in participating countries. 
8.3 
Pregnancy reporting 
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 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 investigational 
treatment and any pregnancy outcome. Any SAE experienced during pregnancy must be 
reported on the SAE Report Form. 
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. 
8.4 
Warnings and precautions 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided [capmatinib 
Investigator’s Brochure] and [nazartinib Investigator’s Brochure]. Additional safety 
information collected between IB updates will be communicated in the form of Investigator 


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Notifications. This information will be included in the participant informed consent and should 
be discussed with the participant during the study as needed. 
8.5 
Data Monitoring Committee 
An independent data monitoring committee will not be formed for this study. 
For the Phase Ib part of the study 
Novartis will host investigator teleconferences on a regular basis during the study. Further, 
Novartis and the investigators will meet at the end of each treatment cohort to discuss and 
evaluate all of the gathered safety data. At the dose escalation teleconference the clinical course 
(safety information including both DLTs and all CTCAE Grade 2 or higher toxicity data during 
the first cycle of treatment, and PK data) for each participant in the current dose cohort will be 
described in detail. Updated safety data on other ongoing participants, including data in later 
cycles, will be discussed as well. 
Dose escalation decisions will be based on a clinical synthesis of all relevant available data and 
not solely on DLT information. Selection of the actual dose for the next cohort of participants 
will be guided by the BLRM’s (with EWOC) recommendation, and a medical review of relevant 
clinical, PK and laboratory data. Novartis and the investigator parties must reach a consensus 
on whether to declare MTD, escalate the dose any further, or whether to de-escalate and/or 
recruit an additional cohort of participants at the current dose level (see ). 
Phase II part of the study 
This is a single arm trial (i.e. no comparator arm) and there is no a priori information as per the 
FDA Guidance of “situations in which safety concerns may be unusually high” or the participant 
population being studied are “potentially fragile population such as children, pregnant women 
or the very elderly, or other vulnerable populations, such as those who are terminally ill or of 
diminished mental capacity.” Thus, an independent data monitoring committee will not be 
constituted for the Phase II part of this study. 
The Novartis clinical team will review the safety data on a regular basis. A review of the safety 
data and assessment of futility, based on the calculated Bayesian probability of success (PoS) 
will be performed at the interim analysis of Group 3 (first line) by the Novartis clinical trial 
team and shared with the investigators in a data review meeting. 
At the time of the interim analysis for Group 3, the best overall response for each participant 
will be derived from the overall lesion response assessments performed by the Investigator. 
These will be used to calculate the overall response rate for the respective group and a Bayesian 
analysis will be performed to estimate the PoS of the trial given the current data (see Section 
10.9 for details). 
It is envisioned that the team may make three types of recommendations at the interim analysis, 
namely: 
• No safety or efficacy issues, ethical to continue the study group as planned 
• PoS is too small and the study group is terminated due to lack of significant activity 
• Serious safety concerns precluding further treatment in the study group, regardless of 
efficacy. 


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At the time of the interim analysis for Group 5, the response for each participant will be derived 
from the overall lesion response assessments performed by the Investigator. These will be used 
to calculate the ORR and a Bayesian analysis will be performed to estimate the POS of the trial 
given the current data (see Section 10.9 for details). 
9 
Data collection and database management 
9.1 
Data confidentiality 
Information about study participants will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed participant authorization informing the 
participant of the following: 
• What protected health information (PHI) will be collected from participants in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research participant to revoke their authorization for use of their PHI. 
In the event that a participant revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of 
participant authorization. For participants that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect follow-up safety information (e.g. has 
the participant experienced any new or worsened AEs) at the end of their scheduled study period. 
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training. 
Prior to entering key sensitive personally identifiable information (participant Initials and Date 
of Birth, where local regulations require it), the system will prompt site to verify that this data 
is allowed to be collected. If the site indicates that country rules or ethics committee standards 
do not permit collection of these items, the system will not solicit participant Initials. Year of 
birth will be solicited (in the place of exact date of birth) to establish that the participant satisfies 
protocol age requirements and to enable appropriate age-related normal ranges to be used in 
assessing laboratory test results. 
9.2 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of participant records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. 


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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 recorded on CRFs must be traceable to source documents in the 
participant's file. The investigator must also keep the original signed informed consent form (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 CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria and documentation 
of SAEs. Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. 
9.3 
Data collection 
For studies using EDC, the designated investigator staff will enter the data required by the 
protocol into the eCRF. The eCRFs have been built using fully validated secure web-enabled 
software that conforms to 21 CFR Part 11 requirements. Investigator site staff will not be given 
access to the EDC system until they have been trained. Automatic validation programs check 
for data discrepancies in the eCRFs and allow modification or verification of the entered data 
by the investigator staff. 
In addition, data entered into the IRT for drug assignment and participant identifiers (i.e. date 
of birth, gender and participant’s ID) will be transferred electronically to Novartis as described 
in the Data Transfer Specifications for the designated IRT vendor. 
The Principal Investigator is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner. 
9.4 
Database management and quality control 
For studies using eCRFs, Novartis personnel (or designated CRO) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system. Designated investigator site staff are 
required to respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
PK and those applicable biomarker samples, clinical laboratory samples and imaging data will 
be processed centrally and the results will be sent electronically to Novartis. 
For EDC studies, after database lock, the investigator will receive copies of the participant data 
for archiving at the investigational site. Data collected by the third parties (such as imaging, 
safety laboratories, biomarkers and PK) will be sent electronically to Novartis. 
For Phase II participants, data about all study treatments dispensed to the participant and all 
IRT assigned dosage changes will be tracked using an Interactive Response Technology. The 


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system will be supplied by a vendor(s), who will also manage the database. The data will be 
sent electronically to Novartis personnel. 
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. 
10 
Statistical methods and data analysis 
Study data will be analyzed by Novartis and/or a designated contract research organization 
(CRO). Any data analysis carried out independently by the investigator must be submitted to 
Novartis before publication or presentation. 
Study data will be summarized with respect to demographic and baseline characteristics, 
efficacy observations and measurements, safety observations and measurements, and 
pharmacokinetics measurements. Categorical data will be presented as contingency tables 
(frequencies and percentages). For continuous data summary statistics including mean, standard 
deviation, median, minimum, and maximum will be presented. In addition, individual listings 
of all raw data captured in the clinical database will be presented by treatment group and 
participant. All data from participating centers in this protocol will be combined, so that an 
adequate number of participants will be available for analysis. 
The following rules will be followed for reporting results unless stated otherwise: 
• Phase Ib part: Participants treated during the dose escalation with the same initial dose 
level and schedule of nazartinib and of capmatinib will be pooled into a single treatment 
group. All summaries, listings, figures and analyses will be performed by treatment group 
(unless otherwise specified) 
• Phase II part: Participants will be reported according to the group to which they were 
assigned at baseline based on their mutation status and prior lines of systemic antineoplastic 
therapies. All summaries, listings, figures and analyses will be performed by group.  
The primary analysis for the groups 1 to 4 will be performed when participants enrolled in 
each respective group have completed at least 6 cycles of treatment or discontinued prior to 
that time. Any additional data for participants continuing to receive study treatments past 
the data cut-off date for the primary analysis in each of the groups will be reported in an 
interim CSR when all participants from Phase Ib and Groups 1 to 4 have discontinued the 
study. Note: due to mutation rarity and to allow for enrollment completion within a 
reasonable timeframe, enrollment in the Phase II Group 2 will stop once recruitment is 
completed 
in 
the 
other 
Phase 
II 
groups. 
The primary analysis for Group 5 will be performed when participants in the group have 
completed at least 6 cycles of capmatinib monotherapy or discontinued capmatinib 
monotherapy prior to that time. If participants are ongoing at that time, a further final CSR 
might be prepared. 
Information on modified or missed visits or assessments during a public health emergency as 
declared by local or regional authorities (see Section 2.7), i.e., pandemic, epidemic or natural 
disaster, will be collected to assess the impact on the analysis. 


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10.1 
Analysis sets for Phase Ib and Phase II Groups 1 to 4 
The following analysis sets which will be derived prior to database lock will be used. If required, 
additional analysis sets will be defined in the Statistical Analysis Plan (SAP). 
10.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all participants who have received at least one dose of 
either capmatinib or nazartinib. Participants will be analyzed according to the planned treatment 
they have been assigned to. The FAS will be used for all listings of raw data. 
10.1.2 
Safety Set 
The Safety Set includes all participants who received at least one dose of study treatment (i.e. 
at least one dose of any component of the study treatment). Participants will be analyzed 
according to the study treatment (regimen) they actually received. A precise definition of 
“actually received” will be added in the Statistical Analysis Plan (SAP). 
10.1.3 
Per-Protocol Set 
The Per-Protocol Set (PPS) will consist of a subset of participants from the FAS who have an 
adequate tumor assessment at baseline, are evaluable for efficacy, and no major protocol 
deviations. A participant will be considered evaluable for efficacy if they have at least one post 
baseline response not assessed as 'unknown' or 'not assessed'. 
All major protocol deviations leading to exclusion from the PPS will be detailed in the SAP. 
Participants will be classified according to treatment as assigned. 
The PPS will be used in the Phase II part of the study only and will define the participants used 
in the sensitivity analysis of the primary endpoint (see ). If the PPS and the FAS are identical, 
then analyses described using the PPS below will not be performed. 
10.1.4 
Dose-determining set 
The DDS consists of all participants from the safety analysis set in the Phase Ib dose escalation 
part who either meet the minimum exposure criterion and have sufficient safety evaluations, or 
have experienced a DLT during Cycle 1. This constitutes an evaluable participant for the 
determination of MTD. 
A participant is considered to have met the minimum exposure criterion if he/she has received 
at least 75% of the planned doses of nazartinib and of capmatinib in the first 28 days of dosing, 
i.e. at least 21 out of the 28 full planned daily doses of nazartinib (q.d.) and at least 21 out of 
the 28 full planned daily doses of capmatinib (b.i.d.). Participants who do not experience DLT 
during the first cycle are considered to have sufficient safety evaluations if they have been 
observed for ≥ 28 days following the first dose, and are considered by both Novartis and 
Investigators to have enough safety data to conclude that a DLT did not occur. 
10.1.5 
Pharmacokinetic analysis set for capmatinib /nazartinib 
The pharmacokinetic analysis set (PAS) for capmatinib (for nazartinib, and for LMI258, 
respectively) includes all participants who provide at least one evaluable PK concentration. 


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For a PK concentration to be evaluable, all of the following conditions need to be met: 
• Participants have taken at least one planned dose of capmatinib and nazartinib 
• For PK samples taken on or after Cycle 1 Day 8, participants have taken the planned dose 
of capmatinib and nazartinib, for at least 3 consecutive days prior to sampling for 
capmatinib and for at least 5 consecutive days prior to sampling for nazartinib 
• Participants haven’t vomited within 4 hours after the dosing of capmatinib (respectively 
nazartinib) on PK sample collection days 
• For pre-dose samples on or after Cycle 1 Day 8, have the pre-dose sample collected before 
the next dose administration and 9 to 15 hours after the last dose administration of 
capmatinib and 20 to 28 hours after the last dose administration of nazartinib 
Note: the second part of the condition (at least 9 to 15 hours, at least 20 to 28 hours, 
respectively) can only be evaluated for Phase II participants due to data collection problems 
in Phase Ib. 
• Participant did not take prohibited medicines that could affect capmatinib or nazartinib 
PK/exposure 
• Participant took capmatinib and nazartinib under the assigned prandial conditions on PK 
sample collection days 
The PAS will be used for summaries of PK concentration data, and PK parameters. 
10.1.6 
Full pharmacokinetic analysis set for capmatinib /nazartinib 
The Full pharmacokinetic analysis set (Full PAS) for capmatinib (for nazartinib and for LMI258, 
respectively) includes all PAS participants for capmatinib (for nazartinib and for LMI258, 
respectively) who provide at least one evaluable PK profile for capmatinib (respectively 
nazartinib). 
A PK profile is considered evaluable for capmatinib (for nazartinib and for LMI258 respectively) 
if all of the following conditions are satisfied: 
• Participant received at least one dose of the planned treatments of capmatinib and nazartinib 
• Participant provided at least one valid primary PK parameter (AUCtau or Cmax) on either 
Cycle 1 Day 1, Cycle 1 Day 15 (as applicable) or Cycle 2 Day 1 


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PK parameters of capmatinib, nazartinib, or LMI258 may be excluded on an individual basis 
depending on the evaluation of the concentration-time profile. These participants will be 
identified by the clinical pharmacologist at the time of analysis and the reason for such 
exclusions will be provided. 
10.2 
Analysis sets for Phase II Group 5 
10.2.1 
Full Analysis Set 
The Full Analysis Set comprises all participants enrolled into Group 5 who have been treated 
with at least one dose of capmatinib monotherapy. Demographics and other baseline 
characteristics will be summarized based on the FAS. 
10.2.2 
Evaluable Analysis Set 
The Evaluable Analysis Set (EAS) is a subset of the FAS and includes all participants treated 
with at least one dose of capmatinib monotherapy, who have measurable disease at baseline, 
and centrally confirmed MET amplification. This analysis set will be used for the primary 
efficacy endpoint and the analysis of the secondary efficacy endpoints at the interim and 
primary analysis. 
10.2.3 
Combination Analysis Set  
The Combination Analysis Set (Combo Analysis Set, CAS) is a subset of the FAS and includes 
all participants who are treated with capmatinib monotherapy, receive at least one dose of the 
capmatinib + nazartinib combination therapy, have a baseline tumor assessment prior to the 
start of the combination treatment dosing, and have centrally confirmed MET amplification. In 
case both stages of the study are completed, this analysis set will be used for the analysis of the 
efficacy of the capmatinib plus nazartinib combination therapy for Group 5. 
10.2.4 
Safety Set  
The Safety Set includes all participants who received at least one dose of study treatment 
(capmatinib monotherapy or capmatinib + nazartinib combination therapy). 
10.3 
Participant demographics/other baseline characteristics 
Demographic and other baseline data (including disease characteristics) will be summarized 
descriptively by treatment group for the FAS. 
10.4 
Treatments (study treatment, concomitant therapies, 
compliance) 
Duration of exposure to study treatment in days, as well as actual total doses, actual dose 
intensities, and relative dose intensities of both study drugs will be summarized using 
descriptive statistics by treatment group for the safety set. 
Compliance to the study treatment will be assessed by the number of dose reductions, number 
of dose interruptions and percent of days received planned dose for both study drugs separately 
in summary tables by treatment group for the safety set. 


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Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized by treatment group for the safety set. 
10.5 
Primary objective for Phase Ib and Phase II Groups 1 to 4 
Phase Ib: To estimate the MTD or RP2D of nazartinib in combination with capmatinib in 
EGFRL858R/ex19del NSCLC participants who have progressed on EGFR TKI treatment (e.g. 
gefitinib, erlotinib or afatinib). 
Phase II: To estimate the preliminary anti-tumor activity of nazartinib in combination with 
capmatinib measured by overall response rate (ORR) determined by the Investigators’ 
assessment in accordance with RECIST 1.1 in each of the Groups 1 to 3. To characterize the 
safety and tolerability of nazartinib in combination with capmatinib taken with food in Group 
4. 
Group 1 (EGFRmut, any T790M, any MET, 2/4L antineoplastic, EGFR TKI resistant): 
at least 40 NSCLC participants with EGFR activating mutation (L858R or ex19del or other rare 
mutations such as L861Q, G719X and S768I) who had disease progression on one and only one 
prior treatment with a first or second generation EGFR TKI. The enrollment will continue until 
20 participants with an acquired EGFR T790M+ mutation (subgroups 1a + 1c) and 20 
participants without the T790M mutation (subgroups 1b + 1d) have entered the treatment phase. 
The resistance mechanism status will be determined centrally by the Novartis designated 
laboratory and prospectively tracked in the IRT system. 
Group 2 (EGFRmut, de novo T790M, any MET, 1/3L antineoplastic, EGFR TKI naïve): 
approximately 5 NSCLC participants who are EGFR inhibitor treatment naïve and harbor 
T790M de novo mutation. 
Group 3 (EGFRmut, T790M negative, any MET, 1L antineoplastic): at least 40 treatment 
naïve NSCLC participants with EGFR activating mutation (L858R or ex19del) and no T790M 
mutation, nor MET dysregulation. The resistance mechanism status will be determined centrally 
by the Novartis designated laboratory and prospectively tracked in the IRT system. 
Group 4 (EGFRmut, any T790M, any MET, 1L (treatment naïve) 2-3L antineoplastic): 
approximately 30 NSCLC participants with EGFR activating mutation (e.g.: L858R or ex19del) 
who failed (defined as intolerance to treatment or documented disease progression) on 
maximum 2 prior lines of antineoplastic therapies in the advanced setting. The resistance 
mechanism status will be determined centrally by the Novartis designated laboratory and 
prospectively tracked in the IRT system. Group 4 participants will take study drug with food 
(unrestricted meal type). 
For the purpose of this study, common EGFR activating/sensitizing mutations are L858R point 
mutation and exon 19 deletions which account for approximately 90% of the cases. Other rare 
EGFR mutations such as L861Q, G719X, and S768I are also considered activating/sensitizing 
mutations for enrollment onto the Phase II Group 1, Group 3 and Group 4. 
10.5.1 
Variable 
Phase Ib: Incidence of dose limiting toxicities (DLTs) in Cycle 1. Estimation of the MTD of 
the study treatment will be based upon the estimation of the probability of DLT in Cycle 1 for 


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participants in the DDS. This probability is estimated by the model described in  
Section 10.4.2. 
Phase II, Group 1–3: Overall response rate, determined as the proportion of participants 
experiencing a best overall response of confirmed CR or PR per RECIST 1.1 at any time on 
study by investigator assessment. 
ORR will be estimated by group and for Group 1 by T790M status as assigned based on baseline 
mutation status and prior systemic antineoplastic therapy. 
Phase II, Group 4: Frequencies of treatment-emergent adverse events. 
10.5.2 
Statistical hypothesis, model, and method of analysis 
10.5.2.1 Phase Ib 
An adaptive BLRM guided by the EWOC principle will give recommendations to the dose 
escalation of the proposed combination treatment to its MTD/RP2D. The DLT data in DDS 
from the first cycle of treatment accumulated throughout the dose escalation part will be used 
for modeling the dose-DLT relationship of nazartinib when given in combination with 
capmatinib. 
The BLRM is formulated as follows: let π1(d1) be the probability of a DLT if nazartinib is given 
as a single agent (q.d. schedule) at dose d1, and π2(d2) the probability of a DLT if capmatinib is 
given as a single agent (b.i.d.) at dose d2. 
The marginal dose-DLT relationships are then modeled as: 
nazartinib: 
logit(π1(d1)) = log(α1) + β1log(d1/d1*) 
capmatinib: 
logit(π2(d2)) = log(α2) + β2log(d2/d2*), 
where logit(π.(d.)) = log[π.(d.) /{1 − π.(d.)}], nazartinib reference dose d1*= 300 mg (q.d.) and 
capmatinib reference dose d2*= 200 mg (b.i.d., so total daily dose 400 mg), and α1, α2, β1, β2 >0. 
The combination dose-response relationship is subsequently modeled as: 
Odds(π12(d1,d2)) = π12(d1,d2)/(1 − π12(d1,d2)) 
= exp(η(d1/d1*)(d2/d2*))(π1(d1)+ π2(d2) – π1(d1)π2(d2))/((1 − π1(d1))(1 − π2(d2)), 
where the interaction term −∞ < η < ∞ is a scalar. 
The Bayesian approach requires the specification of prior distributions for the model parameters. 
The prior distributions and the process for their derivation and update based on available pre-
clinical and clinical data are provided in Section 14.2, along with examples of hypothetical 
decisions that may be followed during the dose escalation. 
Starting dose combination using the tablet formulation of nazartinib 
Once the tablet formulation of nazartinib is ready to be used in the new cohort, (i) data from all 
the previous cohorts of this study and (ii) updated DLT data from the three single agent studies 
 and [CEGF816X2101] will be appropriately down-
weighted (refer to Appendix 2 for more details on down-weighting data coming from different 


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sources) and used to run the BLRM. Results from the BLRM with EWOC principle will be 
used to support the starting dose for the new formulation as mentioned in Section 6.2.1. 
The starting dose for each of the components of the combination cannot be higher than those 
already used in the previous cohorts for the same dose escalation. 
Dose recommendation 
Dose recommendation will be based on summaries of the posterior distribution of model 
parameters and the posterior distribution of DLT rates, including the mean, median, standard 
deviation, 95% credibility interval, and the probability that the true DLT rate for each dose 
combination lies in one of the following categories: 
• [0%, 16%) under-dosing 
• [16%, 35%) targeted toxicity 
• [35%, 100%] excessive toxicity 
Following the principle of EWOC, after each cohort of participants the recommended dose 
combination is the one with the highest posterior probability of DLT in the target interval [16%, 
35%) among the doses fulfilling the overdose criterion that there is less than 25% chance of 
excessive toxicity. Decisions on dose escalation will follow the procedure outlined in  
Section 6.2.3. 
Listing/ summary of DLTs 
DLTs will be listed and their incidence summarized by primary system organ class, preferred 
term and by treatment group. The dose-determining set will be used for these summaries. 
10.5.2.2 Phase II 
A simple Bayesian design will be used in order to estimate the ORR and to provide inferential 
summaries (e.g., mean, median, standard deviation, 95% credible intervals, and interval 
probabilities) based on the posterior distribution of ORR in the Phase II part. Minimally 
informative unimodal Beta distributions (Neuenschwander et al 2008) will be used as prior 
distribution for the different study groups. These prior distributions reflect the current 
uncertainty about the efficacy of capmatinib in combination with nazartinib. For the primary 
analysis the posterior distributions of the ORR will be computed using the available data. 
The primary analysis will be performed using the FAS when all participants enrolled in each of 
the Groups 1 to 4 have completed at least 6 cycles of treatment or discontinued prior to that 
time for any reason.  
Group 3 (EGFRmut, T790M negative, any MET, 1L antineoplastic) will have one interim 
analysis for futility when approximately 20 participants have completed at least 4 cycles of 
treatment or discontinued treatment prior to that time. 
Group 1 (EGFRmut, any T790M, any MET, 2/4L antineoplastic, EGFR TKI resistant) 
For participants harboring the T790M mutation and participants not harboring the T790M 
mutation the posterior distribution of the ORR will be computed using the available data at the 
time of the primary analysis. A minimally informative beta distribution with parameters 


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a = 0.1765 and b = 1 based on a conservative assumption about the mean response rate will be 
used. 
Summaries (e.g., mean, median, standard deviation, 95% credible intervals, and interval 
probabilities) for the posterior distribution of the ORR will be provided for the T790M+ and 
T790M− subgroup. 
Group 2 (EGFRmut, de novo T790M, any MET, 1/3L antineoplastic, EGFR TKI naïve) 
This group will only be analyzed descriptively due to the expected maximum number of 5 
participants enrolled. 
Group 3 (EGFRmut, T790M negative, any MET, 1L antineoplastic) 
The ORR will be classified according to the following intervals: 
• [0, 40%) 
unacceptable anti-tumor activity 
• [40%, 55%) 
limited anti-tumor activity 
• [55%, 70%) 
moderate anti-tumor activity 
• [70%, 100%] strong anti-tumor activity 
An observed ORR ≥ 55% based on Investigators’ assessments will be considered clinically 
meaningful in this group. 
The preliminary anti-tumor activity of the study treatment will be declared if the following two 
conditions are both fulfilled: 
• The posterior median ORR is equal to or greater than 55% 
• The posterior risk of being in the unacceptable anti-tumor activity interval is lower than 5% 
This will require observing at least 22 responses in 40 participants. Otherwise, the inferential 
summaries for the 4 intervals above will be assessed for further characterization of the anti-
tumor activity. A minimally informative beta distribution with parameters a = 1 and 
b = (1 – 0.55)/0.55 = 0.818 based on an assumed mean response rate of 0.55 will be used as 
prior distribution for the Bayesian estimation of the ORR. 
An interim analysis for futility will be performed when approximately 20 participants have 
completed at least 4 cycles of treatment or discontinued treatment prior to that time. More 
details on the interim analysis are presented in  nazartinib. 
Group 4 (EGFRmut, any T790M, any MET, 1L (treatment naïve) 2-3L antineoplastic) 
Frequencies of adverse events will be analyzed descriptively in this group as described in 
Section 10.6.1.2. 
10.5.3 
Handling of missing values/censoring/discontinuations 
Incidence of DLTs in Cycle 1: If a Phase Ib participant is considered as non-evaluable for the 
DDS, enrollment of a new participant to the current cohort will be considered if there is less 
than the required number of evaluable participants (Section 6.2.3). 
Overall response rate: Participants who have missing BOR will be considered as a treatment 
failure for the primary analysis of ORR.  




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combination treatment and responses after the use of new (non-study treatment) anti-cancer 
therapy considered as non-response. 
4. Intercurrent events: 
• Switching to capmatinib plus nazartinib combination treatment: BOR assessments after 
switching will be considered as nonresponses and have been accounted for in the 
variable attribute using the composite strategy 
• Start of new anti-cancer therapy: BOR assessments after the use of new anti-cancer 
therapy will be considered as nonresponses and have been accounted for in the variable 
attribute using the composite strategy 
• Discontinuation of study treatment for any reason (other than starting combination 
treatment or new anti-cancer therapy): BOR will take into account all response 
assessments irrespective of the reasons for discontinuing capmatinib monotherapy 
(treatment policy strategy) 
• Any unforeseen intercurrent events (e.g., related to a public health emergency) will be 
handled by the treatment policy strategy 
5. Summary measure: ORR defined as the proportion of participants with confirmed BOR of 
CR or PR based on investigator assessment per RECIST 1.1 
10.6.2 
Statistical model, hypothesis, and method of analysis 
The analysis of the primary endpoint will be performed for participants in the EAS who were 
treated with capmatinib monotherapy and based on the time period of monotherapy treatment. 
ORR is defined as the proportion of participants with confirmed best overall response of CR or 
PR, and will be assessed by the investigator according to RECIST 1.1. 
The analysis of Group 5 data will be performed when all participants enrolled in the group have 
completed at least 6 treatment cycles (about 6 months) or discontinued prior to that time for any 
reason, provided the Group 5 continued into Stage 2. 
The primary efficacy endpoint ORR will be estimated and the 2-sided exact 95% CI 
(Clopper  and Pearson 1934) provided. Capmatinib monotherapy treatment will be considered 
to have clinically relevant efficacy if the following criteria are fulfilled: 
• the ORR estimate is > 45% and 
• the lower bound of the two-sided 95% exact CI is >35%. 
Based on historical data (Soria et al 2015, Mok et al 2017), the ORR in this population is 
expected to be around 35% and the threshold of 45% is considered of clinical interest. 
10.6.3 
Handling of intercurrent events of the primary estimand 
The intercurrent events for the primary estimand are described in Section 10.5.1. 
10.6.4 
Handling of missing values not related to intercurrent events 
Participants without a baseline tumor assessment will not be included in the EAS. 


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10.7 
Secondary objectives 
10.7.1 
Safety objectives 
10.7.1.1 Analysis set and grouping for the analyses 
For all safety analyses, the safety set will be used if not otherwise specified. All listings and 
tables will be presented by treatment group. 
Phase Ib and Phase II Group 1 to Group 4 
The overall observation period will be divided into three mutually exclusive segments: 
• pre-treatment period: from day of participant’s informed consent to the day before first dose 
of study medication 
• on-treatment period: from day of first dose of study medication to 30 days after last dose of 
study medication 
• post-treatment period: starting at day 31 after last dose of study medication. 
Phase II Group 5 
For the safety analysis of capmatinib monotherapy in Group 5, the overall observation period 
will be divided into the following three mutually exclusive segments: 
• pre-treatment period: from day of participant’s informed consent to the day before first dose 
of study medication 
• on-treatment period: 
• from day of first dose of study medication to 30 days after last dose of capmatinib 
monotherapy, if the participant did not continue on combination therapy, or 
• from day of first dose of study medication to the data prior to the start of capmatinib 
plus nazartinib combination therapy, if the participant continued on combination 
therapy 
• post-treatment period: 
• starting at day 31 after last dose of study medication, i.e., capmatinib monotherapy, if 
the participant did not continue on combination therapy, or 
• starting at day 31 after last dose of combination therapy, if the participant received 
combination therapy. 
For the safety analysis of capmatinib plus nazartinib combination therapy 5, the overall 
observation period will be divided into the following three mutually exclusive segments: 
• pre-treatment period: from day of participant’s informed consent to the day before the first 
dose of combination therapy 
• on-treatment period: from day of first dose of combination therapy to 30 days after last dose 
of study medication 
• post-treatment period: starting at day 31 after last dose of study medication. 


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10.7.1.2 Adverse events (AEs) 
Summary tables for AEs have to include only AEs that started or worsened during the on-
treatment period, the treatment-emergent AEs. However, all safety data (including those from 
the pre and post-treatment periods) will be listed and those collected during the pre-treatment 
and post-treatment period are to be flagged. Listings of all AEs will be provided based on the 
FAS. 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class or preferred term, severity (based on CTCAE grades), 
relationship to study treatment and by treatment group. 
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by participant and 
tabulated by type of adverse event and treatment group. 
Serious adverse events, non-serious adverse events and adverse events of special interest (AESI) 
during the on-treatment period will be tabulated. 
10.7.1.3 Laboratory abnormalities 
For laboratory tests covered by the CTCAE version 4.03 for participants in Phase Ib and Phase 
II (Groups 1 to 4) and version 5.0 for participants in Phase II Group 5, the study’s biostatistical 
and reporting team will grade laboratory data accordingly. The calculation of CTCAE grades 
will be based on the observed laboratory values only, clinical assessments will not be taken into 
account. For laboratory tests covered by CTCAE, a 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, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges. 
The following by-treatment summaries will be generated separately for hematology, 
biochemistry and urinary laboratory tests: 
• frequency table for newly occurring on-treatment grades 3 or 4 (see below for details) 
• shift tables using CTCAE grades to compare baseline to the worst on-treatment value 
• for laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-treatment 
value. 
• listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades and the classifications relative to the laboratory normal ranges. 
10.7.1.4 Other safety data 
ECG 
• shift table baseline to worst on-treatment result for overall assessments 
• listing of ECG evaluations for all participants with at least one abnormality. 
Vital signs 
• shift table baseline to worst on-treatment result 


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• table with descriptive statistics at baseline, one or several post-baseline time points and 
change from baseline to this/these post-baseline time points. 
10.7.1.5 Tolerability 
Tolerability of study drugs will be assessed by summarizing the frequency of dose interruption, 
frequency of dose reduction, and dose intensity. Reasons for dose interruption and dose 
reduction will be listed by participant and summarized. 
10.7.2 
Efficacy objectives 
CT/MRI assessments will be used for all efficacy assessments of anti-tumor activity on study. 
BOR, ORR, PFS, DCR, duration of response (DOR) and Time To Response (TTR) will be 
defined as per RECIST 1.1 (see Section 14.1) based on investigator assessment. The analyses 
will be based on the FAS for groups 1 to 4 and the EAS for Group 5. Summaries by group will 
be based on baseline mutation status and prior systemic antineoplastic therapies as specified in 
the eCRF. Listings of efficacy endpoints will be presented by treatment group. 
If available, the results of the central evaluations by BIRC may be used for secondary analyses 
purposes. 
10.7.2.1 Secondary efficacy endpoints for Phase Ib and Phase II Groups 1 to 4 
Phase Ib part: Overall response rate (ORR), duration of response (DOR), disease control rate 
(DCR), time to response (TTR), and progression-free survival (PFS) by Investigator assessment 
in accordance with RECIST 1.1 and overall survival (OS). 
Phase II part: DOR, DCR, TTR, PFS by Investigator assessment in accordance with 
RECIST 1.1, and overall survival (OS). In addition for Group 4 ORR by investigator assessment 
in accordance with RECIST 1.1. 
Best overall response 
BOR is the best response recorded from the start of the treatment until documented radiological 
disease progression/recurrence. However, any assessments taken more than 28 days after the 
last dose of study treatment will not be included in the best overall response derivation. 
The study requires that for a partial response (PR) or complete response (CR) changes in tumor 
measurements must be confirmed by repeat assessments performed not less than 4 weeks after 
the criteria for the response are first met. 
BOR will be summarized by treatment group. 
Overall response rate 
ORR is defined as the proportion of participants with a best overall confirmed CR or PR per 
RECIST 1.1. 
ORR will be estimated together with the exact binomial 95% confidence interval (CI)  
(Clopper and Pearson 1934). 


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Duration of response 
Among participants with a confirmed PR or CR per RECIST 1.1, DOR is defined as the time 
from first documented response (PR or CR) to the date of first documented disease progression 
or death due to underlying cancer. If a participant did not have an event or received any further 
anticancer therapy before documented disease progression, DOR is censored at the time of the 
last adequate tumor assessment. 
DOR will be described using the Kaplan-Meier method including the estimated median (in 
months) with 95% CI, as well as the 25th and 75th percentiles. For the Phase Ib part the summary 
will be provided only in treatment groups with sufficient numbers of participants. Summary 
statistics of DOR for participants whose best response is CR or PR will be provided for groups 
with ≤ 5 responders. For the Phase II part a Kaplan Meier plot will also be presented. 
Disease control rate 
DCR is defined as the proportion of participants with BOR of CR, PR, or stable disease (SD) 
per RECIST 1.1. 
DCR will be estimated by treatment group and for the Phase II part by T790M status in Group 
1 
and 
by 
sub-group 
otherwise 
together 
with 
the 
exact 
binomial 
95% 
CI 
(Clopper and Pearson 1934). 
Time to response 
TTR is defined as the time between the date of start of treatment and the date of first documented 
response (CR or PR, which must be confirmed subsequently). For participants who did not 
achieve a confirmed PR or CR, the TTR will be censored at the last adequate tumor assessment 
date. 
TTR will be described using the Kaplan-Meier method including the estimated median (in 
months) with 95% CI, as well as the 25th and 75th percentiles. For the Phase Ib part the summary 
will be provided only in treatment groups with sufficient numbers of participants. Summary 
statistics of TTR for participants whose best response is CR or PR will also be provided. 
Progression-free survival 
PFS is defined as the time from the date of first dose of study treatment to the date of first 
documented disease progression per RECIST 1.1 or death due to any cause. If a participant did 
not have an event or received any further anticancer therapy before documented disease 
progression, PFS will be censored at the time of the last adequate tumor assessment. By default, 
if disease progression or death is documented after one single missing tumor evaluation, the 
actual event date of disease progression/death will be used for the PFS event date. If disease 
progression or death is documented after two or more missing tumor evaluations, the PFS time 
of these participants will be censored at the date of the last adequate tumor assessment without 
PD. Clinical deterioration without objective radiological evidence will not be considered as 
documented disease progression. 
PFS will be described using the Kaplan-Meier method including the estimated median (in 
months) with 95% CI, 25th and 75th percentiles. For the Phase Ib part the summary will be 






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data. Details of this procedure and the process for communication with investigators are 
provided in Section 6.2.3. 
Phase II part 
A futility interim analysis (IA) will be conducted for Group 3 (EGFRmut, T790M negative, any 
MET, 1L antineoplastic) and Group 5 (EGFRmut, T790M-, MET GCN ≥ 5, 2L, EGFR TKI 
resistant). No interim analysis is planned for Groups 1, 2 and 4. However, individual participant 
data will be reviewed on an ongoing basis by the study team across the duration of the trial 
(Section 8.5). 
Group 3 (EGFRmut, T790M negative, any MET, 1L antineoplastic) 
One interim analysis for futility will be performed for participants enrolled in Group 3 
(participants in first line setting) when approximately 20 participants have completed at least 4 
cycles of treatment or discontinued treatment prior that time. A close monitoring of the first 20 
measurable participants will be performed. All evaluable participants at the time of the data cut-
off for the interim analysis will be used. 
The decision whether to continue or stop enrollment and/or treatment will be based on the 
probability of success (PoS). PoS is the probability to have a positive conclusion at the end of 
the study, given the interim data. Denoting the number of participants at interim by n1 and the 
number of responders at interim by r1, PoS is found as 
• PoS = Prob [at least x−r1 responders in 40−n1 participants | r1 responders in n1 participants] 
The number of responders (x−r1) to be observed in the remaining 40−n1 participants follows a 
Beta-binomial distribution. This is used in order to calculate PoS. 
The enrollment and/or treatment may be stopped at the interim analysis if PoS<0.10, i.e., if less 
than 9 out of the first 20 participants have the best response of CR or PR. The criterion (number 
of responders) will be based on the actual number of participants in the FAS at the time of the 
interim analysis. 
If futility is concluded, the enrollment of 1L participants (Group 3 and 1L participants in Group 
4) may be stopped. The enrollment in opened groups with pre-treated participants will continue. 
Table 10-2 provides the probabilities of success at the primary analysis based on different 
numbers of responders observed at the interim analysis. For 9 or more responders PoS exceeds 
0.10 and the study will continue at interim. 
Table 10-2 
Probability of success at the primary analysis based on various 
numbers of responders observed at the IA for Group 3 
Responders at IA out of 20 evaluable participants at IA 
Probability of Success 
8/20 
0.04 
9/20 
0.14 
10/20 
0.33 
11/20 
0.57 
12/20 
0.79 
Group 5 (EGFRmut, T790M-, MET GCN ≥ 5, 2L, EGFR TKI resistant) 


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An interim analysis for futility will be performed based on stage 1 of the 2-stage design of 
Group 5 when 10 participants have completed at least 2 tumor assessments while on treatment 
with capmatinib monotherapy, had radiological disease progression per RECIST 1.1, or 
discontinued capmatinib monotherapy treatment prior that time. Recruitment will be on 
temporary halt while conducting the IA. The IA will be based on the EAS. 
The decision to stop for futility at the interim analysis will be based on the predictive probability 
(PP) that the final observed ORR of capmatinib monotherapy is no worse than the historical 
control ORR, given the interim observed data (x) and responders among n participants. Based 
on available data (Soria et al 2015, Mok et al 2017), the ORR in the historical control for this 
population is expected to be around 35%.  Thus, the stop for futility rule is based on 
PP = Prob[Final observed ORR of capmatinib monotherapy ≥ 35% | x, n] 
A minimally informative Beta distribution prior with prior mean equal to 35% will be used, i.e., 
the prior distribution will be Beta (0.5385, 1) for the futility stopping decision rule calculations 
at the interim analysis. 
The group will be stopped for futility at the interim analysis if the PP <1%, i.e., if 0 response 
out of the first evaluable 10 participants is observed. For the purpose of the interim analysis a 
responder is defined as participant having a response of PR or CR per RECIST 1.1. 
All evaluable participants at the time of the data cut-off for the interim analysis will be used to 
obtain the futility boundary using the stopping criteria. The futility boundary will be calculated 
according to the actual number of evaluable participants (in the EAS) in the interim analysis. 
Table 10-3 presents the PP at the final analysis based on different numbers of responders 
observed at the interim analysis and an observed ORR of not worse than 0.35 for capmatinib 
monotherapy. 
Table 10-3 
Predictive probability (PP) for ORR of capmatinib monotherapy at the 
final analysis based on various numbers of responders observed at 
the IA for Group 5 
Responders at IA out of 10 evaluable participants at 
IA 
Predictive probability (PP) 
0 
0.0000 
1 
0.0148 
2 
0.0984 
3 
0.3207 
4 
0.6301 
5 
0.8686 
6 
0.9720 
7 
0.9967 
8 
0.9998 
9 
1.0000 
10 
1.0000 
With 10 evaluable participants for the interim analysis, if no (0) response is observed (PP <1%), 
the Group 5 will be stopped for futility. 


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10.10 
Sample size calculation 
Phase Ib part 
Cohorts of 3 to 6 evaluable participants will be enrolled in the dose-escalation part including at 
least six participants at the MTD/RP2D level, as described in Section 6.2.3. Multiple cohorts 
may be sequentially enrolled to the same dose level. Additional cohorts of 1 to 6 participants 
may be enrolled at any dose level below the estimated MTD/RP2D for further elaboration of 
safety and pharmacokinetic parameters as required. At least 18 participants are expected to be 
treated in the dose escalation part, for the model to have reasonable operating characteristics 
relating to its MTD recommendation. 
Phase II part 
Approximately 145 participants (40 in Group 1, 5 in Group 2, 40 in Group 3, 30 in Group 4 and 
30 in Group 5) will be enrolled in the study if Group 3 or Group 5 is not stopped for futility at 
the time of the interim analysis. 
Group 1 (EGFRmut, any T790M, any MET, 2/4L antineoplastic, EGFR TKI resistant) 
As specified in Section 4.1, the number of participants harboring the T790M mutation among 
sub-groups 1a and 1c is minimum 20, for participants who do not harbor the T790M mutation 
among sub-groups 1b and 1d it is also minimum 20. The actual total sample size in Group 1 
may be greater than 40. 
Table 10-4 shows the 95% credible intervals based on the posterior distribution for different 
observed number of responses. The highlighted rows show examples that might be observed 
for the T790M+ or T790M− participants. If 5 responses out of 20 participants are observed, 
there is 95% probability that the ORR is between 9.1% and 44.3%, whereas it is between 32.0% 
and 73.1% when 11 responses are observed. To have at least 97.5% probability that the ORR is 
larger than 50%, 15 or more responses are required. 
Table 10-4 
Credible intervals for assumed observed responses in Group 1 
Sample Size 
Observed responses 
Median 
95% Credible Interval 
20 
4 
0.188 
[0.062, 0.386] 
20 
5 
0.236 
[0.091, 0.443] 
20 
6 
0.285 
[0.124, 0.497] 
20 
10 
0.480 
[0.277, 0.688] 
20 
11 
0.529 
[0.320, 0.731] 
20 
12 
0.577 
[0.365, 0.772] 
20 
15 
0.724 
[0.512, 0.882] 
Group 2 (EGFRmut, de novo T790M, any MET, 1/3L antineoplastic, EGFR TKI naïve) 
The sample size for this group is based on the potential number of participants with the rare 
condition who can be enrolled into the study and not on formal sample size or operating 
characteristic calculations. 


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Group 3 (EGFRmut, T790M negative, any MET, 1L antineoplastic) 
The operating characteristics of the statistical design are presented below with the probabilities 
to stop for futility at the interim analysis and to declare preliminary anti-tumor activity of the 
study treatment at the primary analysis (observing at least 22 responses in 40 participants) under 
different true ORR values (see also Table 10-5). 
The actual total sample size in Group 3 may be greater than 40. 
• If the true ORR is 40%, it is likely to stop at the interim analysis (probability 0.596) and the 
probability to declare preliminary anti-tumor activity at the end of the study is low (0.038). 
• If the true ORR is 55%, the probability to stop at the interim analysis is low, 0.131, and the 
probability to declare preliminary anti-tumor activity at the end of the study is 0.553. 
• If the true ORR is 70%, it is highly unlikely that the study would be stopped at the interim 
analysis (probability 0.005) and the probability to declare preliminary anti-tumor activity at 
the end of the study is very high (0.982). 
Table 10-5 
Operating characteristics for ORR in Group 3 
True ORR 
Probability to stop for futility at IA 
Success probability at primary analysis 
0.40 
0.596 
0.038 
0.45 
0.414 
0.129 
0.50 
0.252 
0.309 
0.55 
0.131 
0.553 
0.60 
0.057 
0.780 
0.65 
0.020 
0.923 
0.70 
0.005 
0.982 
0.75 
0.001 
0.998 
0.80 
0.000 
1.000 
Group 4 (EGFRmut, any T790M, any MET, 1L (treatment naïve) 2-3L antineoplastic) 
The size of this group is based on practical considerations, not on formal sample size or 
operating characteristic calculations. The precision of estimates in the PK analysis which can 
be expected with the planned sample size of 20 participants with full PK blood samples is 
detailed below. 
Based on published data (Tan et al 2017) at the RP2D (capmatinib  400 mg b.i.d. + 100 mg q.d. 
nazartinib) based on the Phase Ib data, the CV% of Cmax and AUC0-12 for v would be at most 
49.4% and 48.3%, and the CV% of Cmax and AUC0-24 for nazartinib would be at most 58.9% 
and 78.7%. To be conservative, the CV% of 49.4% for capmatinib PK and 78.7% for nazartinib 
PK was used in the calculation below. 
When combining fasted PK data from Phase Ib (n=10) at the RP2D and fasted PK from Group 
1 (approximately n=3) and from Group 3 (n=10) in Phase II, a total of about n=23 participants 
would have full PK in the fasted state. In Group 4 in Phase II, n=20 participants may have full 
PK in the fed state. 
With such sample size (n=23 in the fasted status, and n=20 in the fed status), the half-width of 
a 90% CI on the log-scale is 0.239 and 0.355 from the observed mean difference of log (PK) 
for capmatinib and nazartinib, respectively. Once transformed back to the original scale, this 


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translates into the 90% CI shown in Table 10-6, under different assumptions of what the true 
ratio of the PK parameters is. 
Table 10-6 
Expected 90% confidence limits for different ratios of geometric 
means 
 
Capmatinib PK 
nazartinib PK 
True 
ratio 
Lower Limit of 90% CI 
Upper Limit of 90% CI 
Lower Limit of 90% CI 
Upper Limit of 90% CI 
0.70 
0.550 
0.890 
0.490 
1.001 
0.80 
0.629 
1.107 
0.560 
1.143 
1.00 
0.786 
1.272 
0.700 
1.429 
1.25 
0.983 
1.590 
0.875 
1.787 
1.50 
1.179 
1.908 
1.049 
2.144 
2.00 
1.573 
2.544 
1.399 
2.859 
2.50 
1.966 
3.179 
1.749 
3.573 
Group 5 (EGFRmut, T790M-, MET GCN ≥ 5, 2L, EGFR TKI resistant) 
The operating characteristics (with 30 participants and assuming an interim analysis after 
Stage 1 at 10 participants) were determined for the primary objective to estimate the treatment 
effect of capmatinib monotherapy. Based on available data (Soria et al 2015, Moket al 2017), 
the ORR in the historical control for this population is expected to be around 35%. The success 
criterion defined in Section 10.5.2 requires an estimated ORR of >45% and a lower bound of 
the two-sided 95% exact CI of >35% to conclude that the antitumor activity is of clinical interest. 
Table 10-7 presents the probability of stopping at the interim analysis, the probability for a 
positive conclusion (i.e., not stopped at IA for futility and success criteria met at final analysis 
after stage 2) and for a negative conclusion (i.e., not stopped at IA for futility but success criteria 
not met at final analysis) under different underlying true ORR of capmatinib monotherapy. 
The operating characteristics have up to around 35% probability of stopping the trial for futility 
when the true ORR is ≤ 35%. Also, when the true ORR is 45% then the probability of positive 
conclusion at the final analysis with 30 participants is ca. 50%. If the true ORR is 50% or higher, 
the probability of a positive conclusion at the final analysis with 30 participants is >70%. 
To adjust for potential discordance between local vs central MET amplification testing results, 
additional participants may be enrolled to ensure there are at least 10 in stage 1 and 30 in total 
MET amplified participants centrally confirmed by Novartis-designated laboratory. 
Table 10-7 
Operating characteristics for various assumed true ORR of 
capmatinib monotherapy 
True ORR 
Probability to stop at 
IA* (%) 
Probability of positive 
conclusion at final 
analysis (%) 
Probability of negative 
conclusion at final 
analysis 
0.10 
34.87  
0.00 
65.13  
0.20 
10.74  
0.09  
89.17 
0.25 
5.63  
0.82  
93.55 
0.30 
2.82  
4.00  
93.17 
0.35 
1.35  
12.63  
86.02 


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True ORR 
Probability to stop at 
IA* (%) 
Probability of positive 
conclusion at final 
analysis (%) 
Probability of negative 
conclusion at final 
analysis 
0.40 
0.60  
28.55  
70.85 
0.45 
0.25  
49.75  
50.00 
0.50 
0.10  
70.76  
29.14 
0.55 
0.03 
86.44 
13.53 
*Assuming interim analysis at 10 evaluable participants 
10.11 
Power for analysis of key secondary variables 
Not applicable 
11 
Ethical considerations and administrative procedures 
11.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki. 
11.2 
Responsibilities of the investigator and IRB/IEC 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
before study start. Prior to study start, the investigator is required to sign a protocol signature 
page confirming his/her agreement to conduct the study in accordance with these documents 
and all of the instructions and procedures found in this protocol and to give access to all relevant 
data and records to Novartis monitors, auditors, Novartis Clinical Quality Assurance 
representatives, designated agents of Novartis, IRBs/IECss and regulatory authorities as 
required. 
11.3 
Informed consent procedures 
Eligible participants may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent if applicable, or, if 
incapable of doing so, after such consent has been provided by a legally acceptable 
representative of the participant. In cases where the participant’s representative gives consent, 
the participant should 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 should indicate assent by 
personally signing and dating the written informed consent document or a separate assent form. 
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the participant source documents. The date when a participant’s Informed 
Consent was actually obtained will be captured in their CRFs. 




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study will be either submitted for publication and/or posted in those for interventional clinical 
trials involving pediatric participants within 6 months of study completion. 
Novartis follows the ICMJE authorship guidelines (icmje.org) and other specific guidelines of 
the journal or congress to which the publication will be submitted 
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no honorarium 
provided for such presentations. 
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable. 
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to.novartis.com. 
11.6 
Study documentation, record keeping and retention of 
documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of participants. As part of participating in a Novartis-
sponsored study, each site will permit authorized representatives of the sponsor(s) and 
regulatory agencies to examine (and when required by applicable law, to copy) clinical records 
for the purposes of quality assurance reviews, audits and evaluation of the study safety and 
progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, participants’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and participant files and records 
kept at the pharmacy, at the laboratories, and medico-technical departments involved in the 
clinical trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 


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electronic CRFs an audit trail will be maintained by the system. The investigator should retain 
records of the changes and corrections to paper CRFs. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines. 
11.7 
Confidentiality of study documents and participant records 
The investigator must ensure anonymity of the participants; participants must not be identified 
by names in any documents submitted to Novartis. Signed informed consent forms and 
participant enrollment log must be kept strictly confidential to enable participant identification 
at the site. 
11.8 
Audits and inspections 
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities. 
11.9 
Financial disclosures 
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of participants at the site prior to study start. 
12 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 
to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC it cannot be implemented. All significant protocol deviations will 
be recorded and reported in the CSR. 
12.1 
Amendments to the protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IECOnly 
amendments that are required for participant safety may be implemented prior to IRB/IEC 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any 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 (e.g. UK requires the notification of urgent safety measures 
within 3 days) but not later than 10 working days. 


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13 
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14 
Appendices 
14.1 
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 3:0: 
19-Oct-2009 
Version 2:0: 
18-Jan-2007 
Version 1:0: 
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): 
Glossary 
CR 
Complete response 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CT 
Computed tomography 
DFS 
Disease-free survival 
eCRF 
Electronic Case Report Form 
FPFV 
First patient first visit 
GBM 
Glioblastoma multiforme 
MRI 
Magnetic resonance imaging 
LPLV 
Last patient last visit 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PR 
Partial response 
RAP 
Reporting and Analysis Plan 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SD 
Stable disease 
SOD 
Sum of Diameter 
TTF 
Time to treatment failure 
TTP 
Time to progression 
UNK 
Unknown 


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14.1.1 
Introduction 
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This document 
is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the revised 
RECIST 1.1 guidelines (Eisenhauer et al 2009). 
The efficacy assessments described in Section 14.1.2 and the definition of best response in 
Section 14.1.3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 14.1.3.2 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 14.1.4 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. 
14.1.2 
Efficacy assessments 
14.1.2.1 Definitions 
14.1.2.1.1 
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 14.1.3.2.9. 
Measurable lesions (both nodal and non-nodal) 
• Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm. 
• Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft tissue 
component meets the definition of measurability. 
• Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes ≥15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring ≥10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at baseline, 
regardless of the slice thickness, are normal and not considered indicative of disease. 
• Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no septations, 
and low CT density [water-like] content) should not be considered as malignant lesions 
(neither measurable nor non-measurable) since they are, by definition, simple cysts. 


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• ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
noncystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
• Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with ≥ 10 
to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly identified by 
physical exam that is not measurable by reproducible imaging techniques. 
14.1.2.1.2 
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 14.1.3.2.9. 
14.1.2.2 Methods of tumor measurement - general guidelines 
In this document, the term “contrast” refers to intravenous (i.v) contrast. 
The following considerations are to be made when evaluating the tumor: 
• All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the treatment. 
• Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment. 
• For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-up. 
Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed using 
a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan slice 
thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. If, at 
baseline, a patient is known to have a medical contraindication to CT contrast or develops 
a contraindication during the trial, the following change in imaging modality will be 
accepted for follow up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis. 
• A change in methodology can be defined as either a change in contrast use (e.g. keeping the 
same technique, like CT, but switching from with to without contrast use or vice-versa, 
regardless of the justification for the change) or a major change in technique (e.g. from CT 
to MRI, or vice-versa), or a change in any other imaging modality. A change from 
conventional to spiral CT or vice versa will not constitute a major “change in method” for 
the purposes of response assessment. A change in methodology will result by default in a 
UNK overall lesion response assessment as per Novartis calculated response. However, 


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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 limit they must 
normalize for a patient to be considered in complete clinical response when all lesions have 
disappeared. 
• Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 


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and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed). 
• Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
14.1.2.3 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 14.1.2.1.1. 
• Nodal target: See Section 14.1.2.1.1. 
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. 
14.1.2.4 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 14-1) and non-target lesions (Table 14-2) identified at baseline. These 


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evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 14-3) as well as the presence or absence of new lesions. 
14.1.2.4.1 
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. 
14.1.2.4.1.1 Non-nodal lesions 
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are subject to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance of 
the cut from the longest diameter; such lesions may appear to have responded or progressed on 
subsequent examinations, when, in fact, they remain the same size). 
If the lesion has completely disappeared, the lesion size should be reported as 0 mm. 
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement. This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval. 
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated. 
14.1.2.4.1.2 Nodal lesions 
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are not 
expected to disappear completely, so a “non-zero size” will always persist. 
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval. 
However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
lesions, which may be required subsequently for response determination. 


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14.1.2.4.2 
Determination of target lesion response 
Table 14-1 
Response criteria for target lesions 
Response Criteria 
Evaluation of target lesions 
Complete Response (CR): 
Disappearance of all non-nodal target lesions. In addition, any pathological 
lymph nodes assigned as target lesions must have a reduction in short axis to < 
10 mm 1 
Partial Response (PR): 
At least a 30% decrease in the sum of diameter of all target lesions, taking as 
reference the baseline sum of diameters. 
Progressive Disease (PD): 
At least a 20% increase in the sum of diameter of all measured target lesions, 
taking as reference the smallest sum of diameter of all target lesions recorded 
at or after baseline. In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm.2 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions 
which would qualify for PD. 
Unknown (UNK) 
Progression has not been documented and one or more target lesions have not 
been assessed or have been assessed using a different method than baseline.3 
1. SOD for CR may not be zero when nodal lesions are part of target lesions 
2. Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present and all nodal 
lesions are <10 mm in size. In this case, the target lesion response is CR 
3. In exceptional circumstances an UNK response due to change in the method could be over-ruled by the 
investigator or central reviewer using expert judgement based on the available information (see notes on the 
target lesion response and methodology change See Section 14.1.2.2. 
Notes on target lesion response 
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance (i.e., 
the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually present 
and/or not visualized for technical reasons in this previous assessment. If it is not possible to 
change the 0 value, then the investigator/radiologist has to decide between the following 
possibilities: 
• The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease 
• The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the CRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in Table 14-1 above (i.e., a PD will be 
determined if there is at least 20% increase in the sum of diameters of all measured target 
lesions, taking as reference the smallest sum of diameters of all target lesions recorded at or 
after baseline with at least 5 mm increase in the absolute sum of the diameters). Proper 
documentation should be available to support this decision. This applies to patients who 
have not achieved target response of CR. For patients who have achieved CR, please refer 
to last bullet in this section. 
• For those patients who have only one target lesion at baseline, the reappearance of the target 
lesion which disappeared previously, even if still small, is considered a PD. 
• Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 


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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 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 
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14.1.2.4.3 
Determination of non-target lesion response 
Table 14-2 
Response criteria for non-target lesions 
Response Criteria 
Evaluation of non-target lesions 
Complete Response (CR): 
Disappearance of all non-target lesions. In addition, all lymph nodes assigned a 
non-target lesions must be non-pathological in size (< 10 mm short axis) 
Progressive Disease (PD): 
Unequivocal progression of existing non-target lesions.1 
Non-CR/Non-PD: 
Neither CR nor PD 
Unknown (UNK) 
Progression has not been documented and one or more non-target lesions have 
not been assessed or have been assessed using a different method than 
baseline.2 
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 review does 
prevail and the progression status should be confirmed later on by the review panel (or study chair). 
2 It is recommended that the investigator and/or central reviewer should use expert judgement to assign a non-
UNK response whether 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’ 
there is unequivocal progression of the non-target lesions (in which case response is PD) or 
it is not possible to determine whether there is unequivocal progression (in which case 
response is UNK). 
• Unequivocal progression: To achieve “unequivocal progression” on the basis of non-target 
disease there must be an overall level of substantial worsening in non-target disease such 
that, even in presence of CR, PR or SD in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. A modest “increase” in the size 
of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
non-target disease in the face of CR, PR or SD of target disease is therefore expected to be 
rare. In order for a PD to be assigned on the basis of non-target lesions, the increase in the 
extent of the disease must be substantial even in cases where there is no measurable disease 
at baseline. If there is unequivocal progression of non-target lesion(s), then at least one of 
the non-target lesions must be assigned a status of “Worsened”. Where possible, similar 
rules to those described in Section 14.1.2.4.2 for assigning PD following a CR for the non-
target lesion response in the presence of non-target lesions nodal lesions should be applied. 


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14.1.2.4.4 
New lesions 
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion CRF page. 
• If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion. 
• If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 14.1.2.5). 
• A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to ≥ 10 mm for the first time in the study plus 5 
mm absolute increase. 
FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). See Section 14.1.2.2. 
14.1.2.5 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 14-3. 
Table 14-3 
Overall lesion response at each assessment 
Target lesions 
Non-target lesions 
New Lesions 
Overall lesion response 
CR 
CR 
No 
CR1 
CR 
Non-CR/Non-PD3 
No 
PR 
CR, PR, SD 
UNK 
No 
UNK 
PR 
Non-PD and not UNK 
No 
PR1 
SD 
Non-PD and not UNK 
No 
SD1, 2 
UNK 
Non-PD or UNK 
No 
UNK1 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1. This overall lesion response also applies when there are no non-target lesions identified at baseline. 
2. Once confirmed PR was achieved, all these assessments are considered PR. 
3. As defined in Section 14.1.2.4. 
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR. 


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14.1.3 
Efficacy definitions 
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 14.1.3.2.9 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts. 
14.1.3.1 Best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria. 
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the protocol 
should specifically describe if these will be included in the determination of best overall 
response and/or whether these additional assessments will be required for sensitivity or 
supportive analyses. As a default, any assessments taken more than 30 days after the last dose 
of study treatment will not be included in the best overall response derivation. If any alternative 
cancer therapy is taken while on study any subsequent assessments would ordinarily be 
excluded from the best overall response determination. If response assessments taken after 
withdrawal from study treatment and/or alternative therapy are to be included in the main 
endpoint determination, then this should be described and justified in the protocol. 
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met. 
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed. 
• For non-randomized trials where response is the primary endpoint, confirmation is needed. 
• For trials intended to support accelerated approval, confirmation is needed 
• For all other trials, confirmation of response may be considered optional. 
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules: 
• CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required 
• PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR prior 
to progression where confirmation not required 
• SD = at least one SD assessment (or better) > 6 weeks after randomization/start of treatment 
(and not qualifying for CR or PR). 
• PD = progression ≤ 12 weeks after randomization/ start of treatment (and not qualifying for 
CR, PR or SD). 


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


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The primary analysis of the best overall response will be based on the sequence of 
investigator/central blinded review/calculated (investigator)/calculated (central) overall lesion 
responses. 
Based on the patients’ best overall response during the study, the following rates are then 
calculated: 
Overall response rate (ORR) is the proportion of patients with a best overall response of CR 
or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications. 
Disease control rate (DCR) is the proportion of patients with a best overall response of CR or 
PR or SD. The objective of this endpoint is to summarize patients with signs of “activity” 
defined as either shrinkage of tumor (regardless of duration) or slowing down of tumor growth. 
Clinical benefit rate (CBR) is the proportion of patients with a best overall response of CR or 
PR, or an overall lesion response of SD or Non-CR/Non-PD which lasts for a minimum time 
duration (with a default of at least 24 weeks in breast cancer studies). This endpoint measures 
signs of activity taking into account duration of disease stabilization. 
Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used: 
Early progression rate (EPR) is the proportion of patients with progressive disease within 
8 weeks of the start of treatment. 
The protocol should define populations for which these will be calculated. The timepoint for 
EPR is study specific. EPR is used for the multinomial designs of Dent and Zee (2001) and 
counts all patients who at the specified assessment (in this example the assessment would be at 
8 weeks ± window) do not have an overall lesion response of SD, PR or CR. Patients with an 
unknown (UNK) assessment at that time point and no PD before, will not be counted as early 
progressors in the analysis but may be included in the denominator of the EPR rate, depending 
on the analysis population used. Similarly when examining overall response and disease control, 
patients with a best overall response assessment of unknown (UNK) will not be regarded as 
“responders” but may be included in the denominator for ORR and DCR calculation depending 
on the analysis population (e.g. populations based on an ITT approach). 
14.1.3.2 Time to event variables 
The protocol should state which of the following variables is used in that study. 
14.1.3.2.1 
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, progression-free survival is censored at the date of last adequate 
tumor assessment. 
PFS rate at x weeks is an additional measure used to quantify PFS endpoint. It is recommended 
that a Kaplan Meier estimate is used to assess this endpoint. 
14.1.3.2.2 
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. 
14.1.3.2.3 
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. 
14.1.3.2.4 
PFS2 
A recent EMA guidance (EMA 2012) recommends a substitute end point intermediate to PFS 
and OS called PFS2, a surrogate for OS when OS cannot be measured reliably, which assesses 
the impact of the experimental therapy on next-line treatment. The main purpose of this 
endpoint is to assess long term maintenance strategies, particularly of resensitizing agents and 
where it is necessary to examine the overall “field of influence”. 
PFS2, which could be termed PFS deferred, PFS delayed, tandem PFS, or PFS version 2.0, is 
the time from date of randomization/start of treatment to the date of event defined as the first 
documented progression on next-line treatment or death from any cause. The censoring rules 
for this endpoint will incorporate the same principles as those considered for PFS in this 
document, and in addition may involve other considerations which will need to be detailed in 
the protocol. 
Please note that data collection for the PFS2 is limited to the date of progression and not specific 
read of the tumor assessments. 
It is strongly recommended that the teams consult regulatory agencies for scientific advice given 
the limited experience with the use of this endpoint in regulatory setting in light of 
methodological issues w.r.t. censoring foreseen. 


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14.1.3.2.5 
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. 
14.1.3.2.6 
Duration of response 
The analysis of the following variables should be performed with much caution when restricted 
to responders since treatment bias could have been introduced. There have been reports where 
a treatment with a significantly higher response rate had a significantly shorter duration of 
response but where this probably primarily reflected selection bias which is explained as 
follows: It is postulated that there are two groups of patients: a good risk group and a poor risk 
group. Good risk patients tend to get into response readily (and relatively quickly) and tend to 
remain in response after they have a response. Poor risk patients tend to be difficult to achieve 
a response, may have a longer time to respond, and tend to relapse quickly when they do respond. 
Potent agents induce a response in both good risk and poor risk patients. Less potent agents 
induce a response mainly in good risk patients only. This is described in more detail by  
Morgan (1988). 
It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then interpreted 
with caution by evaluating the results in the context of the observed response rates. If an 
inferential comparison between treatments is required this should only be performed on all 
patients (i.e. not restricting to “responders” only) using appropriate statistical methods such as 
the techniques described in Ellis et al (2008). It should also be stated in the protocol if duration 
of response is to be calculated in addition for unconfirmed response. 
For summary statistics on “responders” only the following definitions are appropriate. (Specific 
definitions for an all-patient analysis of these endpoints are not appropriate since the status of 
patients throughout the study is usually taken into account in the analysis). 
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed the start date is the date of first documented response (CR or PR) and the end date 
and censoring is defined the same as that for time to progression. 
The following two durations might be calculated in addition for a large Phase III study in which 
a reasonable number of responders is seen. 


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Duration of overall complete response (CR): For patients with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression. 
Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to be 
confirmed) or SD the start and end date as well as censoring is defined the same as that for time 
to progression. 
14.1.3.2.7 
Time to response 
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be confirmed 
depending on the type of study and its importance. Where the response needs to be confirmed 
then time to response is the time to the first CR or PR observed. 
Although an analysis on the full population is preferred a descriptive analysis may be performed 
on the “responders” subset only, in which case the results should be interpreted with caution 
and in the context of the overall response rates, since the same kind of selection bias may be 
introduced as described for duration of response in Section 14.1.3.2.6. It is recommended that 
an analysis of all patients (both responders and non-responders) be performed whether or not a 
“responders only” descriptive analysis is presented. Where an inferential statistical comparison 
is required, then all patients should definitely be included in the analysis to ensure the statistical 
test is valid. For analysis including all patients, patients who did not achieve a response (which 
may have to be a confirmed response) will be censored using one of the following options. 
• at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the worst 
possible outcome as it means the patient cannot subsequently respond. Since the statistical 
analysis usually makes use of the ranking of times to response it is sufficient to assign the 
worst possible censoring time which could be observed in the study which is equal to the 
maximum follow-up time (i.e. time from FPFV to LPLV) 
• at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding 
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint. 
14.1.3.2.8 
Definition of start and end dates for time to event variables 
Assessment date 
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest of 
all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that assessment is 
CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the assessment date is 
calculated as the earliest date of all measurement dates at that evaluation number. 
In the calculation of the assessment date for time to event variables, any unscheduled 
assessment should be treated similarly to other evaluations. 


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Start dates 
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date. 
For the calculation of duration of response the following start date should be used: 
• Date of first documented response is the assessment date of the first overall lesion response 
of CR (for duration of overall complete response) or CR / PR (for duration of overall 
response) respectively, when this status is later confirmed. 
End dates 
The end dates which are used to calculate ‘time to event’ variables are defined as follows: 
• Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page). 
• Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease. 
• Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) the date 
of randomization/start of treatment is used. 
• Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 14.1.3.2.9). 
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months. 
• Date of discontinuation is the date of the end of treatment visit. 
• Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date patient alive from the survival follow-up page is used. 
If no survival follow-up is available, the date of discontinuation is used as last contact date. 
• Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery. 
14.1.3.2.9 
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 14-4. 
Table 14-4 
Overall lesion response at each assessment: patients with non-target 
disease only 
Non-target lesions 
New Lesions 
Overall lesion response 
CR 
No 
CR 
Non-CR/Non-PD1 
No 
Non-CR/non-PD 
UNK 
No 
UNK 
PD 
Yes or No 
PD 
Any 
Yes 
PD 
1 As defined in Section 14.1.2.4. 
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category. 
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account. 
For ORR it is recommended that the main (ITT) analysis includes data from patients with only 
non-measurable disease at baseline, handling patients with a best response of CR as “responders” 
with respect to ORR and all other patients as “non-responders”. 
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses which 
exclude these particular patients. Endpoints such as PFS which are reliant on the determination 
and/or timing of progression can incorporate data from patients with only non-measurable 
disease. 
14.1.3.2.10 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 SAP 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 14.1.3.2.8, 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 14-5 
Options for event dates used in PFS, TTP, duration of response 
Situation 
Options for end-date (progression or 
censoring)1 
(1) = default unless specified differently in the 
protocol or RAP 
Outcome 
A 
No baseline assessment 
(1) Date of randomization/start of treatment3 
Censored 
B 
Progression at or before next 
scheduled assessment 
(1) Date of progression 
(2) Date of next scheduled assessment2 
Progressed 
Progressed 
C1 
Progression or death after exactly 
one missing assessment 
(1) Date of progression (or death) 
(2) Date of next scheduled assessment2 
Progressed 
Progressed 
C2 
Progression or death after two or 
more missing assessments 
(1) Date of last adequate assessment2 
(2) Date of next scheduled assessment2 
(3) Date of progression (or death) 
Censored 
Progressed 
Progressed 
D 
No progression 
(1) Date of last adequate assessment 
Censored 
E 
Treatment discontinuation due to 
‘Disease progression’ without 
documented progression, i.e. clinical 
progression based on investigator 
claim 
(1) 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 (IIT approach) 
(2) Date of last adequate assessment prior to 
new anticancer therapy 
(3) Date of secondary anti-cancer therapy 
(4) Date of secondary anti-cancer therapy 
As per above 
situations 
Censored 
 
Censored 
Event 
G 
Deaths due to reason other than 
deterioration of ‘Study indication’ 
(1) Date of last adequate assessment 
Censored (only 
TTP and 
duration of 
response) 
1. =Definitions can be found in Section 14.1.3.2.8. 
2. =After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in  
Section 14.1.3.2.8. 
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 14-5 the 
“Date of last adequate assessment” by the “Date of previous scheduled assessment (from 
baseline)”, with the following definition: 
• Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly followed 
from baseline, immediately before or on the date of the last adequate tumor assessment. 
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on the 
individual requirements for the specific study and disease area and have to be specified in the 
protocol or SAP documentation. 


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14.1.4 
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). 
14.1.4.1 Study/project specific decisions 
For each study (or project) various issues need to be addressed and specified in the protocol or 
SAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the SAP 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 SAP 
documentation before database lock). 
14.1.4.2 End of treatment phase completion 
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow-
up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc. 
The end of treatment visit and its associated assessments should occur within 7 days of the last 
study treatment. 
Patients may discontinue study treatment for any of the following reasons: 
• Adverse event(s) 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 
• Subject/guardian decision 
• Progressive disease 
• Study terminated by the sponsor 
• Non-compliant with study treatment 
• No longer requires treatment 
• Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given) 
Death is a reason which “must” lead to discontinuation of patient from trial 
14.1.4.3 End of post-treatment follow-up (study phase completion) 
End of post-treatment follow-up visit will be completed after discontinuation of study treatment 
and post-treatment evaluations but prior to collecting survival follow-up. 
Patients may provide study phase completion information for one of the following reasons: 


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• Adverse event 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 
• Subject/guardian decision 
• Death 
• Progressive disease 
• Study terminated by the sponsor 
14.1.4.4 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 
SAP documentation and agreed before database lock. This dataset should be created and stored 
as part of the ‘raw’ data. 
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation. 
14.1.4.5 Programming rules 
The following should be used for programming of efficacy results: 
14.1.4.5.1 
Calculation of ‘time to event’ variables 
Time to event = end date - start date + 1 (in days) 


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When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative. 
14.1.4.5.2 
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 14.1.3.2.8). If all measurement dates have 
no day recorded, the 1st of the month is used. 
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation. 
14.1.4.5.3 
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. 
14.1.4.5.4 
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)’. 
14.1.4.5.5 
Study/project specific programming 
The standard analysis programs need to be adapted for each study/project. 
14.1.4.5.6 
Censoring reason 
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page. 
For survival the following censoring reasons are possible: 
• Alive 
• Lost to follow-up 
• For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible: 
• Ongoing without event 
• Lost to follow-up 
• Withdrew consent 
• Adequate assessment no longer available* 
• Event documented after two or more missing tumor assessments (optional, see Table 14-5) 


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• Death due to reason other than underlying cancer (only used for TTP and duration of 
response) 
• Initiation of new anti-cancer therapy 
*Adequate assessment is defined in Section 14.1.3.2.8. This reason is applicable when adequate 
evaluations are missing for a specified period prior to data cut-off (or prior to any other 
censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason should 
also be noted: 
• This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Sponsor decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off). 
• The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative anti-
cancer therapy) has occurred more than the specified period following the last adequate 
assessment. 
• This reason will also be used to censor in case of no baseline assessment. 


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14.1.5 
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, Vol.45: 228-47. 
Ellis S, et al (2008). Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465. 
EMA Guidance: 2012. Guideline on the evaluation of anticancer medicinal products in man. 
FDA Guidelines: 2005. Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005. 
FDA Guidelines: 2007. Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007. 
Morgan TM (1988). Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18. 
Therasse P, Arbuck S, Eisenhauer E, et al (2000). New Guidelines to Evaluate the Response 
to Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16. 




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where n is the sample size of this set of co-data, σ is the “outcome standard deviation” for one 
observation and τ is the between-trial/drug variant standard deviation. n*∞ is the maximum 
prior effective sample size under infinite historical information. σ will be chosen as 2. τ will be 
chosen depending on the degree of heterogeneity. For substantial heterogeneity, the maximum 
prior effective sample size is 16, which implies that τ is set to 0.5. For large heterogeneity, the 
maximum prior effective sample size is 4, which implies that τ is set to 1. 
Note that there may be more than one study/drug variant from which we want to borrow 
information for the current study/drug variant. The weights will vary between these co-data sets 
depending on different sample sizes and also on different degrees of heterogeneity. 
Table 14-6 shows the heterogeneity of data from different sources to be considered. 
Table 14-6 
Levels of heterogeneity for co-data from different studies and/or drug 
formulations 
Co-data 
Levels of heterogeneity considered in data down-
weighting 
Study # 
Formulations 
Formulation: capmatinib 
tablet + nazartinib capsule 
Formulation: capmatinib 
tablet + nazartinib tablet 
CEGF816X2101 
nazartinib capsules 
substantial 
large 
nazartinib tablets 
Large 
substantial 
14.2.3 
Prior specifications 
The Bayesian approach requires the specification of prior distributions for the model parameters 
(log(α1), log(β1)) for nazartinib, (log(α2), log(β2)) for capmatinib and η for interaction. The 
derivation of the prior distributions is described below. 
14.2.3.1 nazartinib prior specification for (log(α1), log(β1)) 
Prior specification 
A weakly informative bivariate normal prior for the model parameters (log(α1), log(β1)) as in 
the first-in-human study [CEGF816X2101] is taken as the prior for the nazartinib parameters. 
Based on prior guesses (medians) from preclinical data and wide confidence intervals for the 
probabilities of DLT at each dose, the prior distribution is derived as follows: 
• For the purposes of tuning the prior for the model, the median DLT rate at 75 mg q.d. is 
assumed to be at 0.1%, and the median DLT rate at 750 mg q.d. is assumed to be at 25%. 
For the remaining doses, median DLT rates a priori are assumed linear in the logit-scale as 
a function of log-dose. 
• Based on the above specified medians for the DLT rate at certain doses and wide prior 
confidence intervals, the optimal parameters of the bivariate normal distribution can be 
obtained following the procedure described by Neuenschwander et al (2008). 


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The parameters of the derived prior distribution for (log(α1), log(β1)) are presented in 
Table 14-7. 
Table 14-7 
Prior distribution of model parameters (log(alpha1), log(beta1)), as in 
CEGF816X2101 
Parameter 
Means 
Standard deviations 
Correlation 
log(α1), log(β1) 
-3.068, 0.564 
2.706, 0.728 
-0.817 
Newly available dose-DLT data from the [CEGF816X2101] study will be used to update the 
model after down-weighting the data as mentioned in Section 14.2.1. Substantial heterogeneity 
will be assumed: 
 
At the time of protocol amendment 1, new dose-DLT data has been available from study 
[CEGF816X2101] (refer to Table 14-9), and are included in the model to update the distribution 
of the DLT rate of the combination (as detailed in Section 14.2.3.4). 
14.2.3.2 Capmatinib prior specification for (log(α2), log(β2)) 
Historical data 
The currently available dose-DLT data of capmatinib single agent in capsule formulation and 
b.i.d. dosing schedule from the following clinical studies are considered as the relevant 
information (
) and used to derive the prior distribution for the BLRM parameters 
(log(α2), log(β2)). 


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Prior specification 
A mixture prior for the model parameters (log(α2), log(β2)), which are assumed to follow a 
bivariate normal distribution, is derived in the following steps as for 
: 
1. To use the historical dose-DLT data from the clinical studies in Table 14-8, each capsule 
dose level need to be converted to a tablet dose level. Given a conversion factor c, a capsule 
dose level dc is considered to be equivalent to a tablet dose level dt = dc/c. Based on data of 
the relative bioavailability study 
 in healthy volunteers, the estimated 
relative exposure (AUClast) of tablet vs. capsule has a geometric mean ratio of 
 and a 
90% CI of [
]. To account for uncertainty of dose conversion between the two 
formulations, three values of c are considered: 
, i.e. the estimated mean 
and confidence limits, to generate three informative prior components (Table 14-9) using 
the meta-analysis predictive (MAP) approach: 
• The prior distribution of mean of (log(α2), log(β2)) is assumed to follow a normal 
distribution with mean  and standard deviation  for log(α2), and mean  and standard 
deviation  for log(β2). 
• A substantial between-study heterogeneity is assumed and captured in the prior 
distributions of the standard deviations of (log(α2), log(β2)), denoted by τα and τβ. Both 
τα and τβ are assumed to follow a log-normal distribution with mean log(
) and 
log(
), respectively, and a standard deviation of 
 for both. 
• The prior distribution of correlation between log(α2) and log(β2) is assumed to follow a 
uniform distribution in [-1, 1]. 








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Table 14-12 
Hypothetical dose escalation scenarios 
Scenari
o 
Current status 
For next cohort 
capmatini
b 
(mg b.i.d.) 
nazartini
b 
capsule 
(mg q.d.) 
# 
Participa
nt 
# 
DL
T 
capmatini
b 
(mg b.i.d.) 
nazartini
b 
capsule 
(mg q.d.) 
P(targe
t) 
P(over
) 
Media
n DLT 
rate 
1 
200 
50 
3 
0 
200 
400 
100 
50 
0.081 
0.156 
0.006 
0.020 
0.049 
0.069 
2 
200 
50 
4 
1 
200 
100 
0.234 
0.033 
0.101 
3 
200 
50 
3 
2 
STOP 
 
 
 
 
4 
200 
50 
4 
2 
100 
50 
0.226 
0.027 
0.102 
5 
200 
200 
50 
100 
3 
3 
0 
0 
200 
400 
200 
100 
0.114 
0.152 
0.021 
0.033 
0.048 
0.060 
6 
200 
200 
50 
100 
3 
4 
0 
1 
200 
400 
200 
100 
0.274 
0.316 
0.090 
0.111 
0.116 
0.136 
7 
200 
200 
50 
100 
3 
3 
0 
2 
200 
50* 
0.323 
0.020 
0.127 
8 
200 
400 
50 
50 
3 
4 
0 
0 
400 
600 
100 
50 
0.121 
0.148 
0.018 
0.031 
0.052 
0.063 
9 
200 
400 
50 
50 
3 
4 
0 
1 
400 
600 
100 
50 
0.313 
0.344 
0.093 
0.142 
0.130 
0.155 
10 
200 
400 
50 
50 
3 
4 
0 
2 
200* 
50 
0.494 
0.123 
0.192 
11 
200 
200 
50 
100 
3 
5 
0 
2 
200* 
50 
0.244 
0.008 
0.112 
12 
200 
200 
50 
100 
4 
4 
1 
1 
200 
200 
0.366 
0.172 
0.173 
13 
200 
200 
50 
100 
4 
4 
1 
2 
200 
50 
0.460 
0.038 
0.160 
14 
200 
200 
200 
50 
100 
200 
3 
3 
4 
0 
0 
0 
400 
200 
200 
400 
0.134 
0.146 
0.065 
0.080 
0.045 
0.051 
15 
200 
200 
400 
50 
100 
100 
3 
3 
4 
0 
0 
1 
400 
600 
200 
100 
0.266 
0.307 
0.225 
0.204 
0.207 
0.164 
16 
200 
200 
200 
50 
100 
200 
3 
4 
4 
0 
1 
1 
200 
200 
0.395 
0.091 
0.156 
17 
200 
200 
200 
50 
100 
200 
3 
4 
4 
0 
1 
2 
200 
100 
0.457 
0.032 
0.158 
18 
200 
200 
400 
50 
100 
100 
3 
4 
4 
0 
1 
2 
200 
100 
0.396 
0.029 
0.145 
19 
200 
200 
200 
50 
100 
200 
3 
4 
5 
0 
1 
2 
200 
100* 
0.401 
0.018 
0.145 
20 
200 
200 
200 
50 
100 
200 
3 
4 
5 
0 
1 
3 
200 
100 
0.585 
0.066 
0.192 
*- In these scenarios, although the model allows to stay at the same dose level combination, since two 
participants observed DLTs, as per protocol, one of two treatments has to be dose-reduced. 


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The BLRM is performing reasonably for the hypothetical dose escalation scenarios. In  
Table 14-12 it can be seen that the recommendations, based on the BLRM and protocol criteria, 
are in line with clinical sense leading to controlled dose escalation when the observed DLT rate 
is low (0/3 or 1/4), and a dose de-escalation when 2 or more DLTs are observed at a new dose 
level. 
The dose combinations satisfying the overdose criteria at a specific dose escalation meeting 
may differ from those presented in Table 14-12 above since newly available dose-DLT data 
from single-agent studies will be taken into account within the BLRM prior to these meetings. 
14.2.5 
Starting dose of the nazartinib tablet 
Before treating the first cohort of participants with the tablet formulation of nazartinib, the dose-
DLT data shown in Table 14-13 will be down-weighted (refer to Section 14.2.2 for the details 
of the down-weighting process) and incorporated into the BLRM assuming different levels of 
between trial/formulation heterogeneity (refer to Table 14-6 for details). The updated BLRM 
will be run to support the starting dose for this new formulation. 
Table 14-13 shows the historical data from different studies as of February 2015. Data from 
 and [CEGF816X2101] study will need to be further updated by the 
time of running the BLRM prior to starting the first cohort using nazartinib tablet formulation. 
Table 14-13 
Available dose-DLT data from single-agent studies as of February 
2015 
Agent 
Study 
Dose 
# Participants 
# DLT 
nazartinib (capsule) 
CEGF816X2101 
75 mg q.d. 
7 
0 
 
 
150 mg q.d. 
14 
0 
 
 
225 mg q.d. 
14 
1 
 
 
300 mg q.d. 
3 
0 
 
 
350 mg q.d. 
6 
2 
nazartinib (tablet) 
CEGF816X2101 
225 mg q.d. 
6 
0 


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14.2.6 
References (available upon request) 
EMEA (2007). Guideline on Clinical Trials in Small Populations. Committee for Medicinal 
Products for Human Use (CHMP).Neuenschwander B, Branson M, Gsponer T (2008). 
Critical aspects of the Bayesian approach to phase I cancer trials. Statist. Med, 2008; 27: 
2420-2439. 
Neuenschwander B, Capkun-Niggli G, Branson M, et al (2010). Summarizing historical 
information on controls in clinical trials. Clinical Trials; 7 (1):5-18. 
Rogatko A, Schoeneck D, Jonas W, et al (2007). Translation of innovative designs into phase 
I trials. J Clin Oncol; 25: 4982-6. 


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14.3 
Appendix 3 - Permitted concomitant medications requiring 
caution 
If a medication that is listed in both Table 14-14 and Table 14-16, more stringent practice shall 
be applied (that is, the medication shall be prohibited as in Table 14-16). 
Table 14-14 
Permitted concomitant medications requiring caution with capmatinib 
and nazartinib 
Mechanism of Interaction 
Drug Name 
Moderate CYP3A4 inhibitor 
amprenavir, aprepitant, atazanavir, casopitant, cimetidine, ciprofloxacin, 
crizotinib, cyclosporin, darunavir/ritonavir, diltiazem, dronedarone, 
erythromycin, faldaprevir, fluconazole, fosamprenavir, grapefruit juice, 
imatinib, lomitapide, netupitant, nilotinib, schisandra sphenanthera, 
tofisopam, verapamil 
Moderate CYP3A4 inducer 
bosentan, efavirenz, etravirine, genistein, lersivirine, lopinavir, modafinil, 
nafcillin, [talviraline], ritonavir, semagacestat, talviraline, thioridazine 
Sensitive CYP1A2 substrate 
alosetron, caffeine, duloxetine, melatonin, ramelteon, selegiline, tacrine, 
tizanidine 
Sensitive CYP2C9 substrate 
celecoxib 
Sensitive CYP2C19 substrate 
clobazam, dexlansoprazole, diazepam, gliclazide, lansoprazole, (R)-
lansoprazole, (S)-lansoprazole, (R)-mephobarbital, omeprazole, (R)-
omeprazole, pantoprazole, (+) pantoprazole, rabeprazole, tilidine 
Sensitive CYP3A4 substrate 
alfentanil, almorexant, aplaviroc, aprepitant, atazanavir, atorvastatin, 
avanafil, bosutinib, brecanavir, brotizolam, budesonide, buspirone, 
capravirine, casopitant, conivaptan, danoprevir, darifenacin, darunavir, 
dasatinib, 
alpha-dihydroergocryptine, 
eplerenone, 
everolimus, 
felodipine, fluticasone, ibrutinib, indinavir, ivacaftor, levomethadyl, 
lomitapide, lopinavir, lovastatin, lumefantrine, lurasidone, maraviroc, 
midazolam, midostaurin, neratinib, nisoldipine, perospirone, quetiapine, 
ridaforolimus, saquinavir, sildenafil, simeprevir, simvastatin, ticagrelor, 
terfenadine, ticagrelor, tilidine, tipranavir, tolvaptan, triazolam, vardenafil, 
vicriviroc, voclosporin 
P-gp substrates 
aliskiren, ambrisentan, atorvastatin, atorvastatin acid, azithromycin, 
cerivastatin, colchicine, CP-481,715, cyclosporine, dabigatran, digoxin, 
docetaxel, domperidone, doxorubicin, fentanyl, fexofenadine, lapatinib, 
linezolid, loperamide, maraviroc, nevirapine, paclitaxel, proguanil, 
quinidine, ranolazine, ritonavir, saquinavir, simvastatin, sirolimus, 
sofosbuvir, tacrolimus, ticagrelor, voclosporin 
P-gp inhibitors 
alogliptin, amiodarone, azithromycin, canaglifozin, captopril, carvedilol, 
clarithromycin, conivaptan, cremophor RH40, curcumin, diltiazem, 
dronedarone, elacridar, erythromycin, felodipine, fluvoxamine, ginko, 
indinavir, indinavir/ritonavir, itraconazole, ketoconazole, lapatinib, 
lopinavir/ritonavir, mibefradil, milk thisle, mirabegron, nelfinavir, 
nifedipine, nitredipine, paroxetine, propafenone, quercetin, quinidine, 
ranolazine, rifampin, ritonavir, sequinavir/ritonavir, schisandra chinesis 
extract, simepravir, St. John’s wort extract, talinolol, telaprevir, 
telmisartan, 
ticagrelor, 
tipranavir/ritonavir, 
tolvaptan, 
valspodar, 
vandetanib, verapamil, voclosporin 
P-gp inducers 
avasimibe, carbamazepine, efavirenz, genistein, phenytoin, quercetin, 
rifampin, St. John’s Wort extract 
BCRP substrate 
atorvastatin daunorubicin, doxorubicin, hematoporphyrin, imatinib, 
methotrexate, 
mitoxantrone, 
pitavastatin, 
rosuvastatin, 
SN-38 
(irinotecan), ethinyl estradiol, simvastatin, sulfasalazine, sofosbuvir, 
topotecan, sulfasalazine 
MATE substrate 
Metformin, tenfovir 


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Mechanism of Interaction 
Drug Name 
OATP substrates 
aliskiren, ambrisentan, anacetrapib, atenolol, atrasentan, atorvastatin, 
bosentan, bromociptine, caspofungin, cerivastatin, celiprolol, danoprevir, 
empangliflozin, 
ezetimibe, 
fimasartan, 
fexofenadine, 
fluvastatin, 
glyburide, maraviroc, SN-38, rosuvastatin, simvastatin acid, pitavastatin, 
pravastatin, repaglinide, rifampin, valsartan, olmesartan, telmisartan, 
montelukast, ticlopidine 
Source: Adapted from Oncology Clinical Pharmacology Drug-Drug Interaction Database (release date: April 
2015) which was compiled from the Indiana University School of Medicine’s “Clinically Relevant” Table and 
supplemented with the FDA Draft Guidance for Industry, Drug Interaction Studies – Study Design, Data Analysis, 
and Implications for Dosing and Labeling (February 2012), and the University of Washington’s Drug Interaction 
Database. The lists provided may not be exhaustive. 
Sensitive substrates: Drugs that exhibit an AUC ratio (AUCi/AUC) of 5-fold or more when co-administered with 
a known potent inhibitor. 
If a medication that is listed in both Table 14-15 and Table 14-17, more stringent practice shall 
be applied (that is, the medication shall be prohibited as in Table 14-17). 
Table 14-15 
Permitted concomitant medications requiring caution with capmatinib 
monotherapy in Phase II Group 5 
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, phenytoin, 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 


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Mechanism of Interaction 
Drug Name 
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 databases for 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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14.4 
Appendix 4 - Prohibited concomitant medications 
Table 14-16 
Prohibited concomitant medications with capmatinib and nazartinib 
Mechanism of Interaction 
Drug Name 
Strong CYP3A4 inhibitor 
boceprevir, clarithromycin, cobicistat, conivaptan, grapefruit juice10, indinavir, 
itraconazole, ketoconazole, mibefradil, nefazodone, nelfinavir, posaconazole, 
ritonavir, saquinavir, telaprevir, telithromycin, voriconazole, troleandomycin, 
danoprevir/ritonavir, eltegravir/ritonavir, indinavir/ritonavir, lopinavir/ritonavir 
(HIV), saquinavir/ritonavir, tipranoavir/ritonavir 
Strong CYP3A4 inducer 
avasimibe, 
carbamazepine, 
enzalutamide, 
mitotane, 
phenobarbital, 
phenytoin, rifabutin, rifampin, St. John's wort 
CYP1A2 substrate with NTI 
theophylline, tizanidine 
CYP2C8 substrate with NTI 
Paclitaxel 
CYP2C9 substrate with NTI 
phenytoin, warfarin 
CYP2C19 substrate with NTI 
(S)-mephenytoin 
CYP3A4 substrate with NTI 
alfentanil, 
astemizole, 
cisapride, 
cyclosporine, 
diergotamine, 
dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, 
tacrolimus, terfenadine, thioridazine 
P-gp substrate with NTI 
cyclosporine, digoxin, fentanyl, paclitaxel, phenytoin, quinidine, sirolimus, 
tacrolimus 
Source: Adapted from Oncology Clinical Pharmacology Drug-Drug Interaction Database (release date: April 
2015) which was compiled from the Indiana University School of Medicine’s “Clinically Relevant” Table and 
supplemented with the FDA Draft Guidance for Industry, Drug Interaction Studies – Study Design, Data Analysis, 
and Implications for Dosing and Labeling (February 2012), and the University of Washington’s Drug Interaction 
Database. The lists provided may not be exhaustive. NTI: narrow therapeutic index 
Live vaccines 
e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow 
fever, varicella, and TY21a typhoid vaccines, COVID-19 vaccines 
Medications with a known risk to 
prolong the QT interval and/or 
known to cause Torsades de 
Pointe 
amiodarone, anagrelide, arsenic trioxide, astemizole (off US mkt), 
azithromycin, bepridil (off US mkt), chloroquine, chlorpromazine, cisapride (off 
US mkt), citalopram, clarithromycin, cocaine, disopyramide, dofetilide, 
domperidone (not on US mkt), dronedarone, droperidol, erythromycin, 
escitalopram, flecainide, grepafloxacin (off market worldwide), halofantrine, 
haloperidol, ibutilide, levofloxacin, levomethadyl (off US mkt), mesoridazine 
(off US mkt), methadone, moxifloxacin, ondansetron, pentamidine, pimozide, 
probucol (off US mkt), procainamide (oral off US mkt), quinidine, sevoflurane, 
sotalol, sparfloxacin (off US mkt), sulpiride (not on US mkt), terfenadine (off 
US mkt), thioridazine, vandetanib 
For a comprehensive list of drugs, refer to qtdrugs.org 
Table 14-17 
Prohibited concomitant medications with capmatinib monotherapy in 
Phase II Group 5  
Mechanism of Interaction 
Drug Name 
Strong CYP3A 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. 
 

SAP_001.pdf: 


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May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Document History – Changes compared to previous final version of SAP 
Date 
Time point 
Reason for 
update 
Outcome for 
update 
Section and title impacted (Current) 
18-Jul-
2017 
Prior to DB 
lock 
Creation of 
final version 
NA – First 
version 
NA 
11-Feb-
2018 
Prior to 
interim 
analysis DB 
lock 
Creation of 
amendment 
1 
Addition of 
subgroup 
definitions and 
analysis sets 
for the interim 
analysis 
2.1.2 Reports: 
The text was updated to state that 2 
different TFL shells documents will be 
created for the IA and the CSR, resp. 
2.2 Analysis sets: 
A subsection 2.2.1 on specific analysis 
sets for the interim analysis was added. 
The PPS was updated to be aligned 
regarding the definition of evaluable 
subjects. 
‘Subject Classification’ is now section 
2.2.3 and the section ‘Subgroups of 
interest’ 2.2.4. Two new subsections on 
brain metastases and on line of therapy 
were added. 
A new paragraph ‘Interim analysis 
efficacy analyses by subgroup’ was also 
inserted. 
2.14.2 Phase II part: 
The paragraph on analysis sets was 
updated to refer to Section 2.2 and 
2.2.1. 
 
 
 
Addition of an 
overview of 
efficacy 
analyses 
Chapter 5 Appendix: Section 5.5 was 
added. 
 
 
 
Update to the 
AESI 
2.8.1.1 Adverse events of special 
interest / grouping of AEs: The section 
was updated following the change from 
CRS to eCRS for both INC280 and 
EGF816. 
 
 
 
Clarifications 
in the text 
1 Introduction: Reference to the RECIST 
guideline was added, study document 
versions were updated. 
2.3.1 Basic demographic and 
background data: 25th and 75th 
percentiles were added as statistics to 
summarize continuous data. 
2.3.3 Subject disposition: Update to the 
tabulation for protocol deviations. 


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Date 
Time point 
Reason for 
update 
Outcome for 
update 
Section and title impacted (Current) 
2.5.1.2 Statistical hypothesis, model, 
and method of analysis – Phase Ib: 
Updated that the posterior distribution of 
the model parameters and of DLT rates 
will be presented for the model at the 
time of MTD declaration and at the end 
of the Phase Ib. Added that 
corresponding graphs will be produced. 
2.5.2.2.1 Group 1: A typo in the interval 
for moderate anti-tumor activity was 
corrected. 
2.5.2.4 Supportive analyses: Clarified 
that reasons for unknown BOR will be 
presented for both local and BIRC 
assessment results. 
2.8.1 Adverse events (AEs): Update to 
table SAE with fatal outcome. 
6 References: Update to reference 
Kunzmann (2016). 
Corrections of typos. 
31-Jul-
2018 
Prior to DB 
lock for 
primary 
analysis 
(group 3) 
Creation of 
amendment 
2 
Addition of 
subgroup for 
CNS 
metastases 
2.2.5.2 Subjects with CNS metastases: 
the definition of CNS metastases was 
added. 
 
 
 
Study 
documents’ 
versions 
1 Introduction: versions of Study 
specification document and Case 
Retrieval Sheets were updated. 
 
 
 
Cut-off date for 
Group 3 
primary 
analysis 
2.1.2 Reports: the primary analysis of 
Group 3 subjects will be performed for 
internal decision-making. 
 
 
 
Definition of a 
FAS and 
safety subset 
2.2.3 Subsets for the primary analysis of 
Group 3 subjects: FAS – 1L subjects 
and safety set – 1L subjects were 
defined. 
 
 
 
Definition of 
first-line 
patients in 
Group 4 
2.2.5.3 Line of therapy: a new derivation 
for first-line status of subjects in Group 4 
was added. 
 
 
 
 
2.3.1 Basic demographic and 
background data, disease history: 
grouping of metastatic sites (for in-text 
table) was added. 
 
 
 
Revised the 
exclusion of 
Group 2 from 
efficacy 
summaries 
2.7.1 Secondary endpoints: removed the 
sentence excluding Group 2. Despite the 
low number, Group 2 subjects will be 
included in tables.  


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Date 
Time point 
Reason for 
update 
Outcome for 
update 
Section and title impacted (Current) 
 
 
 
Clarification 
Several sections: Minor clarifications. 
19-Sep-
2018 
Prior to DB 
lock for 
primary 
analysis 
(group 3) 
Request from 
upper 
management 
Amendment 3: 
Adding a 
summary of 
time to first 
dose 
modification. 
2.4.1, Study treatment / compliance: 
Derivation rule for interruptions was 
updated. Analysis of time to first dose 
modification was added. 
 
 
 
Study 
document 
versions. 
1 Introduction: version of Study 
specification document was updated. 
12-Sep-
2020 
Prior to DB 
lock for 
final 
analysis 
New version 
of Novartis 
Hepatotoxicit
y Guideline; 
Covid-19-
related 
protocol 
deviations. 
Amendment 4: 
Addition of 
outputs for 
Covid-19 
related PDs. 
Modified 
analysis of 
liver function 
parameters. 
Revised to 
only present 
the required 
analyses and 
specifications 
for the final 
CSR. 
All sections: Text related to analyses 
other than for the final CSR were 
removed. Per program standard ‘c-MET’ 
was replaced by ‘MET’. The list of 
abbreviations was updated. 
1 Introduction: Versions of study 
documents were updated. 
A paragraph about the impact of the 
COVID-19 pandemic was added. 
2.1.4 General definitions: Minor 
clarification for baseline definition. 
2.2.2 Analyses by subgroup: The 
specific analyses were deleted to avoid 
having the same information in several 
sections. Reference is made to the 
sections 2.7, 2.8 and 2.11.6. 
2.3 Subject disposition, demographics 
and other baseline characteristics: 
paragraphs for baseline data that will not 
be analyzed and presented again were 
removed. 
2.3.3 Subject disposition: Analysis of 
COVID-19 related PDs was added. 
2.4.1 Study treatment / compliance: The 
summary of individual dose interruptions 
was removed. The specification for dose 
interruptions ongoing at the time of the 
data cut-off was changed (not expected 
for the final analysis). 
Prior anti-neoplastic therapies will not be 
reported again and the paragraphs were 
removed. 
2.5.1 Phase Ib: No analysis of the 
primary objective for Phase Ib will be 
done and the details were deleted. 


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Date 
Time point 
Reason for 
update 
Outcome for 
update 
Section and title impacted (Current) 
2.5.2.2 Statistical hypothesis, model, 
and method of analysis – Phase II 
Groups 1, 2, and 3: The Bayesian 
estimation of the ORR will not be done 
for the Final CSR; the related 
specifications were deleted. 
2.5.2.3 Handling of missing 
values/censoring/discontinuations – 
Phase II Groups 1, 2, and 3: Additional 
specifications of censoring for new anti-
cancer therapy were added. 
2.7.2 Statistical hypothesis, model, and 
method of analysis (Censoring pattern of 
OS): reason for death will not be 
summarized in the OS table, only the 
number of deaths and censorings. 
2.8.3 Laboratory data: Shift tables for lab 
parameters will not be prepared for the 
final CSR. The analysis of liver function 
parameters was modified to align with 
the current Novartis Hepatotoxicity 
Guideline. 
2.8.4.1 ECG: Change from baseline in 
ECG parameters by time point was 
added. 
2.8.4.3 ECOG performance status: 
Summary of performance status by time 
point was removed. 
2.11.5 Derivation of resistance 
mechanism subgroups for Phase Ib 
subjects: The subgroup categories for 
T790M & MET status crossed were 
updated to also include the missing and 
the individual categories. 
2.11.6 Biomarker analysis: The 
biomarker summary by response status 
(BOR) for MET expression was changed 
to IHC category (instead of H-score). A 
summary of PFS by biomarker 
categories (GCN and IHC) was added. 
Corresponding graphical displays will be 
generated for the Phase II treatment 
groups only (BOR and PFS). 
5.1.3 Other imputations: the imputation 
rules for start dates of post-treatment 
antineoplastic medications were 
specified in more detail (Table 5-3). 
6 References: Typo correction in 
reference Collett D (1994). 


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Date 
Time point 
Reason for 
update 
Outcome for 
update 
Section and title impacted (Current) 
06-Nov-
2020 
Prior to DB 
lock for 
final 
analysis 
Update of the 
last contact 
date 
definition 
Amendment 5:  
Update of the 
last contact 
date for OS 
Update Table 2-1 Last contact date data 
sources.  
Date of assessment collected on the 
“Survival information” eCRF will be 
considered for last contact date, this is 
aligned with eCRF completion guidelines 
(last known date patient alive is not 
required if subject is reported to be alive) 
25-Nov-
2021 
Prior to DB 
lock for 
interim 
CSR 
analysis 
Cancellation 
of final 
analysis and 
CSR 
The previous 
SAP 
(amendment 
5) for the final 
CSR analysis 
will be retired 
in CREDI 
Whole document 
25-Nov-
2021 
Prior to DB 
lock for 
interim 
CSR 
analysis 
Cancellation 
of final 
analysis and 
CSR 
Amendment 5 
(replacing the 
retired 
amendment 5) 
List of abbreviations: abbreviations were 
updated (removed/added). 
 
 
 
 
1 Introduction: Versions of study 
documents were updated. 
A paragraph to explain the canceled 
final CSR was added. 
A paragraph to explain the purpose of 
the current SAP was added. 
The paragraph on COVID-19 pandemic 
related protocol deviations was moved 
and updated. 
 
 
 
 
1.1.2 Phase II part: Final CSR was 
changed to interim CSR. 
 
 
 
 
2.1.1 Data included in the analysis: The 
paragraph was updated to include a 
separate cut-off date for efficacy 
analyses (to be used as censoring date). 
 
 
 
 
2.1.2 Reports: Final CSR was changed 
to interim CSR. 
 
 
 
 
2.1.4 General definitions: The paragraph 
on last contact date was updated. 
 
 
 
 
2.2.2.1 Resistance mechanism to EGFR 
TKI treatment: Update of the derivation 
of biomarker subgroup status for Phase 
II subjects (based on biomarker results 
instead of IRT data). 
 
 
 
 
2.3.3 Subject disposition: An additional 
analysis of COVID-19 related protocol 
deviations was added (per Novartis 
internal guidance). 


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Date 
Time point 
Reason for 
update 
Outcome for 
update 
Section and title impacted (Current) 
 
 
 
 
2.5.1 Phase Ib: Final CSR was changed 
to interim CSR. 
 
 
 
 
2.5.2.2 Statistical hypothesis, model, 
and method of analysis – Phase II 
Groups 1, 2, and 3: Final CSR was 
changed to interim CSR. 
 
 
 
 
2.7.1 Secondary endpoints: the efficacy 
cut-off date was added (TTR, PFS, OS). 
 
 
 
 
2.7.3 Handling of missing 
values/censoring/discontinuations: the 
efficacy cut-off date was added (PFS, 
OS). 
 
 
 
 
2.9 Pharmacokinetic endpoints: Final 
CSR was changed to interim CSR. 
 
 
 
 
2.11.1 Introduction: Final CSR was 
changed to interim CSR. 
 
 
 
 
2.11.4 General data handling and 
preprocessing: Updated the scope of 
Table 2-9 to Phase II. Clarified, that the 
biomarker test method needs to match 
the protocol requirements to be 
considered to derive resistance 
mechanism subgroups. 
 
 
 
 
2.11.5 Derivation of resistance 
mechanism subgroups: Removed “for 
Phase Ib subjects” from the subsection 
title. Also added Phase II in the text. 
Presentation of the T790M and MET 
status subgroups was changed to 
tabular format. 
 
 
 
 
4 Change to protocol specified analyses: 
A paragraph header was added for each 
change. 
 
 
 
 
5.1.1 Investigational drug: Final CSR 
replaced by interim CSR. 
 
 
 
 
6 References: References were 
updated. 
 
 
 
 
General: Correction of typos. 
09-Jun-
2022 
Prior to 
final DB 
lock 
Converting 
the interim 
CSR to the 
final CSR 
Amendment 6 
1 Introduction:  
The list of study documents was 
removed. 
The first paragraph was updated to 
explain that the interim CSR in 
preparation will be converted to the final 
CSR.  


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Date 
Time point 
Reason for 
update 
Outcome for 
update 
Section and title impacted (Current) 
In the paragraph header “Information on 
the cancelled final CSR analysis in 
2020” the “in 2020” was added as 
clarification. 
The paragraph “Information on the 
interim CSR” was changed 
to ”Information on the final CSR” and the 
text updated. 
 
 
 
 
All sections: Interim CSR was updated 
to final CSR, where applicable. 


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Table of contents 
List of abbreviations .......................................................................................................... 11 
1 
Introduction ....................................................................................................................... 13 
1.1 
Study design .......................................................................................................... 14 
1.1.1 
Phase Ib part .......................................................................................... 14 
1.1.2 
Phase II part........................................................................................... 14 
1.2 
Study objectives and endpoints ............................................................................. 16 
2 
Statistical methods ............................................................................................................. 17 
2.1 
Data analysis general information ......................................................................... 17 
 
 17 
2.1.2 
Reports .................................................................................................. 18 
2.1.3 
General analysis conventions ................................................................ 18 
2.1.4 
General definitions ................................................................................ 18 
2.2 
Analysis sets .......................................................................................................... 22 
2.2.1 
Subject classification ............................................................................. 22 
2.2.2 
Subgroups of interest............................................................................. 22 
2.3 
Subject disposition, demographics and other baseline characteristics .................. 25 
2.3.1 
Basic demographic and background data .............................................. 25 
2.3.2 
Medical history...................................................................................... 25 
2.3.3 
Subject disposition ................................................................................ 26 
2.4 
Treatments (study treatment, concomitant therapies, compliance) ....................... 27 
2.4.1 
Study treatment / compliance ................................................................ 27 
2.4.2 
Prior, concomitant and post therapies ................................................... 29 
2.5 
Analysis of the primary objective .......................................................................... 30 
2.5.1 
Phase Ib ................................................................................................. 30 
2.5.2 
Phase II .................................................................................................. 30 
2.6 
Analysis of the key secondary objective ............................................................... 35 
2.7 
Analysis of secondary efficacy objectives ............................................................. 35 
2.7.1 
Secondary endpoints ............................................................................. 35 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 36 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 38 
2.8 
Safety analyses....................................................................................................... 39 
2.8.1 
Adverse events (AEs) ............................................................................ 40 
2.8.2 
Deaths .................................................................................................... 41 
2.8.3 
Laboratory data ..................................................................................... 42 
2.8.4 
Other safety data ................................................................................... 43 


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2.9 
Pharmacokinetic endpoints .................................................................................... 45 
2.10 
Patient-reported outcomes ..................................................................................... 45 
2.11 
Biomarkers ............................................................................................................. 45 
2.11.1 
Introduction ........................................................................................... 45 
 
 46 
2.11.3 
List of biomarkers evaluated and the collection time points ................. 46 
2.11.4 
General data handling and preprocessing ............................................. 48 
2.11.5 
Derivation of resistance mechanism subgroups .................................... 49 
2.11.6 
Biomarker analysis ................................................................................ 51 
2.12 
Other exploratory analyses .................................................................................... 51 
2.13 
Interim analysis ...................................................................................................... 51 
2.13.1 
Phase Ib part .......................................................................................... 51 
2.13.2 
Phase II part........................................................................................... 52 
3 
Sample size calculation ..................................................................................................... 52 
4 
Change to protocol specified analyses .............................................................................. 52 
5 
Appendix ........................................................................................................................... 52 
5.1 
Imputation rules ..................................................................................................... 52 
5.1.1 
Investigational drug ............................................................................... 52 
5.1.2 
AE date imputation ............................................................................... 53 
5.1.3 
Other imputations .................................................................................. 54 
5.2 
AE coding/grading ................................................................................................. 56 
5.3 
Laboratory parameters derivations ........................................................................ 56 
5.3.1 
CTC grading for laboratory parameters ................................................ 56 
5.3.2 
Imputation rules .................................................................................... 56 
5.4 
Statistical models ................................................................................................... 57 
5.4.1 
Phase Ib ................................................................................................. 57 
6 
References ......................................................................................................................... 58 


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List of abbreviations 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANP 
Antineoplastic 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Classification 
BIRC 
Blinded Independent Review Committee 
BLRM 
Bayesian Logistic Regression Model 
BMI 
Body Mass Index 
BOR 
Best Overall Response 
CI 
Confidence Interval 
CNS 
Central Nervous System 
COVID-19 
Coronavirus Disease 2019 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAR 
Dosage Administration Record 
DBL 
Database Lock 
DCR 
Disease Control Rate 
DILI 
Drug-Induced Liver Injury 
DLT 
Dose Limiting Toxicity 
DOR 
Duration Of Response 
FAS 
Full Analysis Set 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
eDISH 
Evaluation of Drug-Induced Serious Hepatotoxicity 
EGFR 
Epidermal Growth Factor Receptor 
EOT 
End of Treatment 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
EWOC 
Escalation With Overdose Control 
FDA 
Food and Drug Association 
FISH 
Fluorescence In Situ Hybridization 
GCN 
Gene copy number 
HGLT 
High Level Group Terms 
HLT 
High Level Terms 
HR 
Heart Rate 
IA 
Interim analysis 
IHC 
Immuno-Histo-Chemistry 


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IRT 
Interactive Response Technology 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NGS 
Next Generation Sequencing 
NMQ 
Novartis MedDRA Query 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Overall Response Rate 
OS 
Overall Survival 
OSO 
Oncology Standard Outputs 
PCR 
Polymerase Chain Reaction 
PDI 
Planned dose intensity 
PDS 
Programming Datasets Specifications 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PPS 
Per-Protocol Set 
PR 
Partial Response 
PS 
Performance Status 
PT 
Preferred Term 
QTcF 
Corrected QT interval using Fridericia correction 
RECIST 
Response Evaluation Criteria in Solid Tumors  
RDI 
Relative dose intensity 
RP2D 
Recommended Phase 2 Dose 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SMQ 
Standard MedDRA Query 
SOC 
System Organ Class 
SSD 
Study Specification Document 
TA 
Tumor assessment 
TBL 
Total bilirubin 
TFLs 
Tables, Figures, Listings 
TKI 
Tyrosine Kinase Inhibitor 
TTP 
Time To Progression 
TTR 
Time To Response 
ULN 
Upper Limit of Normal 
UNK 
Unknown 
WBC 
White Blood Cell(s) 
WHO 
World Health Organization 
WHO DRL 
WHO Drug Reference Listing 
 




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• Planned visits not done at sites 
• Changes in drug supply method 
• Treatment not given 
• Subject discontinuation due to COVID-19 situation 
A cross-tabulation of COVID-19 related PD vs. relationship will also be produced. 
Based on a preliminary assessment, the impact on the efficacy and subjects’ safety is minimal 
and no other analyses are planned. 
1.1 
Study design 
This is a phase Ib/II, multi-center, open-label study in adult subjects with EGFR mutated non-
small cell lung cancer starting with a Phase Ib dose escalation part followed by a Phase II part. 
There is no randomization process, as all subjects will receive the same study treatment. 
1.1.1 
Phase Ib part 
In the Phase Ib part at least 18 subjects who have progressed on previous EGFR TKI treatment 
(e.g. post erlotinib, gefitinib or afatinib) will be enrolled. An adaptive Bayesian Logistic 
Regression Model (BLRM) with escalation with overdose control (EWOC) will guide the dose 
escalation to determine the maximal maximum tolerated dose (MTD) or recommended Phase 
II dose (RP2D). Before a drug dosage can be declared to be the MTD or RP2D, at least six 
subjects should have been treated at that dosage. 
The incidence of dose limiting toxicities (DLTs) is the primary endpoint for the Phase Ib part. 
1.1.2 
Phase II part 
Once the MTD or RP2D has been declared, approximately 115 additional subjects will be 
enrolled in the Phase II part, as shown in Figure 1-1, in order to assess the preliminary anti-
tumor activity of EGF816 in combination with INC280. 


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Figure 1-1 
Study design 
 
In the Phase II Group 1 (EGFRmut, any T790M, any MET, 2/4L antineoplastic, EGFR TKI 
resistant), subjects with a previously documented EGFRmutL858R/ex19del NSCLC, who develop 
resistance to EGFR TKI treatment (e.g. post erlotinib, gefitinib or afatinib) will be enrolled and 
assigned according to their acquired resistance mechanism to one of four sub-groups: 
• sub-group 1a: EGFRmutL858R/ex19del NSCLC with acquired mutation T790M (T790M+, 
MET dysregulation−). 
• sub-group 1b: EGFRmutL858R/ex19del NSCLC with demonstrated MET dysregulation 
(T790M−, MET dysregulation+). 
MET dysregulation is defined as either 
a. IHC 3+ (defined as ≥ 50% of cells staining with high intensity) and/or 
b. MET gene copy number ≥ 4 
• sub-group 1c: EGFRmutL858R/ex19del NSCLC with evidence of both acquired T790M and 
MET dysregulation (T790M+, MET dysregulation+). 
• sub-group 1d: EGFRmutL858R/ex19del NSCLC with MET dysregulation below the levels for 
sub-group b (T790M−, MET dysregulation−). 
At least 40 subjects will be enrolled in the Phase II part Group 1 with a minimum of 20 subjects 
harboring the T790M mutation among sub-groups 1a and 1c, and a minimum of 20 subjects 
who do not harbor the T790M mutation among sub-groups 1b and 1d. 
The Phase II part Group 2 (EGFRmut, de novo T790M, any MET, 1/3L antineoplastic, EGFR 
TKI naïve) will enroll approximately 5 NSCLC subjects who are EGFR inhibitor treatment 
(including anti-EGFR monoclonal antibodies) naïve and harbor T790M de novo mutation. The 
subjects may harbor or may not harbor an EGFR activating mutation (L858R and/or ex19del) 


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in addition to the EGFR T790M mutation of resistance. The incidence of de novo T790M 
mutation is rare (~1%). The enrollment in Group 2 will stop once the enrollment in the other 
groups is completed to allow for completion of recruitment within a reasonable timeframe. 
In the Phase II Group 3 (EGFRmut, T790M negative, any MET, 1L antineoplastic), a minimum 
of 40 subjects with documented EGFRmutL858R/ex19del NSCLC, who have never received any 
systemic antineoplastic therapy will be enrolled. 
In the Phase II Group 4 (EGFRmut, any T790M, any MET, 1L (treatment naïve) or 2–3L 
antineoplastic) approximately 30 subjects, with documented EGFRmut NSCLC, who have 
never received any systemic antineoplastic therapy or have failed a maximum of 2 lines of 
antineoplastic therapies for advanced disease will be enrolled. Group 4 subjects will take study 
treatment with food (unrestricted meal type) whilst subjects from all other groups will take the 
study treatment under fasting conditions. Approximately 10 subjects who are treatment-naïve 
for the advanced setting should be enrolled in Group 4 in order to collect some safety 
information on this subject population. 
Note for Phase II all groups: subjects who have received no more than 1 cycle of systemic 
antineoplastic therapy in the advanced setting are allowed. 
Treatment-naïve subjects should be enrolled in Group 3 as priority before being enrolled into 
Group 4. De novo T790M subjects should be enrolled into Group 4 as priority before being 
enrolled into Group 2. 
Overall response rate (ORR), as assessed by local investigators review of tumor response and 
using RECIST 1.1 criteria, is the primary endpoint in the Phase II of the study. 
One interim analysis was conducted for Phase II Group 3 (EGFRmut, T790M negative, any 
MET, 1L antineoplastic) when 21 evaluable subjects had completed at least 4 cycles of 
treatment or discontinued treatment prior to that time. 
The primary analysis was conducted based on all subjects’ data of the Phase Ib dose escalation 
part and the Phase II part up to the time when all treated subjects had completed 6 cycles (about 
6 months) of treatment. The primary analysis data were summarized in the primary CSR. 
 
1.2 
Study objectives and endpoints 
Table 1-1 
Study protocol objectives and related endpoints 
Objective 
Endpoint 
Primary 
 
Phase Ib part: To estimate the MTD or RP2D of 
EGF816 in combination with INC280 
Incidence of DLTs 
Phase II part: To estimate the preliminary anti-
tumor activity of EGF816 in combination with 
INC280 (Groups 1, 2 and 3) 
Overall response rate (ORR) per RECIST v1.1 
based on investigator’s assessment 
To characterize the safety and tolerability of 
EGF816 in combination with INC280 when taken 
with food (Group 4) 
Safety: Incidence and severity of AEs and SAEs 
Tolerability: Dose interruptions, reductions and 
dose intensity 






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Date of first administration of investigational drug 
The date of first administration of investigational drug is defined as the first date when a nonzero 
dose of investigational drug is administered and recorded on the ‘Dosage Administration 
Record’ (DAR) eCRF. The date of first administration of investigational drug will also be 
referred to as start of investigational drug or start of study drug. 
Date of last administration of investigational drug 
The date of last administration of investigational drug is defined as the last date when a non-
zero dose of investigational drug is administered and recorded on the DAR eCRF. The date of 
last administration of investigational drug will also be referred to as end of investigational drug 
or last date of exposure to the study drug. (Example: A subject had a permanent discontinuation 
of the study drug on 06-Jan-2015 after being put on a temporary interruption since 01-Jan-2015. 
In this case the last date of exposure is 31-Dec-2014). 
Date of first administration of study treatment 
The date of first administration of study treatment is derived as the first date when a nonzero 
dose of any component of study treatment was administered as per the DAR eCRF. (Example: 
if first dose of INC280 is administered on 05-Jan-2015, and first dose of EGF816 is 
administered on 03-Jan-2015, then the date of first administration of study treatment is on 03-
Jan-2015). 
Date of last administration of study treatment 
The date of last administration of study treatment is derived as the last date when a nonzero 
dose of any component of study treatment was administered as per DAR eCRF. (Example: if 
the last INC280 dose is administered on 15-Apr-2015, and the last dose of EGF816 is 
administered on 17-May-2015, then the date of last administration of study treatment is 17-
May-2015). 
Study day 
The study day describes the day of the event or assessment date, relative to the reference start 
date. 
The study day is defined as: 
• The date of the event (visit date, onset date of an event, assessment date etc.) − reference 
start date + 1 if the event is on or after the reference start date; 
• The date of the event (visit date, onset date of an event, assessment date etc.) − reference 
start date if the event precedes the reference start date. 
The reference start date for all assessments (e.g. safety, efficacy, PK) is the start of study 
treatment. 
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative. The displayed study day might be 
calculated based on an imputed date (see Section 5.1 regarding imputation rules). 


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Time unit 
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If 
duration is reported in months, duration in days will be divided by 30.4375. If duration is 
reported in years, duration in days will be divided by 365.25. 
Baseline 
For safety and efficacy evaluations, the last available assessment within 28 days on or before 
the date of start of study treatment is defined as ‘baseline’ assessment, unless otherwise stated 
under the related assessment section. 
Baseline can be the day before the first administration of study treatment or the same day as 
first administration of study treatment if a pre-dose assessment/value is available (e.g., ECG, 
PK samples, samples for biomarkers). 
If time is recorded for the first administration of study treatment and for a specific assessment 
performed on the day of first administration of study treatment, this assessment will be 
considered as baseline only if the assessment is performed at a time before the first 
administration of study treatment. 
In cases where multiple measurements meet the baseline definition, with no further flag or label 
that can identify the chronological order, the following rule will be applied: If values are from 
central and local laboratories, the value from the central assessment will be considered as 
baseline. If there are multiple values from the same laboratory (local or central), or collected 
for ECGs or vital signs, then the last value will be considered as baseline. 
If subjects have no value as defined above, the baseline result will be missing. 
On-treatment assessment/event and observation periods 
The overall observation period will be divided into three mutually exclusive segments: 
1. pre-treatment period: from day of subject’s informed consent to the day before first 
administration of study treatment 
2. on-treatment period: from date of first administration of study treatment to 30 days after 
date of last actual administration of any study treatment (including start and stop date) 
3. post-treatment period: starting at day 30 + 1 after last administration of study treatment 
If a clear assignment to the pre-, on-, or post-treatment period cannot be made, e.g., in case of 
specific incomplete dates, then the respective data will be assigned to the on-treatment period. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on-treatment and 
post-treatment deaths will be provided. In particular, summary tables for adverse events (AEs) 
will summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs). 
However, all safety data (including those from the post-treatment period) will be listed and 
those collected during the pre-treatment and post-treatment period will be flagged. 


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Windows for multiple assessments 
In order to summarize ECG data collected over time (including unscheduled visits), the 
assessments will be time slotted. The following general rule will be applied in creating the 
assessment windows: If more than 1 assessment is done within the same time window, the 
assessment performed closest to the target date will be used. If 2 assessments within a time 
window are equidistant from the target date, then the earlier of the 2 assessments will be used. 
If multiple assessments occur on the same date then the worst case will be used except for 
ECGs. Three ECGs are targeted to be measured at the protocol-defined (nominal) time-points. 
If a subject has more than one measurement at a specific time point, the average of all available 
measurements associated with the nominal time point will be used for the analysis. Data from 
all assessments (scheduled and unscheduled), including multiple assessments, will be listed. 
Last contact date 
The last contact date will be derived for subjects not known to have died at the analysis cut-off 
 using the last complete date among the following. 
Table 2-1 
Last contact date data sources 
Source data 
Conditions 
Last known date patient alive collected on the 
‘Survival information’ eCRF 
Subject status is reported to be unknown or lost 
to follow-up  
Date of assessment collected on the ‘Survival 
information’ eCRF 
Subject status is reported to be alive and missing 
last known date patient alive 
Start/end dates of anti-neoplastic therapies 
administered after study treatment discontinuation 
Non-missing medication or procedure term 
Study medication start/end dates from DAR eCRF 
 
Non-missing dose; zero doses are allowed 
Date of discontinuation from ‘End of Treatment’ 
eCRF and ‘End of post-treatment phase’ eCRF 
None 
Start/End dates of AE  
Non-missing verbatim AE term 
Tumor (RECIST) assessment date 
Evaluation is marked as ‘done’ 
Laboratory/PK collection dates 
Sample collection marked as ‘done’ 
Vital signs, ECG assessment dates 
At least one non-missing parameter value 
Performance status dates 
Non-missing performance status 
The last contact date is defined as the latest complete date from the above list or the cut-off date 
whichever comes first. The cut-off date will not be used for last contact date, unless the subject 
was seen or contacted on that date. No date post cut-off date will be used. Completely imputed 
dates (e.g. the analysis cut-off date programmatically imputed to replace the missing end date 
of a dose administration record) will not be used to derive the last contact date. Partial date 
imputation is allowed for event (death)/censoring if coming from ‘Survival information’ eCRF. 
The last contact date will be used for censoring of subjects in the analysis of overall survival. 


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2.2 
Analysis sets 
Full analysis set 
The Full analysis set (FAS) comprises all subjects who have received at least one dose of either 
INC280 or EGF816. Subjects will be analyzed according to the planned treatment they have 
been assigned to. 
Safety set 
The Safety set includes all subjects who received any study treatment (i.e. at least one dose of 
any component of the study treatment). Subjects will be analyzed according to the study 
treatment (regimen) they actually received. 
The actual treatment received corresponds to: 
• the assigned treatment if subjects took at least one dose of that treatment 
• the first treatment received if the assigned treatment was never received 
Each subject will be classified into and analyzed consistently within one (and only one) 
combination treatment group. 
2.2.1 
Subject classification 
Subjects may be excluded from the analysis sets defined above based on the protocol deviations 
(PDs) entered in the database and/or on specific subject classification rules defined in Table 2-
2. 
Table 2-2 
Subject classification based on protocol deviations and non-PD 
criteria 
Analysis set 
Protocol deviations leading to exclusion 
Non protocol deviation leading to 
exclusion 
FAS  
No written informed consent – INCL01 
– 
Safety set 
No written informed consent – INCL01 
– 
Withdrawal of informed consent 
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis data sets. The date on which 
a subject withdraws full consent is recorded in the eCRF. 
Additional data for which there is a separate informed consent, e.g. biomarker, collected in the 
clinical database without having obtained that consent will not be included in the analysis. 
These data will be excluded by the presence of the appropriate protocol deviation criterion. 
2.2.2 
Subgroups of interest 
The following subgroups will be used in analyses of efficacy. 


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2.2.2.1 
Resistance mechanism to EGFR TKI treatment 
Three subgroups will be considered regarding the acquired resistance mechanism to EGFR TKI 
treatment, based on the acquired T790M mutation status, the MET dysregulation status, and 
both combined. 
For subjects in Phase Ib the subgroup category will be derived from the biomarker results. 
Details are given in Section 2.11.5. 
For subjects in Phase II the subgroup category is collected in the IRT system 
. For 
the subgroup classification, the biomarker results will be used similar to the Phase Ib case, see 
Section 2.11.5. The subgroups will be summarized by means of a frequency table 
(T790M & MET status) and a contingency table (MET dysregulation status vs T790M mutation 
status) by treatment group. Percentages will be calculated using the number of subjects in the 
relevant analysis set or subgroup as the denominator. 
The subgroups will mainly be used in analyses for the Phase II Group 1. In addition, some 
analyses for Phase Ib subjects will also be prepared by these subgroups. 
Subjects in Phase II Group 3 and Group 4 also have subgroup categories collected in the IRT 
system. These will only be presented in a listing. 
T790M & MET status 
• T790M+, MET dysregulation− (Group 1 subgroup a) 
• T790M−, MET dysregulation+ (Group 1 subgroup b) 
• T790M+, MET dysregulation+ (Group 1 subgroup c1) 
• T790M−, MET dysregulation− (Group 1 subgroup c2) 
• Other/Unknown (Group 1 subgroup c3) 
T790M mutation status 
• T790M positive (or short T790M+): subjects with T790M mutation present (Group 1 
subgroup a or c1) 
• T790M negative (or short T790M−): subjects without acquired mutation T790M (Group 1 
subgroup b or c2) 
• T790M unknown (or short T790M?): subjects with unknown T790M status (Group 1 
subgroup c3) 
MET dysregulation status 
• MET dysregulated: subjects whose tumor sample analysis shows 
• IHC 3+ (defined as ≥ 50% of cells staining with high intensity) and/or 
• MET gene copy number ≥ 4 
(Group 1 subgroup b or c1) 
• MET not dysregulated: subjects without MET dysregulation as defined above (Group 1 
subgroup a or c2) 


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2.2.2.2 
Subjects with CNS metastases 
The presence or absence of CNS metastases (CNS mets) will be identified from the lesion 
locations (RECIST eCRF page) at baseline 
. 
• Category ‘CNS mets present’: subjects whose lesion locations contain one or more of the 
following values (case insensitive) 
BRAIN 
BRAIN STEM 
CEREBELLUM 
CEREBRAL CORTEX 
CEREBRUM 
CERVICAL SPINE 
CNS - NOT OTHERWISE SPECIFIED 
CNS: SUPRATENTORIAL 
CNS: INFRATENTORIAL 
CORPUS CALLOSUM 
FRONTAL 
LEPTOMENINGEAL 
LUMBAR SPINE 
OCCIPITAL 
PARIETAL 
PITUITARY 
PONS 
SPINAL CORD 
TEMPORAL 
THALAMUS 
THORACIC SPINE 
WHOLE BRAIN 
• Category ‘CNS mets absent’: will be assigned to all other subjects 
For outputs based on the investigator assessment, identification of CNS metastases at baseline 
will use the data from the investigator review. For outputs based on the BIRC assessment, 
identification of CNS metastases at baseline will use the data from the BIRC review. 
The number of subjects with CNS metastases in target lesions, non-target lesions, and new 
lesions as well as the responses on target lesions and non-target lesions will be summarized 
based on investigator and BIRC assessment, respectively. 
The CNS metastases subgroups will be used for efficacy analyses of ORR, DOR and PFS. 
Note: metastatic sites data collected in the Diagnosis and Extent of Cancer eCRF page will not 
contribute to the subgroup derivation. 




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Other 
Not all data collected at baseline will be listed again. The corresponding listings were provided 
in the [Primary CSR]. 
2.3.3 
Subject disposition 
The number (%) of subjects in the FAS who discontinued the study phases and the reason for 
discontinuation will be presented overall and by treatment group. 
The following summaries will be provided with percentages based on the total number of FAS 
subjects: 
Study treatment phase 
• Number (%) of subjects who are still on-treatment at the time of the data cut-off date for 
the analysis (based on the ‘End of Treatment Disposition’ eCRF not completed; for the 
final analysis the number is expected to be zero and will not be presented) 
• Number (%) of subjects who discontinued the study treatment phase (based on the ‘End of 
Treatment Disposition’ eCRF) 
• Primary reason for study treatment phase discontinuation (based on the discontinuation 
reason entered in the ‘End of Treatment Disposition’ eCRF) 
Post-treatment follow-up phase for subjects who discontinued the treatment phase 
• Number (%) of subjects who did not enter the post-treatment follow-up 
• Number (%) of subjects who entered the post-treatment follow-up and are still ongoing at 
the time of the data cut-off date for the analysis (based on the ‘End of Post Treatment 
Phase Disposition’ eCRF; for the final analysis the number is expected to be zero and will 
not be presented) 
• Number (%) of subjects who entered the post-treatment follow-up and have discontinued 
• Primary reason for discontinuation from the post-treatment phase 
Survival follow-up phase 
• Number (%) of subjects who did not enter the survival follow-up (based on the ‘End of 
Treatment Phase’ or ‘End of Post-treatment follow-up’ page) 
• Number (%) of subjects who entered the survival follow-up and are ongoing (based on the 
‘End of Treatment Phase’ or ‘End of Post-treatment follow-up’ page and the ‘Survival 
information’ page) 
• Number (%) of subjects who entered the survival follow-up and discontinued (based on 
the ‘End of Treatment Phase’ or ‘End of Post-treatment follow-up’ page and the ‘Survival 
information’ or ‘Death’ page) 
A listing of study completion by treatment group for Phase Ib and Phase II will be produced 
separately using the FAS.  


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Protocol deviations 
The number (%) of subjects in the FAS with any protocol deviation will be tabulated by 
deviation category and deviation (as specified in the study Data Handling Plan) overall and by 
treatment group. All protocol deviations will be listed. 
An additional table and listing will be provided to summarize and list, respectively, deviations 
related to the Covid-19 pandemic. A cross-tabulation of COVID-19 related PD vs. relationship 
will also be prepared. 
Analysis sets 
The number (%) of subjects in each analysis set (defined in Section 2.2) will be summarized by 
treatment group using the FAS as denominator. In addition, subjects excluded and reasons for 
exclusion from each analysis set will be listed. 
2.4 
Treatments (study treatment, concomitant therapies, 
compliance) 
2.4.1 
Study treatment / compliance 
Duration of exposure, actual cumulative dose, dose intensity (DI) and relative dose intensity 
(RDI) will be summarized by treatment group, separately for each component of study 
treatment. Duration of exposure will also be presented for the study treatment. Duration of 
exposure will be categorized into time intervals; frequency counts and percentages will be 
presented for the number of subjects in each interval. The number (%) of subjects who have 
dose reductions or interruptions, and the reasons, will be summarized by treatment group. 
Subject level listings of all doses administered on treatment along with dose change reasons 
will be produced. 
The safety set will be used for all summaries and listings of study treatment. 
Duration of exposure to study treatment 
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to the investigational drugs: 
Duration of exposure to study treatment (days) = (last date of exposure to study treatment) − 
(date of first administration of study treatment) + 1. 
The last date of exposure to study treatment is the latest of the last dates of exposure to any of 
the investigational drugs (see Section 2.1.4). 
Summary of duration of exposure to study treatment will include categorical summaries and 
continuous summaries (i.e. mean, standard deviation etc.) using the time unit weeks. The 
following time intervals will be presented: ≤ 4 weeks, 4–≤ 8 weeks, 8–≤ 12 weeks, 12–
≤ 16 weeks, 16–≤ 24 weeks, 24–≤ 32 weeks, 32–≤ 52 weeks, 52–≤ 78 weeks and >78 weeks. 


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Duration of exposure to investigational drugs 
Duration of exposure to investigational drug (days) = (last date of exposure to investigational 
drug) − (date of first administration of investigational drug) + 1. 
The last date of investigational drug exposure is defined as the date of last administration of a 
non-zero dose of the drug (see Section 2.1.4). 
For subjects who did not take any drug, the duration of drug exposure is by definition equal to 
zero. 
The exposure duration may include periods of temporary interruption. If a subject is still on 
treatment at the time of data cut-off, the end date of investigational drug/study treatment will 
be replaced by the data cut-off date and the above calculations will be applied. 
Summary of duration of exposure of investigational drug (INC280, EGF816) will include 
categorical summaries (based on the same time intervals as for study treatment) and continuous 
summaries (i.e. mean, standard deviation etc., with time unit day). 
Cumulative dose 
Cumulative dose of study treatment is defined as the total dose given during the study treatment 
exposure and will be summarized for each of the study treatment components (INC280 and 
EGF816, respectively). 
The planned cumulative dose for a study treatment component (INC280 or EGF816) refers to 
the total planned dose as per the protocol up to the last date of investigational drug 
administration. The planned cumulative dose will not be summarized or listed. It will be used 
for relative dose intensity calculations. 
The actual cumulative dose refers to the total actual dose administered, over the duration for 
which the subject is on the study treatment as documented in the DAR eCRF. 
For subjects in the Safety Set who did not take one component of study treatment the cumulative 
dose for that component is by definition equal to zero. 
For continuous dosing, the actual cumulative dose is the sum of the non-zero doses recorded 
over the dosing period and the planned cumulative dose is the planned starting dose summed 
over the same dosing period. 
Dose intensity and relative dose intensity 
Dose intensity (DI) for subjects with non-zero duration of exposure is defined as follows for 
each of the study treatment components (INC280, EGF816): 
DI (mg/day) = actual cumulative dose (mg) / duration of exposure (days). 
For subjects who did not take any drug the DI is by definition equal to zero. 
Planned dose intensity (PDI) is defined as follows: 
PDI (mg/day) = planned cumulative dose (mg) / duration of exposure (days). 
Relative dose intensity (RDI) is defined as follows: 


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RDI = DI (mg/day) / PDI (mg/day). 
DI and RDI will be summarized separately for each of the study treatment components, using 
the duration of exposure of each of the components. The summary of RDI includes categorical 
summaries for RDI expressed as percentage for the following intervals: ≤ 75%, >75–90%, >90–
110%, ≥ 110%. 
Dose reductions, interruptions or permanent discontinuations 
The number of subjects who have dose reductions, permanent discontinuations or interruptions, 
and the reasons, will be summarized separately for each of the study treatment components 
(INC280, EGF816). 
 ‘Dose interrupted’ and ‘Dose permanently discontinued’ fields from the DAR eCRF together 
with the dose taken will be used to derive the dose reductions, dose interruptions, and permanent 
discontinuations, respectively. 
The corresponding field ‘Reason for dose change/dose interrupted’ will be used to summarize 
the reasons. 
A dose change is either ‘change in prescribed dose level’ or ‘dosing error’ where actual dose 
administered/total daily dose is different from the prescribed dose. 
For the purpose of summarizing interruptions and reasons, in case multiple entries for 
interruption are entered on consecutive days with different reasons they will be counted as 
separate interruptions. However, if the reason is the same in these mentioned multiple entries 
on consecutive days, then it will be counted as one interruption. 
Interruption: To derive dose interruptions at the end of the treatment period or around the date 
of the cut-off, the following rules will be used. 
• A dose interruption followed by a permanent discontinuation will be counted as 
permanent discontinuation, not as interruption. 
• A dose interruption which is ongoing at the time of the data cut-off is not expected for the 
final analysis; such cases will be considered as a permanent discontinuation. 
Reduction: A dose change where the prescribed dose level is lower than the previous prescribed 
dose level or where the actual dose administered/total daily dose is lower than the calculated 
dose amount based on the prescribed dose. Therefore any dose change to correct a dosing error 
will not be considered a dose reduction. Only dose change is collected in the CRF, number of 
reductions will be derived programmatically based on the change and the direction of the 
change. 
2.4.2 
Prior, concomitant and post therapies 
Anti-neoplastic medications and concomitant medications will be coded using the WHO Drug 
Reference Listing (DRL) dictionary that employs the WHO Anatomical Therapeutic Chemical 
(ATC) classification system. Anti-neoplastic surgery as well as concomitant surgical and 
medical procedures will be coded using MedDRA. Details regarding MedDRA and WHO DRL 
version will be included in the footnote in the tables/listings. 


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Prior anti-cancer therapy 
The number and percentage of subjects who received any prior anti-neoplastic medications, 
prior anti-neoplastic radiotherapy or prior anti-neoplastic surgery was summarized in the 
[Primary CSR] and will not be reported. 
Post-treatment anti-cancer therapy 
Anti-neoplastic medications since discontinuation of study treatment will be summarized by 
ATC class, preferred term, overall and by treatment group by means of frequency counts and 
percentages using the FAS. Separate listings will be produced for medications, radiotherapies, 
and surgeries. 
Concomitant medications 
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a subject coinciding with the study treatment 
period. Concomitant therapy includes medications (other than investigational drugs) starting on 
or after the start date of study treatment or medications starting prior to the start date of study 
treatment and continuing after the start date of study treatment. 
Concomitant medications will be summarized by lowest ATC class and preferred term using 
frequency counts and percentages. Surgical and medical procedures will be summarized by 
SOC and preferred term. These summaries will include: 
1. Medications starting on or after the start of study treatment but no later than 30 days after 
start of last dose of study treatment and 
2. Medications starting prior to start of study treatment and continuing after the start of study 
treatment. 
All concomitant therapies will be listed. Any concomitant therapies starting and ending prior 
to the start of study treatment or starting more than 30 days after the last date of study treatment 
will be flagged in the listing. The safety set will be used for all concomitant medication tables 
and listings. 
2.5 
Analysis of the primary objective 
2.5.1 
Phase Ib 
The primary objective of the study’s Phase Ib part is to estimate the MTD or RP2D of EGF816 
in combination with INC280 in EGFRL858R/ex19del NSCLC subjects who have progressed on 
EGFR TKI treatment (e.g. gefitinib, erlotinib, or afatinib). 
The primary objective for the Phase Ib was analyzed in the primary analysis and reported in the 
[Primary CSR]. No analysis will be done for the final CSR. 
2.5.2 
Phase II 
The primary objective of the Phase II part is to estimate the preliminary anti-tumor activity of 
EGF816 in combination with INC280 measured by ORR determined by the Investigators’ 
assessment in accordance with RECIST 1.1 in each of the groups 1 to 3. In Group 4 the primary 


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objective is to characterize the safety and tolerability of EGF816 in combination with INC280 
when taken with food. 
The primary objective for the Phase II was analyzed in the primary analysis and reported in the 
[primary CSR]. The analyses described below will be updated including the data collected for 
subjects ongoing at the cutoff date for the primary analysis. 
2.5.2.1 
Primary endpoint – Phase II Groups 1, 2, and 3 
ORR is defined as the proportion of subjects with best overall response (BOR) of complete 
response (CR) or partial response (PR) according to RECIST 1.1 (see [CSP Appendix 1]). ORR 
will be calculated based on the FAS using local investigators review of tumor assessment data. 
Tumor assessments performed before the start of any further antineoplastic therapy (i.e. any 
additional secondary antineoplastic therapy or surgery) will be considered in the assessment of 
BOR. Radiotherapy to the bone or central nervous system (CNS), and surgical resection of CNS 
metastases as well as palliative bone radiotherapy is allowed as per protocol, and will not be 
considered in determining antineoplastic therapy usage. 
The ORR will be estimated by group or sub-group as assigned based on baseline mutation status 
and prior systemic antineoplastic therapy. The following groups will be considered (see also 
Section 1.1.2). 
• Group 1, EGFRmut, any T790M, any MET, 2/4L antineoplastic, EGFR TKI resistant 
• Group 2, EGFRmut, de novo T790M, any MET, 1/3L antineoplastic, EGFR TKI naïve 
• Group 3, EGFRmut, T790M negative, any MET, 1L antineoplastic first line 
Best overall response 
BOR is the best response recorded from the start of the treatment until documented radiological 
disease progression/recurrence. However, any assessments taken more than 30 days after the 
last dose of study treatment will not be included in the best overall response derivation. 
The study requires that for a partial response (PR) or complete response (CR) changes in tumor 
measurements must be confirmed by repeat assessments performed no less than 4 weeks after 
the criteria for the response are first met. 
The best overall response for each subject 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 the end of treatment. 
• PR = at least two determinations of PR or better at least 4 weeks apart before the end of 
treatment (and not qualifying for a CR). 
• SD = at least one SD assessment (or better) >7 weeks after start of treatment (and not 
qualifying for CR or PR). 
• PD = progression ≤ 17 weeks after 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 7 weeks or early progression within the first 17 weeks). 


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Subjects discontinuing from the study for PD must have it documented by radiologic evaluation. 
In cases of clinically-evident disease progression, all efforts should be made to perform a 
radiologic evaluation. Subjects with symptoms of rapidly progressing disease without 
radiologic evidence will not be classified as progression. 
2.5.2.2 
Statistical hypothesis, model, and method of analysis – Phase II 
Groups 1, 2, and 3 
The Bayesian model employed for the primary analysis will not be repeated. 
For the final CSR frequencies of the BOR categories will be presented and the response rate 
will be summarized using descriptive measures including 95% confidence intervals (CI) using 
the exact method [Clopper and Pearson 1934]. 
Individual lesion measurements and overall response at each assessment will be listed by group 
and subject. 
2.5.2.3 
Handling of missing values/censoring/discontinuations – Phase II 
Groups 1, 2, and 3 
Subjects with unknown or missing BOR will be counted as failures. If there is no baseline tumor 
assessment, all post-baseline overall lesion responses are expected to be ‘Unknown’. If no valid 
post-baseline tumor assessments are available, the best overall response must be ‘Unknown’ 
unless progression is reported. For the computation of ORR, these subjects will be included in 
the FAS and will be counted as failures. 
Censoring for new anti-cancer therapy 
For BOR only tumor assessments performed before the start of any new anti-cancer therapy 
(including medication, radiotherapy and surgery) will be considered. 
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 or before the start of the new anti-cancer therapy date, 
whichever is earlier. 
The protocol allows radiotherapy to the bone or central nervous system (CNS), and surgical 
resection of CNS metastases as well as palliative bone radiotherapy (that is, these will not lead 
to censoring). 
Derivation of new anti-cancer therapy 
To determine the use of new anti-cancer therapy, data entered in the following CRFs will be 
considered 
: 
• Antineoplastic Therapy Since Discontinuation of Study Treatment – Medication, 
• Antineoplastic Therapy Since Discontinuation of Study Treatment – Radiotherapy, 
• Antineoplastic Therapy Since Discontinuation of Study Treatment – Surgery. 
In addition certain therapies entered in the CRF Prior and Concomitant Medications (domain 
CM) will be considered, if they were started after start of study treatment. 


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Medications in CM will be taken into consideration if they are anti-cancer therapies, as 
determined from the project-wide list for therapy type (updated with anti-cancer medication 
yes/no). 
Radiotherapies and surgeries in CM will be considered except if the MedDRA preferred term 
is ‘radiotherapy to brain’ or ‘gamma radiation therapy to brain’ or some synonym of these. 
Cases where the preferred term is radiotherapy or radiation without giving a location and the 
indication is ‘brain metastasis’, ‘brain metastases’, or some synonym will also be excluded. 
Radiation to other locations like for example lung will lead to censoring. 
 
 


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2.5.2.5 
Primary endpoint – Phase II Group 4 
Frequencies of treatment-emergent AEs will be calculated to characterize the safety and 
tolerability of the study treatment. The Safety Set will be used for summary tables. 
2.5.2.6 
Statistical hypothesis, model, and method of analysis – Phase II 
Group 4 
Adverse events will be analyzed as described in the section on safety analysis, Section 2.8.1. 
2.5.2.7 
Handling of missing values/censoring/discontinuations – Phase II 
Group 4 
Summary tables for AEs will include events collected in the on-treatment period. If dates are 
incomplete and no clear assignment to pre-, on-, or post-treatment period can be made, then on-
treatment will be assumed (see Section 5.1.2). 
2.6 
Analysis of the key secondary objective 
No key secondary objective was defined. 
2.7 
Analysis of secondary efficacy objectives 
The secondary efficacy objective for Phase Ib as well as Phase II is to evaluate the preliminary 
anti-tumor activity of EGF816 in combination with INC280. 
2.7.1 
Secondary endpoints 
The secondary efficacy endpoints in Phase Ib and Phase II are BOR, ORR (if not already part 
of the primary analysis), disease control rate (DCR), duration of response (DOR), time to 
response (TTR), and progression-free survival (PFS). These endpoints are based on investigator 
assessment in accordance with RECIST 1.1. An additional endpoint is overall survival (OS). 
For supportive analyses BOR, ORR, DCR, DOR, TTR, and PFS will also be evaluated based 
on the BIRC review of tumor data in accordance with RECIST 1.1. For Phase Ib data the 
independent review will only be performed for subjects from cohorts with the RP2D. 
The secondary efficacy endpoints will be analyzed using the FAS. 
Overall response rate and best overall response 
See definitions in Section 2.5.2.1. 
Duration of response 
DOR only applies to subjects whose best overall response is CR or PR according to RECIST 1.1 
based on local investigators or BIRC review of tumor assessment data. The start date is the date 
of first documented response of CR or PR (i.e., the start date of response, not the date when 
response was confirmed), and the end date is defined as the date of the first documented 
progression or death due to any cause. Subjects continuing without progression or death will be 
censored at the date of their last adequate tumor assessment using the censoring rule described 
for the PFS analysis. 


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Disease control rate 
DCR is defined as the proportion of subjects with a BOR of CR or PR, or SD according to 
RECIST 1.1 criteria. 
Time to response 
TTR is the time from date of first administration of study treatment to first documented response 
of CR or PR (which must be confirmed subsequently) using local investigators or BIRC review 
of tumor assessment data and according to RECIST 1.1. Subjects who did not achieve a 
confirmed PR or CR will be censored at: 
• the maximum follow-up time (i.e. FPFV − LPLV used for the analysis in the respective 
subject group) for subjects who had a PFS event (i.e. either progressed or died due to any 
cause); 
 
• the last adequate tumor assessment date for all other subjects 
Progression-free survival 
PFS is defined as the time from the date of first administration of study treatment to the date of 
the first documented progression or death due to any cause. PFS will be based on local 
investigators or BIRC review of tumor assessments and using RECIST 1.1 criteria (see [CSP 
Appendix 1]). 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 
 or before the start of the new 
anti-cancer therapy date, whichever is earlier. (See Section 2.7.3 for additional details regarding 
censoring rules and determination of date of last adequate tumor assessment, see Section 2.5.2.1 
regarding exceptions in determining anti-cancer therapy usage). Discontinuation due to disease 
progression (collected on the ‘End of treatment’ and ‘End of post treatment follow up’ 
disposition pages without supporting objective evidence satisfying progression criteria per 
RECIST 1.1 will not be considered disease progression for PFS derivation. Clinical 
deterioration will not be considered as a qualifying event for progression. 
Overall survival 
OS is defined as the time from date of first administration of study treatment to date of death 
due to any cause. All deaths occurring on or before the efficacy cut-off date will be used in the 
OS analysis. If a subject is not known to have died at the time of the analysis, the OS time will 
be censored at the date of last contact. 
2.7.2 
Statistical hypothesis, model, and method of analysis 
ORR, BOR, and DCR 
ORR and DCR will be summarized using descriptive statistics (N, %) by treatment group (Phase 
Ib) or group (Phase II) along with two-sided exact binomial 95% CIs [Clopper and Pearson 
1934]. As a supportive analysis ORR and DCR based on the BIRC review of tumor data will 
also be summarized. Frequencies of the BOR categories will also be presented. Subjects with 
‘unknown’ BOR will be summarized by reason for having unknown status (see Section 2.5.2.4) 
based on both investigator and BIRC assessment. A concordance analysis of BOR (see Section 
2.5.2.4) will be provided for Phase Ib (RP2D) and Phase II groups. 


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A listing will be presented with overall responses at all assessment timepoints, with percentage 
change from baseline, difference between NADIR and sum of diameters, and BOR per subject. 
Waterfall plots based on both investigator and BIRC assessment will be prepared per treatment 
group. 
Time to event endpoints 
TTR, DOR, PFS and OS data will be listed and summarized by treatment group. The 
distribution of TTR, DOR, PFS, and OS, respectively, will be estimated using the Kaplan-Meier 
method. The results will be presented graphically. The median, 25th and 75th percentiles along 
with 95% CI will be presented along with the survival probabilities at 6, 9, 12, 18, and 24 
months and their associated 95% CI. 
These analyses will be based on both investigator and BIRC assessment. 
Listings of TTR and DOR details as well as PFS and OS data by treatment group (Phase Ib) 
and Phase II group will be provided. 
Censoring pattern of PFS 
The number of subjects with a PFS event and the number of subjects censored for the PFS 
analysis will be summarized. In addition, a summary of reasons for PFS censoring will be 
provided by treatment group based on the following reasons: 
1. Ongoing without event 
2. Lost to follow-up 
3. Withdrew consent 
4. Adequate assessment no longer available 
5. Initiation of new cancer therapy prior to progression 
6. 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 (TA) date and the earliest of the 
following dates is less than or equal to the interval of 2 missing TAs (see Section 2.7.3 for 
definition): 
1. Analysis cut-off date 
2. Start date of further anti-neoplastic therapy 
3. Date of consent withdrawal 
4. 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. ‘New cancer therapy added’ 
3. ‘Withdrew consent’ 
4. ‘Lost to follow-up’ 


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If the time interval is larger than the interval of 2 missing TAs 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 TA date and the PFS event date is larger than the interval 
of 2 missing TAs then the subject will be censored and 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 BIRC assessment. 
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. 
Subgroup analyses for secondary efficacy endpoints 
For the secondary efficacy endpoints the following subgroup analyses will be prepared. 
The ORR and DCR summaries based on investigator and BIRC assessment will be analyzed by 
T790M mutation status and MET dysregulation status for Phase Ib subjects. Overall survival 
will be analyzed by MET dysregulation status. 
2.7.3 
Handling of missing values/censoring/discontinuations 
ORR 
See Section 2.5.2.3. 
TTR 
Subjects who did not achieve a confirmed PR or CR will be censored as described in Section 
2.7.1. 
DOR 
Subjects continuing without progression or death will be censored at the date of their last 
adequate tumor assessment using the censoring rule described for the PFS analysis. 
PFS 
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 or before the start of the new anti-cancer 
therapy date, whichever is earlier. 
The date of last adequate tumor assessment is the date of the last tumor assessment with overall 
lesion response of CR, PR or SD before an event or a censoring reason occurred. 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 start date of treatment 
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 a new anti-cancer therapy was administered 
(see also Section 2.5.2.3); the event occurred after two or more missing tumor assessments. 
The term ‘missing adequate tumor assessment’ is defined as a TA not performed or TA with 
overall lesion response of ‘UNK’. 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 2-4 for censoring and event date options and outcomes for PFS. 
Table 2-4 
Outcome and event/censor dates for PFS analysis 
Situation 
Date 
Outcome 
No baseline assessment 
Start date of treatment 
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 anti-cancer therapy given prior 
to protocol defined progression 
Date of last adequate assessment 
on or prior to starting new anti-
cancer therapy 
Censored 
Death before first PD assessment 
Date of death 
Progressed 
OS 
If a subject is not known to have died at the time of the analysis, then OS time will be censored 
at the date of last known date subject was alive, i.e., last contact date (see Section 2.1.4). If the 
tick box for ‘Lost to follow-up’ is ticked on the ‘Survival information’ eCRF or if the time 
between the last contact date and the 
 analysis cut-off date is longer than the protocol 
specified interval between the survival follow-up assessments plus 2 weeks, i.e., 15 weeks for 
this study (3 × 30.4375 + 14 days = 91.3125 + 14 days = 105.3125 days ≈ 15 weeks), subjects 
OS time will be censored for ‘Lost to follow-up’. 
2.8 
Safety analyses 
All safety analyses will be based on the safety set. All listings and tables will be presented by 
treatment group and will include Phase Ib and Phase II groups. For individual subject data 
listings in section 16 of the CSR the FAS will be used. 


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2.8.1 
Adverse events (AEs) 
Coding and grading of AEs 
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. The grading is done according to the Common Terminology Criteria for Adverse 
Events (CTCAE). See Section 5.2 in the appendix for further details. 
AE summaries 
AE summaries will include all AEs occurring during the on-treatment period (see Section 2.1.4). 
All AEs collected in the AE eCRF page will be listed along with the information collected on 
those AEs, e.g. AE relationship to study treatment, AE outcome etc. AEs with start date outside 
of the on-treatment period will be flagged in the listings. 
AEs will be summarized by number and percentage of subjects having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT) 
using MedDRA coding. A subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. A subject 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 ‘All subjects’ column combining 
subjects from Phase Ib and Phase II. 
The following adverse event summaries will be produced: 
• Overview of adverse events and deaths 
• AEs regardless of study treatment relationship (including CTC grade 3/4) 
• AEs suspected to be study treatment related (including CTC grade 3/4) 
• AEs regardless of study treatment relationship leading to discontinuation of study 
treatment 
• AEs suspected to be study treatment related leading to discontinuation of study treatment 
• AEs regardless of study treatment relationship requiring dose adjustment or study 
treatment interruption 
• SAEs regardless of study treatment relationship 
• SAEs suspected to be study treatment related 
• SAEs with fatal outcome 
In addition, tables required for ClinicalTrials.gov and EudraCT will be provided (see Section 
2.8.1.2). 
2.8.1.1 
Adverse events of special interest / grouping of AEs 
An adverse event of special interest (AESI) is a grouping of adverse events that are of scientific 
and medical concern specific to the compound INC280 and/or EGF816. These groupings are 




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All deaths will be listed, post-treatment deaths will be flagged.  
2.8.3 
Laboratory data 
On analyzing laboratory, data from all sources (central and local laboratories) will be combined. 
The summaries will include all assessments available for the lab parameter collected no later 
than 30 days after the last study treatment administration date (see Section 2.1.4). 
A summary of the worst post-baseline CTC grade (regardless of the baseline status) will be 
produced for hematology and biochemistry laboratory data (by laboratory parameter and 
treatment group). Each subject will be counted only for the worst grade observed post-baseline. 
The following listings will be produced for the laboratory data (including urinalysis): 
• Listings of hematology data (primary hematology variables, WBC and differentials, 
coagulation) and biochemistry data (g, renal) with CTC grades and classification relative 
to the laboratory normal range. Lab data collected during the post-treatment period will be 
flagged. 
• Listing of all CTC grade 3 or 4 laboratory toxicities 
• Listing of hepatitis B and C monitoring (during the trial) 
Liver function parameters 
Liver function parameters of interest are total bilirubin (BILI), ALT, AST and alkaline 
phosphatase (ALP). The number (%) of subjects with worst post-baseline values as per Novartis 
Liver Toxicity guideline will be summarized. Because the protocol (inclusion criteria) allowed 
subjects to be enrolled with elevated baseline ALT or AST values, these are distinguished in 
the assessment. 
The following summaries will be produced: 
• Peak post-baseline values 
• ALT >3×ULN 
• ALT >5×ULN 
• ALT >8×ULN 
• ALT >10×ULN 
• ALT >20×ULN 
• AST >3×ULN 
• AST >5×ULN 
• AST >8×ULN 
• AST >10×ULN 
• AST >20×ULN 
• ALT or AST >3×ULN 
• ALT or AST >5×ULN 
• ALT or AST >8×ULN 
• ALT or AST >10×ULN 
• ALT or AST >20×ULN 


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• BILI >2×ULN 
• BILI >3×ULN 
• Combined elevations post-baseline 
• AST and ALT ≤ ULN at baseline 
a. (ALT or AST >3×ULN) and BILI >2×ULN 
b. (ALT or AST >3×ULN) and BILI >2×ULN and ALP ≥ 2×ULN 
c. (ALT or AST >3× ULN) and BILI >2× ULN and ALP <2×ULN 
• ALT or AST >ULN at baseline 
a. (Elevated ALT or AST) and BILI >2×BL and BILI >2×ULN 
b. (Elevated ALT or AST) and BILI >2×BL and BILI >2×ULN and ALP ≥ 2×ULN 
c. (Elevated ALT or AST) and BILI >2×BL and BILI >2×ULN and ALP <2×ULN 
Combined elevations post-baseline are based on the peak values at any post-baseline time for a 
subject. 
(Elevated AST or ALT) is defined as: 
• >3×ULN if ≤ ULN at baseline, or 
• (>3×BL or >8×ULN) if >ULN at baseline 
Potential Hy’s Law events are defined as those subjects who, depending on their baseline status, 
fulfill one of the criteria. Further medical review has to be conducted to assess potential 
confounding factors such as liver metastases, liver function at baseline etc. 
In addition, a listing of the hepatic laboratory values (TBL, ALT, AST and ALP) will be 
provided with values x.x times above ULN and CTCAE grades flagged. Peak total bilirubin vs 
peak ALT values will also be graphically presented (eDISH plot). 
2.8.4 
Other safety data 
2.8.4.1 
ECG 
Data handling 
Triplicate ECGs are required at all assessments. The average of the ECG parameters at an 
assessment (including baseline) will be used in the analyses. 
If a subject has more than one post-baseline measurement at a specific time point, the average 
of all available measurements associated with the nominal time point will be used. 
Data analysis 
Standard 12-lead ECGs including PR, QRS, QT, QTcF, and HR intervals will be obtained for 
each subject during the study. ECG data will be read and interpreted locally. 
The number and percentage of subjects with notable ECG values will be presented by treatment 
group: 
• QT, QTcF 
• New value of >450 and ≤ 480 ms 


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• New value of >480 and ≤ 500 ms 
• New value of >500 ms 
• Increase from baseline of >30 ms to ≤ 60 ms 
• Increase from baseline of >60 ms 
• HR 
• Increase from baseline >25% and to a value >100 bpm 
• Decrease from baseline >25% and to a value <50 bpm 
• PR 
• Increase from baseline >25% and to a value >200 ms 
• New value of >200 ms 
• QRS 
• Increase from baseline >25% and to a value >120 ms 
• New values of QRS >120 ms 
Change from baseline in ECG parameters by time point will be presented by treatment group. 
A listing of all ECG assessments will be produced by treatment group and notable values will 
be flagged. A separate listing of only the subjects with notable ECG values will also be 
produced. In the listings, the assessments collected during the post-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: height (cm), weight (kg), body temperature (°C), heart 
rate (beats per minute, bpm), systolic and diastolic blood pressure (mmHg). 
Data handling 
Vital signs collected on treatment will be summarized. Values measured outside of the on-
treatment period will be flagged in the listings. 
Data analysis 
For analysis of vital signs the clinically notable vital sign criteria are provided in Table 2-5 
below. 
Table 2-5 
Clinically notable changes in vital signs 
Vital sign (unit) 
Clinically notable criteria 
above normal value 
below normal value 
Weight (kg) 
increase >10% from baseline 
decrease >10% from baseline 
Systolic blood pressure 
(mmHg) 
≥ 180 with increase from baseline 
of ≥ 20 
≤ 90 with decrease from baseline of 
≥ 20 
Diastolic blood 
pressure (mmHg) 
≥ 105 with increase from baseline 
of ≥ 15 
≤ 50 with decrease from baseline of 
≥ 15 






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Biomarker 
Time point 
Sample 
Method 
 
 
Tumor 
(preferably same specimen 
as for MET) 
Central:  
PCR 
Cell-free DNA 
Screening or 
C1D1 (pre-dose), 
C3D1 and every 
3rd cycle, EOT 
Blood 
Central: 
PCR, NGS and/or 
other methods 
Table 2-8 
Sample biomarker summary table – Phase II part 
Biomarker 
Time point 
Sample 
Method 
Activating EGFR 
mutation, L858R or 
ex19Del 
Pre-screening 
Tumor 
Local: 
Any method 
MET 
Pre-screening 
Tumor 
(newly obtained formalin-
fixed biopsy [preferred] or 
archival tumor block or 
slides of a formalin fixed 
paraffin embedded biopsy) 
Central: 
FISH and/or-IHC 
EGFR T790M 
Pre-screening 
Tumor 
(preferably same specimen 
as for MET) 
Central: 
PCR 










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2.13.2 
Phase II part 
The futility interim analysis was conducted for subjects enrolled in Group 3 (EGFRmut, T790M 
negative, any MET, 1L antineoplastic) with 21 subjects who had completed at least 4 cycles of 
treatment or discontinued treatment prior to that time (see [primary CSR] for details and 
results). 
3 
Sample size calculation 
Please refer to the [Primary CSR] for details about sample size calculations. 
4 
Change to protocol specified analyses 
 
Hepatotoxicity 
To implement the Novartis Hepatotoxicity Guideline released in 2019, the analysis of liver 
function parameters was modified accordingly. 
COVID-19 
Analysis of protocol deviations related to COVID-19 were added. 
Imputation rules 
Imputation rules for partial dates of anti-cancer therapies were updated. 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Investigational drug 
The following rule should be used for the imputation of the dose end date for a given study 
treatment component: 
Scenario 1: If the dose end date is completely missing and there is no EOT page and no death 
date, the subject is considered as on-going 
The subject should be treated as on-going and the cut-off date should be used as the dose end 
date. Scenario 1 should not be applicable for the final CSR. All subjects in the current analysis 
have the EOT page completed before DBL for the final CSR. 
Scenario 2: If the dose end date is completely or partially missing and the EOT page is available 
• Case 1: The dose end date is completely missing and the EOT completion date is 
complete, then this latter date should be used 
• Case 2: Only year (YYYY) of the dose end date is available and YYYY < the year of 
EOT date, then use 31DECYYYY 


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• Case 3: Only year (YYYY) of the dose end date is available and YYYY = the year of 
EOT date, then use EOT date 
• Case 4: Both year (YYYY) and month (MMM) are available for dose end date and 
YYYY = the year of EOT date and MMM < the month of EOT date, then use last day of 
the Month (MMM) 
All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study. 
After imputation, compare the imputed date with start date of treatment 
• If the imputed date is < start date of treatment, then use the treatment start date 
• Otherwise, use the imputed date 
Subjects with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If start date is missing then end-date should 
not be imputed. 
5.1.2 
AE date imputation 
Table 5-1 
Imputation of start dates (AE, CM) and assessments (LB, EG, VS) 
Missing element 
Rule 
Day, month, and 
year 
No imputation will be done for completely missing dates 
Day, month 
• 
If available year = year of study treatment start date then 
• 
If stop date contains a full date and stop date is earlier than study 
treatment start date then set start date = 01JanYYYY 
• 
Else set start date = study treatment start date 
• 
If available year > year of study treatment start date then 01JanYYYY 
• 
If available year < year of study treatment start date then 01JulYYYY 
Day 
• 
If available month and year = month and year of study treatment start date 
then 
• 
If stop date contains a full date and stop date is earlier than study 
treatment start date then set start date= 01MonYYYY 
• 
Else set start date = study treatment start date 
• 
If available month and year > month and year of study treatment start date 
then 01MonYYYY 
• 
If available month and year < month year of study treatment start date 
then 15MonYYYY 
Table 5-2 
Imputation of end dates (AE, CM) 
Missing element 
Rule 
Day, month, and 
year 
• 
Completely missing end dates (incl. ongoing events) will be imputed by 
the end date of the on-treatment period * 
Day, month 
• 
If partial end date contains year only, set end date = earliest of 
31DecYYYY and end date of the on-treatment period * 
Day 
• 
If partial end date contains month and year, set end date = earliest of last 
day of the month and end date of the on-treatment period * 


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Missing element 
Rule 
* last treatment date plus 30 days not > (death date, cut-off date, withdrawal of consent date) 
Any AEs and concomitant medications with partial/missing dates will be displayed as such in 
the data listings. 
Any AEs and concomitant medications which are continuing as per data cut-off will be shown 
as ‘ongoing’ rather than the end date provided. 
The above imputations are only used for analyses of time to and duration of AEs and 
concomitant medications. 
5.1.3 
Other imputations 
Incomplete date of initial diagnosis of cancer and date of most recent 
recurrence 
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 
01Jan. 
If because of this imputation the chronology of the events is altered then the imputation should 
be made to the minimum value up to where chronology remains unchanged. E.g. if due to 
imputation the date of most recent recurrence becomes prior to the initial diagnosis date then it 
should be set to initial diagnosis date. 
Incomplete assessment dates for tumor assessment 
All investigation dates (e.g. MRI scan, CT scan) must be completed with day, month and year. 
If one or more assessment dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date and 
assessment date is calculated as the latest of all investigation dates (e.g. MRI scan, CT scan) if 
the overall response at that assessment is CR/PR/SD/UNK. Otherwise – if overall response is 
progression – the assessment date is calculated as the earliest date of all investigation dates at 
that evaluation number. If all measurement dates have no day recorded, the 1st of the month is 
used. If the month is not completed, for any of the investigations, the respective assessment will 
be considered to be at the date which is exactly between the previous and following assessment. 
If a previous and following assessment is not available, this assessment will not be used for any 
calculation. 
Applying the cut-off to tumor assessment 
For tumor related assessments, if an evaluation has some assessments done prior to cut-off date 
and others after the cut-off date, then the evaluation is considered post-cut-off date and will be 
excluded from analysis. 
Incomplete or missing death date 
For cases when either day is missing or both month and day are missing for the date of death, 
the following imputation rules will be implemented: 
• If only day is missing, then impute the 15th day of the month and year of death 


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• If both day and month are missing, then impute 01Jul of the year of death 
Prior antineoplastic therapies date imputation 
• Start dates 
The same rule which is applied to the imputation of AE/concomitant medication start 
dates will be used with the following exception: 
• If month and day are missing and the available year = year of study treatment start 
date, then impute with study treatment start date − 1 
• End dates 
• If day is missing, imputed date = min(reference end date, last day of the month) 
• If month and day are missing, imputed date = min(reference end date, 31Dec) 
Reference end date will be the start date of study treatment. 
If the end date is not missing and the imputed start date is after the end date, use the end date as 
the imputed start date. If both the start date and the end date are imputed and if the imputed start 
date is after the imputed end date, use the imputed end date as the imputation for the start date. 
Post-treatment antineoplastic therapies date imputation 
For new antineoplastic (ANP) therapies starting after study treatment was discontinued or 
starting while study treatment was still ongoing (protocol deviation), a missing or partial start 
date of this new therapy will be imputed as specified in Table 5-3. 
The complete (imputed) dates are required for censoring of efficacy endpoints. Therefore, 
partial or missing start dates will only be imputed for the first such therapy. Partial or missing 
end dates of the first new therapy and any partial or missing dates of second or later new 
antineoplastic therapies will not be imputed. 
Table 5-3 
Imputation of start dates for post-treatment antineoplastic 
medications 
Missing 
element 
Rule 
Day 
• 
If available year ≥ year of study treatment end date then ANP start date = max 
(study treatment end date + 1, 01MonYYYY)  
 
• 
If available year < year of study treatment end date then ANP start date = 
max(study treatment start date + 1, 01MonYYYY) 
Day, month 
• 
If available year = year of study treatment end date then ANP start date = 
min(study treatment end date + 1, 31DecYYYY) 
 
• 
If available year > year of study treatment end date then ANP start date = 
01JanYYYY 
 
• 
If available year < year of study treatment end date, 
 
• 
If available year < year of study treatment start date, do not impute 
• 
If available year > year of study treatment start date, then ANP start date = 
01JulYYYY 
 
• 
If available year = year of study treatment start date and day/month of 
study treatment start date <01JulYYYY, then ANP start date = 01JulYYYY 


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Missing 
element 
Rule 
 
• 
If available year = year of study treatment end date and day/month of study 
treatment start date ≥ 01JulYYYY, then ANP start date = min(middle between 
the treatment start and end date, 31DecYYYY) 
Day, month, 
and year 
For completely missing start dates, set to study treatment end date + 1 
If the end date is not missing and the imputed start date is after the end date, use the end date as 
the imputed start date. 
In case there are any scenarios found in the final data that are not covered by the rules above, 
they will be handled in the respective dataset program and documented in the PDS. 
5.2 
AE coding/grading 
Adverse events are coded using the MedDRA terminology. The latest available MedDRA 
version at the time of the analyses will be used and the version will be specified in the CSR as 
well as in a footnote in the applicable tables and listings. 
AEs will be assessed according to CTCAE version 4.03. 
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding 
to mild, moderate, severe, life threatening, and death. This grading system inherently places a 
value on the importance of an event, although there is not necessarily proportionality among 
grades (a grade 2 is not necessarily twice as bad as a grade 1). 
5.3 
Laboratory parameters derivations 
5.3.1 
CTC grading for laboratory parameters 
Grade categorization of lab values will be assigned programmatically as per CTCAE version 
4.03. The calculation of laboratory CTC grades will be based on the observed laboratory values 
only, clinical assessments will not be taken into account. The criteria to assign CTCAE grades 
are given in Novartis internal criteria for CTCAE grading of laboratory parameters. The latest 
available version of the document based on the underlying CTCAE version 4.03 at the time of 
analysis will be used. For laboratory tests where grades are not defined by CTCAE version 4.03, 
results will be graded by the low/normal/high classifications based on laboratory normal ranges. 
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 will not be used. For laboratory tests that are graded for both low and high values, 
summaries will be done separately and labelled by direction, e.g., sodium will be summarized 
as hyponatremia and hypernatremia. 
5.3.2 
Imputation rules 
CTC grading for blood differentials is based on absolute values. However, this data may not be 
reported as absolute counts but rather as percentage of WBC. 


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If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X. 
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for an xxx differential: 
xxx count = (WBC count) × (xxx %value / 100). 
Further derivation of laboratory parameters might be required for CTCAE grading. For 
instance, corrected calcium can be derived using the reported total calcium value and albumin 
at the same assessment using the following formula: 
Corrected Calcium (mg/dL) = Calcium (mg/dL) − 0.8 × [Albumin (g/dL) − 4]. 
In order to apply the above formula, albumin values in g/L will be converted to g/dL (by 
multiplying by 0.1), calcium values in mmol/L will be converted to mg/dL by dividing by 
0.2495. For calculation of laboratory CTC grades 0 and 1, the normal range for derived 
corrected calcium is set to the same limits (in mg/dL) as for calcium. 
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium will be assigned as described above for grading. 
5.4 
Statistical models 
5.4.1 
Phase Ib 
Refer to the [Primary CSR] for details. 
Kaplan-Meier estimates 
An estimate of the survival function in each treatment group, subgroup or overall will be 
constructed using the Kaplan-Meier (product-limit) method as implemented in SAS PROC 
LIFETEST with METHOD=KM option. The PROC LIFETEST statement will use the option 
CONFTYPE=LOGLOG. 
Median survival for each treatment group, subgroup or overall 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]). 
Confidence interval for response rate 
Responses will be summarized in terms of percentage rates with 95% CIs. An exact binomial 
confidence interval (implemented using SAS procedure FREQ with EXACT statement for one-
way tables) will be calculated ([Clopper and Pearson 1934]). 
 
 


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6 
References 
Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival Time. 
Biometrics; 38:29-41. 
Clopper CJ and Pearson ES (1934). The use of confidence or fiducial limits illustrated in the 
case of the binomial. Biometrika; 26:404-413. 
Collett D (1994). Modelling survival data in medical research. London, Chapman & Hall. 
European Medicines Agency (2021). Guidance on the management of clinical trials during the 
COVID-19 (coronavirus) pandemic (Version 4.0). 
Food and Drug Administration (2020). FDA Guidance on Conduct of Clinical Trials of 
Medical Products during COVID-19 Pandemic: Guidance for Industry, Investigators, and 
Institutional Review Boards (September 2020).