Clinical trial NCT04816214
Conditions: Carcinoma, Non-Small-Cell Lung
Keywords: INC280 capmatinib osimertinib pemetrexed platinum-based chemotherapy NSCLC Non-Small Cell Lung Cancer Carcinoma EGFR Mutation T790M negative MET amplification second line therapy GEOMETRY GEOMETRY-E
Sponsor: Novartis Pharmaceuticals
Start date: 2021-09-22; Completion date: 2022-12-27
Enrollment: 6 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study aimed to evaluate the anticancer activity of capmatinib in combination with osimertinib compared to platinum-pemetrexed based doublet chemotherapy as second line treatment in patients with advanced or metastatic non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation, T790M negative, mesenchymal-to-epithelial transition factor (MET) amplified who progressed following EGFR tyrosine kinase inhibitors (TKIs).

Detailed description:
This was a multicenter, open-label, randomized, active-controlled, global phase III study that enrolled adult participants with locally advanced or metastatic NSCLC with epidermal growth factor receptor (EGFR) activating mutation, T790M negative, mesenchymal-to-epithelial transition factor (MET) amplified who had progressed following EGFR tyrosine kinase inhibitors (TKIs).

The study was conducted in two parts. The initial part was a safety run-in part, which aimed at assessing the safety and tolerability of capmatinib in combination with osimertinib and at determining the recommended dosage for the subsequent randomized part. The randomized part compared the efficacy and safety of capmatinib in combination with osimertinib to a platinum-based doublet chemotherapy regimen using either cisplatin or carboplatin, combined with pemetrexed, as second-line treatment.The randomized part was not initiated.

In the randomized part (if initiated), participants were to receive their assigned treatment (either capmatinib in combination with osimertinib or platinum-pemetrexed based doublet chemotherapy) until they experienced any of the following: documented disease progression according to the Response Evaluation Criteria In Solid Tumors 1.1 (RECIST 1.1) as assessed by the investigator during the run-in part and confirmed by a blinded independent review committee (BIRC) during the randomized part, withdrawal of consent, pregnancy, lost to follow-up, or death. Participants who progressed in the platinum-pemetrexed arm were to be permitted to switch to capmatinib in combination with osimertinib therapy after BIRC-confirmed, RECIST 1.1-defined progressive disease. If, in the judgment of the investigator, there was evidence of clinical benefit and the participant wished to continue, study treatment could be continued beyond the initial disease progression according to RECIST 1.1 criteria. After treatment discontinuation, all participants were to be followed for safety evaluations during the safety follow-up period.

On 11-May-2022, Novartis decided to halt enrollment for this study due to a business consideration unrelated to any safety concerns. Ongoing patients in the run-in part were allowed to continue treatment through other post-trial drug supply options, as applicable. On 27-Dec-2022 the last patient was transitioned off the study, and following the study protocol this date was declared the Global end of trial date. Randomized part was not initiated.

Arms: arm 1: In the run-in part, up to two dose levels of capmatinib in combination with osimertinib were planned to be investigated. The initial dose level for the combination therapy was capmatinib 400 mg orally twice daily (b.i.d) and osimertinib 80 mg orally once per day (q.d). If a dose de-escalation was necessary, a lower dose level was defined as capmatinib 400 mg orally b.i.d and osimertinib 40 mg orally q.d. arm 2: In the randomized part, capmatinib in combination with osimertinib was to be administered at the recommended Phase III regimen (defined in the safety run-in part).

The study was terminated early based on Sponsor's decision unrelated to safety concerns and the randomized part of the study was not initiated. arm 3: In the randomized part, platinum-pemetrexed based doublet chemotherapy was to follow local guidelines as per standard of care and products labels. Participants randomized to platinum-pemetrexed based doublet chemotherapy arm were to be allowed to crossover to receive capmatinib in combination with osimertinib. The study was terminated early based on Sponsor's decision unrelated to safety concerns and the randomized part of the study was not initiated.
Interventions: intervention 1: Capmatinib intervention 2: Osimertinib intervention 3: Pemetrexed intervention 4: Cisplatin intervention 5: Carboplatin
Intervention descriptions: intervention 1: Capmatinib was available as a film-coated tablet for oral use, with a strength of either 150 mg or 200 mg. The initial dose of the combination therapy consisted of capmatinib 400 mg administered orally twice daily (b.i.d). intervention 2: Osimertinib was available as a tablet for oral use, with a strength of either 80 mg or 40 mg. The initial dose of the combination therapy consisted of osimertinib 80 mg administered orally once per day (q.d) intervention 3: Pemetrexed concentrate for solution for intravenous use was to be administered intravenously. The procurement of pemetrexed was to be done locally, following local practices and regulations. intervention 4: Cisplatin concentrate for solution for intravenous use was to beadministered intravenously during the study. The procurement of cisplatin was to be done locally, following local practices and regulations. intervention 5: Carboplatin concentrate for solution for intravenous use was to be administered intravenously during the study. The procurement of carboplatin was to be done locally, following local practices and regulations.

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development 
INC280/capmatinib 
Clinical Trial Protocol CINC280L12301 / NCT04816214
A phase III randomized, controlled, open-label, multicenter, 
global study of capmatinib in combination with osimertinib 
versus platinum - pemetrexed based doublet chemotherapy in 
patients with locally advanced or metastatic NSCLC harboring 
EGFR activating mutations who have progressed on prior 
EGFR‑TKI therapy and whose tumors are T790M mutation 
negative and harbor MET amplification (GEOMETRY-E) 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2020-003677-21 
Version number: 
02 (Clean) 
Clinical Trial Phase: 
III 
Release date: 
03-Mar-2022 (content final)
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 7 
List of abbreviations ............................................................................................................ 8 
Glossary of terms ............................................................................................................... 13 
Amendment 02 (03-Mar-2022) ......................................................................................... 16 
Amendment 01 (14-Sep-2021) .......................................................................................... 19 
Protocol summary .............................................................................................................. 25 
1 
Introduction ....................................................................................................................... 29 
1.1 
Background ............................................................................................................ 29 
1.1.1 
Non-small cell lung cancer (NSCLC) treatment landscape .................. 29 
1.1.2 
Overview of capmatinib (INC280) ....................................................... 32 
1.1.3 
Overview of osimertinib ....................................................................... 35 
1.1.4 
Capmatinib in combination with EGFR TKI non clinical and 
clinical experience ................................................................................. 35 
1.2 
Purpose .................................................................................................................. 36 
2 
Objectives, endpoints and estimands ................................................................................. 36 
2.1 
Primary estimands ................................................................................................. 38 
2.2 
Secondary estimands ............................................................................................. 40 
3 
Study design ...................................................................................................................... 41 
4 
Rationale ............................................................................................................................ 48 
4.1 
Rationale for study design ..................................................................................... 48 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 49 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 50 
4.4 
Purpose and timing of interim analyses ................................................................. 50 
4.5 
Risks and benefits .................................................................................................. 50 
4.5.1 
Capmatinib ............................................................................................ 52 
4.5.2 
Osimertinib ............................................................................................ 53 
4.5.3 
Cisplatin, carboplatin and pemetrexed .................................................. 53 
4.6 
Rationale for Public Health Emergency mitigation procedures ............................ 54 
5 
Study Population ............................................................................................................... 54 
5.1 
Inclusion criteria .................................................................................................... 55 
5.2 
Exclusion criteria ................................................................................................... 56 
6 
Treatment ........................................................................................................................... 60 
6.1 
Study treatment ...................................................................................................... 60 


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6.1.1 
Investigational and control drugs .......................................................... 60 
6.1.2 
Additional study treatments .................................................................. 61 
6.1.3 
Treatment arms/group ........................................................................... 61 
6.1.4 
Guidelines for continuation of treatment .............................................. 62 
6.1.5 
Treatment duration ................................................................................ 62 
6.2 
Other treatment(s) .................................................................................................. 64 
6.2.1 
Concomitant therapy ............................................................................. 65 
6.2.2 
Prohibited medication ........................................................................... 67 
6.3 
Participant numbering, treatment assignment, randomization .............................. 67 
6.3.1 
Participant numbering ........................................................................... 67 
6.3.2 
Treatment assignment, randomization .................................................. 68 
6.4 
Treatment blinding ................................................................................................. 69 
6.5 
Dose escalation and dose modification .................................................................. 69 
6.5.1 
Dose De-escalation guidelines .............................................................. 69 
6.5.2 
Guidelines for confirmation of recommended dose .............................. 69 
6.5.3 
Definitions of Dose Limiting Toxicities (DLTs) (Run-In Part) ............ 70 
6.5.4 
Dose modifications ................................................................................ 73 
6.5.5 
Follow-up for toxicities ......................................................................... 90 
6.6 
Additional treatment guidance ............................................................................... 97 
6.6.1 
Treatment compliance ........................................................................... 97 
6.6.2 
Emergency breaking of assigned treatment code .................................. 97 
6.7 
Preparation and dispensation ................................................................................. 97 
6.7.1 
Handling of study treatment and additional treatment .......................... 98 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 99 
7 
Informed consent procedures .......................................................................................... 101 
8 
Visit schedule and assessments ....................................................................................... 103 
8.1 
Screening ............................................................................................................. 128 
8.1.1 
Eligibility screening ............................................................................ 130 
8.1.2 
Information to be collected on screening failures ............................... 130 
8.2 
Participant demographics/other baseline characteristics ..................................... 131 
8.3 
Efficacy ................................................................................................................ 132 
8.3.1 
Tumor imaging assessment ................................................................. 132 
8.3.2 
Appropriateness of efficacy assessments ............................................ 136 
8.3.3 
Overall survival ................................................................................... 137 
8.4 
Safety ................................................................................................................... 137 
8.4.1 
Laboratory evaluations ........................................................................ 138 
8.4.2 
Electrocardiogram (ECG) ................................................................... 140 


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8.4.3 
Pregnancy and assessments of fertility ............................................... 143 
8.4.4 
Appropriateness of safety measurements ............................................ 144 
8.5 
Additional assessments ........................................................................................ 144 
8.5.1 
Clinical Outcome Assessments (COAs) ............................................. 144 
8.5.2 
Pharmacokinetics ................................................................................ 147 
 
 150 
9 
Study discontinuation and completion ............................................................................ 156 
9.1 
Discontinuation and completion .......................................................................... 156 
9.1.1 
Discontinuation from study treatment and from study ....................... 156 
9.1.2 
Withdrawal of informed consent/Opposition to use data/biological 
samples ................................................................................................ 158 
9.1.3 
Lost to follow-up ................................................................................. 158 
9.1.4 
Early study termination by the sponsor ............................................... 159 
9.2 
Study completion and post-study treatment ........................................................ 159 
9.2.1 
Follow-up for safety evaluations ......................................................... 160 
9.2.2 
Efficacy follow-up and PROs ............................................................. 160 
9.2.3 
Survival follow-up .............................................................................. 160 
10 Safety monitoring, reporting and committees ................................................................. 161 
10.1 
Definition of adverse events and reporting requirements .................................... 161 
10.1.1 
Adverse events .................................................................................... 161 
10.1.2 
Serious adverse events ........................................................................ 163 
10.1.3 
SAE reporting...................................................................................... 164 
10.1.4 
Pregnancy reporting ............................................................................ 165 
10.1.5 
Reporting of study treatment errors including misuse/abuse .............. 166 
10.2 
Additional Safety Monitoring .............................................................................. 166 
10.2.1 
Data Monitoring Committee ............................................................... 166 
10.2.2 
Steering Committee ............................................................................. 166 
11 Data Collection and Database management .................................................................... 167 
11.1 
Data collection ..................................................................................................... 167 
11.2 
Database management and quality control .......................................................... 167 
11.3 
Site monitoring .................................................................................................... 168 
12 Data analysis and statistical methods .............................................................................. 168 
12.1 
Analysis sets ........................................................................................................ 169 
12.1.1 
Full analysis set ................................................................................... 169 
12.1.2 
Full analysis set brain metastases ........................................................ 169 
12.1.3 
Safety set ............................................................................................. 169 
12.1.4 
Pharmacokinetic analysis set ............................................................... 169 


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12.1.5 
Dose-Determining Set (DDS) ............................................................. 170 
12.2 
Participant demographics and other baseline characteristics ............................... 170 
12.3 
Treatments ........................................................................................................... 170 
12.4 
Analysis supporting primary objectives .............................................................. 171 
12.4.1 
Definition of primary endpoint(s) ....................................................... 171 
12.4.2 
Statistical model, hypothesis, and method of analysis ........................ 171 
12.4.3 
Handling of intercurrent events of primary estimand ......................... 172 
12.4.4 
Handling of missing values not related to intercurrent event ............. 173 
12.4.5 
Sensitivity analyses ............................................................................. 173 
12.4.6 
Supplementary analysis ....................................................................... 173 
12.4.7 
Supportive analyses ............................................................................. 174 
12.5 
Analysis supporting secondary objectives ........................................................... 174 
12.5.1 
Efficacy endpoint(s) ............................................................................ 174 
12.5.2 
Safety endpoints .................................................................................. 178 
12.5.3 
Pharmacokinetics ................................................................................ 181 
12.5.4 
Patient reported outcomes ................................................................... 181 
 
 182 
12.7 
Interim analyses ................................................................................................... 182 
12.8 
Sample size calculation ........................................................................................ 183 
12.8.1 
Primary endpoint(s) ............................................................................. 183 
12.8.2 
Secondary endpoint(s) ......................................................................... 184 
13 Ethical considerations and administrative procedures .................................................... 186 
13.1 
Regulatory and ethical compliance ...................................................................... 186 
13.2 
Responsibilities of the investigator and IRB/IEC ................................................ 186 
13.3 
Publication of study protocol and results............................................................. 186 
13.4 
Quality Control and Quality Assurance ............................................................... 187 
13.5 
Participant Engagement ....................................................................................... 187 
14 Protocol adherence .......................................................................................................... 187 
14.1 
Protocol amendments ........................................................................................... 187 
15 References ....................................................................................................................... 189 
16 Appendices ...................................................................................................................... 195 
16.1 
Appendix 1: Guidelines for Response, Duration of Overall Response, TTF, 
TTP, Progression-Free Survival, and Overall Survival (based on RECIST 1.1) 195 
16.1.1 
Introduction ......................................................................................... 195 
16.1.2 
Efficacy assessments ........................................................................... 195 
16.1.3 
Efficacy definitions ............................................................................. 204 
16.1.4 
Data handling and programming rules ................................................ 214 


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16.2 
Appendix 2: Response assessment in neuro-oncology (RANO) criteria for 
Brain Metastases .................................................................................................. 218 
16.2.1 
Introduction ......................................................................................... 218 
16.2.2 
Efficacy assessments ........................................................................... 218 
16.2.3 
Efficacy definitions ............................................................................. 227 
16.3 
Appendix 3: Permitted concomitant therapy requiring caution and/or action ..... 232 
16.4 
Appendix 4: Prohibited QT prolongation concomitant medication for 
capmatinib and osimertinib .................................................................................. 234 
16.5 
Appendix 5: Prohibited drugs .............................................................................. 235 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 36 
Table 4-1 
Rationale for study design ..................................................................... 48 
Table 6-1 
Investigational and control drug ............................................................ 60 
Table 6-2 
Provisional dose levels .......................................................................... 69 
Table 6-3 
Capmatinib and osimertinib overlapping toxicities .............................. 71 
Table 6-4 
Criteria for defining dose-limiting toxicities......................................... 72 
Table 6-5 
Dose reduction steps for capmatinib ..................................................... 75 
Table 6-6 
Dose reduction steps for osimertinib..................................................... 75 
Table 6-7 
Dose modifications for capmatinib in combination with osimertinib ... 75 
Table 6-8 
Dose modifications for capmatinib (if osimertinib permanently 
discontinued and capmatinib continued as monotherapy) .................... 86 
Table 6-9 
Toxicity follow-up evaluation ............................................................... 91 
Table 6-10 
Guidance to rule out other alternative causes of observed LFT 
abnormalities ......................................................................................... 96 
Table 6-11 
Dose and treatment schedule ................................................................. 99 
Table 8-1 
Visit Window ...................................................................................... 103 
Table 8-2 
Assessment Schedule, Part 1 ............................................................... 105 
Table 8-3 
Assessment Schedule, Part 2 ............................................................... 113 
Table 8-4 
Imaging Assessment Collection Plan .................................................. 132 
Table 8-5 
Physical Assessments .......................................................................... 137 
Table 8-6 
ECOG Performance Status .................................................................. 138 
Table 8-7 
Clinical laboratory parameters collection plan ................................... 139 
Table 8-8 
Central ECG (run-in part) collection plan ........................................... 141 
Table 8-9 
Central ECG (randomized part and ET part) collection plan .............. 142 
Table 8-10 
Pharmacokinetic blood collection log for capmatinib (run-in part) .... 147 
Table 8-11 
Pharmacokinetic blood collection log for osimertinib, AZ5104 and 
AZ7550 (run-in part) ........................................................................... 148 


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Table 8-12 
Pharmacokinetic blood collection log for capmatinib 
(randomization part) ............................................................................ 149 
Table 8-13 
Pharmacokinetic blood collection log for osimertinib, AZ5104 and 
AZ7550 (randomization part) ............................................................. 150 
 
 153 
 
 154 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ....................................................................................... 166 
Table 12-1 
Simulated probabilities to stop for futility at the interim or final 
PFS analysis ........................................................................................ 183 
Table 12-2 
Number of OS events expected at the time of the final PFS analysis 
under different assumptions and scenarios ......................................... 185 
Table 16-1 
Response criteria for target lesions ..................................................... 200 
Table 16-2 
Response criteria for non-target lesions .............................................. 202 
Table 16-3 
Overall lesion response at each assessment ........................................ 203 
Table 16-4 
Overall lesion response at each assessment: patients with non-
target disease only ............................................................................... 211 
Table 16-5 
Options for event dates used in PFS, TTP, duration of response ........ 212 
Table 16-6 
Response assessment of target lesions ................................................ 222 
Table 16-7 
Response assessment of non-target lesions ......................................... 223 
Table 16-8 
Overall Lesion Response at each assessment ...................................... 224 
Table 16-9 
CNS and non-CNS response assessment ............................................ 227 
Table 16-10 
Overall Lesion Response at each assessment: Participants with 
only non-target disease at baseline ...................................................... 230 
Table 16-11 
Drugs to be used with caution during co-administration with 
capmatinib and osimertinib ................................................................. 232 
Table 16-12 
Drugs with a known risk of Torsades de Pointes ................................ 234 
Table 16-13 
Capmatinib and osimertinib: prohibited drugs .................................... 235 
List of figures 
Figure 3-1 
Part 1: Run-in Part ................................................................................. 43 
Figure 3-2 
Part 2: Randomized Part ........................................................................ 45 
Figure 12-1 
Graphical gate-keeping procedure to test the key secondary 
endpoints in order to control overall type 1 error ............................... 172 


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List of abbreviations 
ABCP 
atezolizumab (anti-PD-L1) and bevacizumab with carboplatin and paclitaxel 
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 
ANC 
Absolute Neutrophil Count 
ART 
Antiretrovial Therapy  
AST 
Aspartate transaminase 
ATP 
Adenosine Triphosphate  
AUC 
Area under curve 
b.i.d. 
bis in die/twice a day 
BAL 
Bronchoalveolar Lavage  
BCG 
Bacille Calmette-Guérin 
BCRP 
Breast Cancer Resistance Protein 
BIRC 
Blinded Independent Review Committee 
BMA 
Bone Modifying Agents 
BOIR 
Best Overall Intracranial Response  
BOR 
Best Overall Response  
BRAF 
v-raf murine sarcoma viral oncogene homolog B1 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CDS 
Core Data Sheet 
CI 
Confidence Interval  
CIOMS 
Council for International Organizations of Medical Sciences 
CLIA 
Clinical Laboratory Improvement Amendments 
CNS 
Central Nervous System 
COA 
Clinical Outcome Assessment 
COVID 19 
Corona Virus Disease 2019 
CR 
Complete Response 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria Adverse Event 
 
 
CV 
coefficient of variation 
CVD 
Cardio Vascular Diseases 
CYP 
Cytochrome P450 Enzymes 
DBP 
Diastolic Blood Pressure 
DCR 
Disease Control Rate  
DDI 
Drug-Drug Interaction 


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DDS 
Dose-Determination Set  
DFS 
Disease-free survival 
DILI 
Drug-Induced Liver Injury 
DL 
Dose Level  
DLCO 
Diffusing capacity of the Lungs for Carbon monoxide 
DLRTM 
Dose level review team meeting  
DLT 
Dose Limiting Toxicity 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic Acid 
DOIR 
Duration Of Intracranial Response 
DOR 
Duration of Response 
EBV 
Epstein-Barr Virus 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
 
  
EGFRm 
Epidermal growth factor receptor mutated  
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
End Of Treatment 
EQ-5D-5L 
EuroQoL-5 Dimension-5 Level 
ERCP 
Endoscopic retrograde cholangiopancreatography 
eSource 
Electronic Source 
ET 
Extension Treatment 
FACT 
Functional Assessment of Cancer Therapy  
FAS 
Full Analysis Set 
FAS-BM 
Full Analysis Set – Brain Metastases  
FBrSI 
FACT-Brain Symptom Index 
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose- Positron Emission Tomography 
FFPE 
Formalin Fixed Paraffin Embedded 
FISH 
Fluorescence In Situ Hybridization 
FPFV 
First Patient First Visit 
FSH 
Follicle Stimulating Hormone 
FUP 
Follow-Up Period 
G-CSF 
Granulocyte Colony-Stimulating Factor 
GCN 
Gene Copy Number 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
GGT 
Gamma-glutamyl transferase 
GI 
Gastrointestinal 
GLDH 
Glutamate dehydrogenase 
GM-CSF 
Granulocyte-Macrophage Colony-Stimulating Factor 
h 
Hour 
HBsAg 
Hepatitis B surface antigen 


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HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HER2 
Human Epidermal growth factor Receptor 2 
HEV 
Hepatitis E Virus 
Hgb 
Hemoglobin 
HGF 
Hepatocyte Growth Factor  
HGRAC 
Human Genetic Resource Administration of China  
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
HRQoL 
Health-Related Quality of Life 
HSV 
Herpes Simplex Virus 
i.v. 
Intravenous 
IA 
Interim Analysis 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for Pharmaceuticals for 
Human Use 
ICI 
Immuno Checkpoint Inhibitors  
IDCR 
Intracranial disease control rate 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IHC 
Immunohistochemistry 
ILD 
Interstitial Lung Disease 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IUS 
Intra-uterine System 
KM 
Kaplan-Meier 
KRAS 
Kirsten rat sarcoma viral oncogene homolog  
LFT 
Liver function test  
LLN 
lower limit of normal 
LLOQ 
lower limit of quantification 
LPLV 
Last Patient Last Visit 
LVEF 
Left ventricular ejection fraction 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical dictionary for regulatory activities  
MET 
Mesenchymal-to-Epithelial Transition factor 
mg 
milligram(s) 
mL 
milliliter(s) 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
MUGA 
Multiple gated acquisition 
NCCN 
National Comprehensive Cancer Network 
 
  
NSCLC 
Non-small-cell lung cancer 


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NT 
Non-target  
NT-
proBNP 
N-terminal pro-brain natriuretic peptide  
NTI 
Narrow Therapeutic Index  
OHP 
Off-site healthcare Professional 
OIRR 
Overall Intracranial Response Rate  
ORR 
Overall Response Rate  
OS 
Overall survival  
P-gp 
P-glycoprotein 
PAS 
Pharmacokinetic Analysis Set 
PD  
Progressive disease  
PD-L1 
Programmed Death-Ligand 1 
PFS 
Progression free survival  
PFS2 
Progression-Free Survival after next line of treatment 
PK 
Pharmacokinetic(s) 
PLT 
Platelet 
PR 
Partial Response 
PRO 
Patient Reported Outcomes 
PT 
Prothrombin time 
QD 
Once a day 
QLQ 
Quality of Life Questionnaire 
QMS  
Quality Management System 
 
 
QTcF 
Fridericia QT correction formula 
R Value 
ALT/ALP x ULN 
RANKL 
Receptor activator of nuclear factor kappa-B ligand 
RANO 
Response assessment in neuro-oncology  
RANO-BM 
Response Assessment in Neuro-Oncology Brain Metastases 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RNA 
Ribonucleic Acid 
ROS1 
c-ros oncogene 1 
RP2D 
Recommended phase two dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Stable Disease 
SJS 
Stevens-Johnson Syndrome 
SOCs 
System Organ Classes 
TFQ 
Trial feedback questionnaires  
TKI 
Tyrosine Kinase Inhibitors  
TSH 
Thyroid Stimulating Hormone 
TTE 
Transthoracic echocardiography 
TTIR 
Time To Intracranial Response 
TTR 
Time To Response 


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Ty21a 
Live-attenuated TY2 strain of S. Typhi 
ULN 
upper limit of normal 
USA 
United States of America 
USPI 
United States Prescribing Information  
WoC 
Withdrawal of Consent 


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Glossary of terms 
Additional 
treatment 
Medicinal products that may be used during the clinical trial as described in the protocol, 
but not as an investigational medicinal product (e.g., any background therapy) 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, urine, 
stool, etc. taken from a study participant  
Cohort 
A group of individuals who share a common exposure, experience or characteristic, or a 
group of individuals followed-up or traced over time  
Control drug 
A study intervention (active or placebo) used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study validity, and/or evaluate 
comparative effects of the investigational drug 
Cycles 
Number and timing or recommended repetitions of therapy are usually expressed as 
number of days (e.g., 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 intervention administration, if any). 
Participant agrees to the other protocol required assessments including follow-up. No 
specific request is made to stop the use of their samples or data. 
Dosage 
Dose of the study treatment given to the participant in a time unit (e.g., 100 mg once a 
day, 75 mg twice a day) 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study data using data 
collection systems, such as Web-based applications, interactive voice response systems 
and clinical laboratory interfaces. EDC includes the use of Electronic Case Report Forms 
(eCRFs) which are used to capture data transcribed from 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 at a later 
point in time as defined by the protocol  
Enrollment 
Point/time of participant entry into the study at which informed consent must be obtained. 
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 
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 
Investigational 
drug/ treatment 
The drug whose properties are being tested in the study 
Medication number 
A unique identifier on the label of medication kits 
Mis-randomized 
participants 
Mis-randomized participants are those who were not qualified for randomization and who 
did not take study treatment, but have been inadvertently randomized into the study or 
the participants allocated to an invalid stratification factor 
Off-site 
Describes trial activities that are performed at remote location by an off-site healthcare 
professional, such as procedures performed at the participant's home 


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 Off-site healthcare 
Professional (OHP) 
A qualified healthcare professional, such as include those used in the study e.g., Nurse, 
Phlebotomist, Physician, who performs certain protocol procedures for the participant in 
an off-site location such as a participant's home. Add in specific terms used for off-site 
health professionals in the protocol only where you are sure this will be the case 100% of 
the time, for example if blood samples may be collected by an Off-site Research Nurse 
(ORN) or Off-site Phlebotomist use the broader term Off-site Healthcare Professional 
(OHP) to cover all situations., e.g., Off-site Research Nurse (ORN): Refer to Off-site 
healthcare professional 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e., concomitant 
or rescue therapy) 
Part  
A sub-division of a study used to evaluate specific objectives or contain different 
populations  
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 
A unique number assigned to each participant upon signing the informed consent. This 
number is the definitive, unique identifier for the participant and should be used to identify 
the participant throughout the study for all data collected, sample labels, etc. 
Patient-Reported 
Outcome (PRO) 
A measurement based on a report that comes directly from the participant about the status 
of a participant’s health condition without amendment or interpretation of the participant’s 
report by a clinician or anyone else 
Period 
The subdivisions of the trial design (e.g., Screening, Treatment, Follow-up) which are 
described in the Protocol. Periods define the study phases and will be used in clinical trial 
database setup and eventually in analysis 
Personal data 
Participant information collected by the Investigator that is coded and transferred to 
Novartis for the purpose of the clinical trial. This data includes participant identifier 
information, study information and biological samples 
Randomization 
The process of assigning trial participants to investigational drug or control/comparator 
drug using an element of chance to determine the assignments in order to reduce bias 
Randomization 
number 
A unique identifier assigned to each randomized participant 
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 in the 
protocol 
Remote 
Describes any trial activities performed at a location that is not the investigative site where 
the investigator will conduct the trial, but is for example a home or another appropriate 
location 
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 clinical trial is defined as the signature of the informed consent by the first 
participant 
Study device 
Study device is a medical device (marketed or investigational) that is used in a 
circumstance that makes it part of the investigation 
Study treatment 
Any drug or combination of drugs or intervention administered to the study participants as 
part of the required study procedures; includes investigational drug(s), control(s) or 
background therapy 
Treatment 
arm/group  
A treatment arm/group defines the dose and regimen or the combination, and may consist 
of 1 or more cohorts 


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


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Amendment 02 (03-Mar-2022) 
Amendment rationale 
As of 03-Mar-2022, 3 patients have been enrolled in the study.  
The main purpose of this amendment is to include the possibility for participants who 
progressed in the platinum – pemetrexed chemotherapy arm to crossover to the capmatinib + 
osimertinib arm. The new treatment period has been named Extension Treatment. The decision 
to allow crossover of participants who have progressed on chemotherapy arm is due to the fact 
that this population does not have many effective therapeutic alternatives, and the combination 
of capmatinib + osimertinib has shown significant preliminary meaningful clinical activity in 
this MET amplified NSCLC population. 
The main updates cover the following: 
• Inclusion of an additional study treatment period called Extension Treatment (ET) for 
participants allowed to crossover from platinum – pemetrexed chemotherapy arm to 
capmatinib + osimertinib treatment arm. Participants will be allowed to crossover only after 
BIRC confirmed, RECIST 1.1-defined PD and after meeting eligibility criteria outlined in 
Section 6.1.5.2.  
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version using 
strikethrough red font for deletion and red underline for insertions as described below: 
• Abbreviation for Bone Modifying Agents (BMA), Extension Treatment (ET) and Off-site 
healthcare Professional have been added to the List of abbreviations 
• The Glossary of terms has been updated as per Novartis Protocol template version 5  
• ET has been added to the Protocol Summary in the Study Design subsection 
• “Platinum – pemetrexed doublet based chemotherapy” has been corrected to “platinum – 
pemetrexed based doublet chemotherapy” throughout the document when applicable 
• In Section 3, the possibility for participants to crossover from platinum – pemetrexed 
chemotherapy arm to capmatinib + osimertinib treatment arm has been added and eligibility 
criteria have been defined 
• In Section 3, clarification on safety follow-up and survival follow-up for participants 
crossing over to capmatinib + osimertinib therapy has been added 
• Figure 3-2 has been updated to include the crossover to capmatinib + osimertinib arm 
• The crossover has been added to the Rationale for study design in Table 4-1 
• Section 4.5 was updated to explain the risks associated with the investigational status of the 
centralized MET amplification assay 
• A statement has been added in Section 4.5.1 related to risks associated with COVID-19 
while on capmatinib treatment 
• The range of definition of high frequency hearing loss has been corrected in  
Section 4.5.3 from 4000-8000 Hz to 2000-8000 Hz  
• A clarification has been added in Section 5.1, inclusion criterion # 5 related to the possibility 
to have central T790M testing when local T790M result is not available (only applicable for 
randomized part) 


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• Wording has been revised for inclusion criterion # 7 in Section 5.1 to add clarity 
• Wording has been revised for exclusion criterion # 18 and # 19 in Section 5.2 to add clarity, 
and as per Novartis Protocol template version 5 
• Wording of Table 6-1 has been revised as per Novartis Protocol template version 5 
• Crossover wording has been added in Section 6.1.3 and Section 6.3.2 
• In Section 6.1.5, the possibility of participants to crossover to capmatinib + osimertinib arm 
has been added 
• In Section 6.1.5.1, the possibility of participants who crossover to ET to receive treatment 
beyond progression has been added 
• Section 6.1.5.2 (Crossover to capmatinib in combination with osimertinib therapy) has been 
added to the protocol. The Section describes in details the eligibility criteria that participants 
have to fullfil to be allowed to crossover and defines the EOT visit to be performed in case 
of crossover 
• Section 6.2.1.2, Section 6.5.5.1 , Section 6.7.1.1 and Section 7 have been updated as per 
Novartis Protocol template version 5 
• Information on ET visit windows have been added to Table 8-1 
• Table 8-3 has been updated to include the additional ET period and the related assessments 
which will be performed for participants who crossover to ET. Visit numbers have also been 
updated accordingly 
• A statement in Table 8-3 has been added to clarify that participants who crossover must be 
consented under Protocol Amendment 02 
• Language in Section 8.1 has been revised to clarify that central MET ampfliciation test is 
investigational and sufficiently validated for the purposes of identifying patients for this 
study 
• A statement has been added in Section 8.1 to confirm that participants who crossover to ET 
do not have to re-confirm eligibility with regards to molecular testing 
• A clarification on MET amplification testing requirements has been added in  
Section 8.1 
• In Table 8-2, Table 8-3 and Section 8.2, collection of PD-L1 status has been added 
• A clarification has been added in Table 8-2, Table 8-3, Table 8-14 and Table 8-15 where 
tumor samples for pre-screening can be collected during or after progression from prior 
EGFR TKI treatment (not only after progression) 
• In Section 8.3.1.3, for participants who crossover, instructions for determining disease 
progression and clarification on imaging assessments have been added 
• In Section 8.4.1 and in Table 8-3, a statement explaining local laboratory evaluations for 
ET has been added  
• In Table 8-9 and in Section 8.4.2, ET period timelines for ECGs have been included 
• Section 8.4.3.1 has been updated as per Novartis Protocol template version 5 to add clarity 
on fertility assessment 
• The possibility to have central T790M testing when local T790M result is not available has 
been removed from Table 8-2 and Table 8-14, since it is only applicable for randomized 
phase 


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• Language of Section 8.5.1 has been modified as per Novartis Protocol template version 5 
• In Section 8.5.1 and in Table 8-3, a clarification has been added for PROs collection stating 
that for participants who crossover to ET, PROs will be only collected post-platinum – 
pemetrexed progression  
• In Section 8.5.2, a statement has been added to clarify that participants crossing over ET do 
not undergo any scheduled PK sample collection 
 
 
 
• In Section 8.5.3.1, wording has been revised to add clarity 
• In Section 8.5.3.2, clarification on blood samples collection for Part 2 has been added 
• Language of Section 9.1.2 and Section 9.1.3 has been updated as per Novartis Protocol 
template version 5 
• The collection of PROs in case of death has been removed from Section 9.2.2 
• In Section 9.2.3, a clarification on survival follow-up for participants who crossover has 
been added 
• Section 10.1.3 updated to comply with BfArM requirements regarding SAE reporting in 
Germany 
• Section 10.1.3 updated for SAE collection schedule to be consistent with protocol 
• In Section 10.1.3, wording has been revised for participants’ pre-screening procedures in 
regards of molecular pre-screening ICF signature 
• Pregnancy reporting for ET has been added in Section 10.1.4 
• In Section 12.5.1, a statement has been added related to the possibility of assessing PFS2 
on participants who crossover if a sufficient number of participants fit specific criteria 
• In Section 12.5.2, clarification on observation period for participants who crossover to ET 
has been added 
• Language in Section 13.1 has been updated as per Novartis Protocol template version 5 
• Language in Section 13.5 was updated to add flexibility for Patient Engagement initiatives 
In addition, as part of this amendment, minor editorial changes to improve flow and consistency 
have been made throughout the protocol. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes described 
in this amended protocol require IRB/IEC approval prior to implementation. The changes herein 
affect the Informed Consent. Sites are required to update and submit for approval a revised 
Informed Consent that takes into account the changes described in this protocol amendment. 


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Amendment 01 (14-Sep-2021) 
Amendment rationale 
As of 14 Sep-2021, enrollment has not yet started. 
The main purpose of this amendment is to add clarity on few sections as suggested by some 
health authorities. The main updates cover the following:  
• Revision of inclusion- exclusion criteria.  
• Remove the requirements to have a T790M negative results for participant previously 
treated with osimertinib based on the concept that T790M mutation is an acquired 
resistance mechanism of 1st or 2nd generation EGFR TKI rather than osimertinib.  
• Allow patients who previously received 3rd generation EGFR TKIs other than 
osimertinib to participate in this study. 
• Exclude participants with known druggable molecular alterations who might be 
candidates for alternative targeted therapies. 
• Exclude participants with known EGFR T790M positive status. 
• Exclude participants who received live vaccines within 30 days prior to the first dose 
of study treatment.  
• Revision of the DLT wording criteria.  
 
 
 
Changes are implemented throughout the document to reflect the updated Novartis protocol 
template. In addition, a new ICF is added to capture the participant consent to continue the 
combination treatment (capmatinib-osimertinib) following disease progression.  
Few minor editorial changes and corrections were applied throughout the protocol.  
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strikethrough red font for deletions and red underline for insertions as described 
below.  
• Add to the Background Section 1.1 updated information concerning other 3rd generation 
EGFR TKIs that have demonstrated similar efficacy compared to osimertinib which are 
expected to be approved in China. 
 
 
 
 
• Update the Protocol summary to align with the changes made in the protocol and to correct 
a typo error stating that effect of combination treatment as compared to platinum-
pemetrexed on patient-reported disease-related symptoms, functioning, and health-related 
quality of life (HRQoL) by evaluating the change from baseline and time to symptom 


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deterioration “end point” will be applicable for EORTC QLQ-C30, QLQ-LC13 and NCCN 
FBrSI questionnaires, instead of EQ-5D-5L questionnaire as previously stated. The same is 
reflected in Table 2-1.  
• Clarification for the intercurrent event related to start of new anti-cancer therapy (for ORR 
and OIRR) are added to Section 2.2. 
• Modify Section 3 and Section 4.1 to reflect the updated inclusion exclusion criteria. The 
text was updated throughout the document to include patient who had progressed on other 
third generation EGFR TKI other than osimertinib. An additional threshold of 10% for 
participant who progressed on other third generation EGFR TKI other than osimertinib was 
added. It was additionally stated that participants previously treated with osimertinib are not 
required to have central confirmation of EGFR T790M negative tumor status however those 
with known T790M positive tumor status are excluded from the study. The stratification 
factors were also updated throughout the text accordingly.  
• Update Figure 3-1 Part 1: Run-in Part to remove the PRO assessment that are not applicable 
to this part of the trial. 
• The Rationale wording was clarified in Section 4 and throughout the text to state that it is 
due to the unmet medical need and lack of a current targeted approved therapy for the MET 
amplification that is one of the leading mechanisms of resistance to EGFR TKI in EGFR 
mutated NSCLC 
• Clarify the DMC meeting schedule to ensure timely safety monitoring for participants 
treated with the combination (capmatinib + osimertinib) in Section 4.5 Risks and benefits. 
• Update Sections 4.5.2 and Section 6.5.4 to add further clarification concerning additional 
precaution for the study treatment.  
• Add Section 4.5.3 Cisplatin, carboplatin and pemetrexed in order to provide further 
clarification to outline the precautions related to the comparator therapy in the protocol.  
• Clarified the wording in inclusion criterion (#3) in Section 5.1 to add “chemoradiation” to 
“curative surgery and radiation”. 
• Update inclusion criterion (#5) in Section 5.1 to clarify the types of EGFR mutations which 
are known to be associated with TKI sensitivity, the specifications for local testing and 
which participants are required to have confirmed T790M negative tissue status. Clarify the 
sample types for MET amplification in both run-in and randomization parts. 
• Clarify inclusion criterion (#7) in Section 5.1 by removing the word “maximum” describing 
participants who must have failed one prior line of therapy and updating to include all of 
previous of EGFR TKI treatment for advanced/metastatic disease (stage IIIB/IIIC [not 
amenable to curative surgery, chemoradiation or radiationor stage IV NSCLC) used per 
local standard of care, instead of either 1st/2nd generation EGFR TKI or osimertinib all over 
the document and title. It was also clarified that adjuvant osimertinib therapy will count as 
prior line of EGFR TKI treatment if relapse occurs during the adjuvant osimertinib therapy. 
• Exclusion criteraion (#11) in Section 5.2 was udpated to read as follow: Treatment with a 
prior 1st or 2nd generation EGFR TKIs (e.g., erlotinib, gefitinib, afatinib, dacomitinib) 
osimertinib or another 3rd generation EGFR TKIs such as almonertinib and furmonertinib 
within 14 days or approximately 5x half-life, whichever is shorter, of the first dose of study 
treatment. 


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• Remove “follow chemotherapy schedule” from exclusion criterion (#14) in Section 5.2 
• Adjust the exclusion criterion (#15) in Section 5.2 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 randomization. Additional criteria were 
clarified for exclusion of HIV patients.  
• Exclusion criterion (#16) in Section 5.2 was updated to add “contraindications” to read: 
Participants with known hypersensitivity or contraindications to capmatinib or osimertinib 
or carboplatin or pemetrexed or cisplatin, or any excipient of these agents 
• Adjust the exclusion criterion (#18) for women of childbearing potential in Section 5.2 to 
add the use of hormonal contraceptive not prone to DDI and to specify that the use of 
hormonal contraceptives should be combined to the use of condom, in order to minimize 
the risk of exposure.  
• Add an additional exclusion criterion (#20) in Section 5.2 to exclude participants with 
known druggable molecular alterations who might be candidates for alternative targeted 
therapies, as per the local regulations and treatment guidelines. 
• Add an additional exclusion criterion (#21) in Section 5.2 to exclude participants with 
documented EGFR genetic aberration mediating resistance to previous treatment with a 3rd 
generation EGFR TKI or any other known genetic aberration concomitant to MET 
amlification that could negatively impact the treatment outcome of capmatininb in 
combination with osimertinib. 
• Add an additional exclusion criterion (#22) in Section 5.2 to exclude participant with known 
EGFR T790M positive status by either tissue or blood after progression on 1st, 2nd or 3rd 
generation EGFR TKIs including osimertinib.  
• Add an additional exclusion criterion (#23) in Section 5.2 to exclude participants who 
received live vaccines within 30 days prior to the first dose of study treatment. 
• Stratification factor for patients in randomized phase has been updated from “prior treatment 
with osimertinib” to “prior treatment with EGFR TKIs” in Protocol Summary, Section 3, 
Section 6.3.2 and Section 12.4.2. 
• Add wording to Section 6.1.3 to provide additional guidance on chemotherapy treatment as 
per the local guidelines.  
• Update Section 6.1.5.1, Table 8-2, Table 8-3 and Section 7 to include an additional 
participant consent to continue on the study treatment beyond progression only for patient 
treated with the combination treatment (capmatinib + osimertinib).  
• Update Section 6.2.2 to add live vaccines into prohibited medications during study treatment 
and 30 days after the last dose of study treatment.  
• Clarify that the threshold for enrollement of different population will be monitored throught 
the IRT system in Section 6.3.2 
• Clarify the treatment blinding wording in Section 6.4  
• Update criteria for defining DLTs in Table 6-4 to include neutropenia grade 4 regardless of 
duration, thrombocytopenia grade 4 regardless of duration or bleeding, laboratory 
abnormalities ≥ grade 3 that result in hospitalization and any death not clearly related to the 
underlying disease or extraneous causes.  


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• Add to Section 6.5.4 and Table 6-7, a clarification that for confirmed pneumonitis and 
interstitial lung disease, both capmatinib and osimertinib should be discontinued.  
• Update Section 6.7 Preparation and dispensation, to exclude platinum pemetrexed from 
applicable study treatment to be shipped to the participant home as per the local regulations 
in case of public health emergency as declared by local or regional authorities. 
• Update Section 6.5.4 to remove dose re/escalation of study treatment. 
• Update Section 6.7.1.1 with instructions on how to handle study treatment according to 
updated Novartis Protocol template version 4. 
• Update Section 6.7.2.1.1 in order to be consistent with the Table 8-2 and Table 8-3 
concerning the food consumption information to be captured on the CRF; information of 
whether capmatinib was administered with or without food must be recorded in the 
appropriate eCRF. 
• Update Table 6-8 to add clarity on measures related to dose modification for capmatinib, if 
osimertinib is permanently discontinued and capmatinib continued as monotherapy. 
• The molecular Pre-screening wording was udpated in Section 8.1 to reflect the inclusion 
and exclusion updated criteria and to add information about the validated accepted tests. 
Clarification was also added to indicate that previously treated participant with osimertinib 
do not require EGFR T790M negative status confirmation.  
• Update ECHO/MUGA assessment window from ≤ 72h before C1D1 to ≤ 15 days before 
C1D1 in Section 8.4.2.1 and Table 8-1, Table 8-2 and Table 8-3. 
 
 
 
• Update Table 8-2 and Table 8-3 to remove ECOG assessment at C1D15 time point. 
• Table 8-7 has been updated to include red blood cells analysis in Hematology panel as per 
updated Novartis Protocol template version 4. 
 
 
 
• Replace the 72 hrs window with a 15 days window prior to study medication/C1D1 for 
Cardiac imaging assessment (Table 8-2 and Table 8-3, and Section 8.4.2.1).  
• Adjust the typo error (30% instead of 25%) in the hypothesis for OIRR in Section 12.5.1.1 
to match what is correctly stated in Section 12.8.2 and adjust the PFS event to 162 instead 
of 177 in Section 12 Data analysis and statistical methods.  
• Update the wording in Section 12.5.1.2 to read “participants will also be censored if they 
did not have an event” instead of “Participants will also be censored for death due to other 
causes” to be consistent within the section and aligned with internal Novartis RANO-BM 
guidelines.  
 
 
 
 
 
 
 
  
• “Patients” and “Subjects” were replaced with the term “Participants” where applicable. 
• Glossary of terms was updated to reflect changes in the new Novartis Protocol template 
version 4. 


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• Rationale was added in the Protocol Summary as per updated Novartis Protocol template 
version 4. 
• Title of Section 2 was modified to “Objectives, endpoints and estimands” and Table 2-1 
was updated as per updated Novartis Protocol template version 4. 
• The definition of estimand was added to Section 2.1 
• Exclusion criterion #18 updated as per updated Novartis Protocol template version 4 to 
include the definition of women not considered of childbearing potential. 
• Heading of Table 6-1 was modified as per updated Novartis Protocol template version 4. 
• Abbreviations were updated to reflect additional wording and were clarified as per updated 
Novartis Protocol template version 4 in Section 6.5.5.1. 
• Section 6.6.1, Section 6.7, Section 6.7.1.1, Section 7, Section 8.4.1, Section 8.4.2 and 
Section 8.4.3: language related to Public Health Emergencies and potential off-site study 
visits have been added as per updated Novartis Protocol template version 4. 
• Discontinuation language was modified in Section 8 and Section 9 as per updated Novartis 
Protocol template version 4. 
• Section 8.3.1.2, Section 9.1.1 and Section 9.1.2: Withdrawal of consent language was 
modified to include use of data and biological samples as per updated Novartis Protocol 
template version 4. 
• Section 8.4.2 was modified as per updated Novartis Protocol template version 4 for clarity 
and standardization across divisions. In addition, transmission of unscheduled ECG was 
updated to reflect that the ECG collection strategy applies to all parts of the trial and not the 
randomization part only. 
• In Section 9, language for participant discontinuation has been modified as per updated 
Novartis Protocol template version 4.  
• Title of Section 10 was modified to “Safety monitoring, reporting and committees” as per 
updated Novartis Protocol template version 4. 
• In Section 10.1.2 redundant text has been deleted. 
• In Section 10.1.3, SAE reporting instructional text has been modified as per updated 
Novartis Protocol template version 4.  
• In Section 10.1.4, Pregnant Participant language has been modified for clarity as per updated 
Novartis Protocol template version 4. 
• In Section 12.2 and Section 12.3, text has been modified as per updated Novartis Protocol 
template version 4. 
• Title of Section 12.4 has been modified to “Analysis supporting primary objectives” as per 
updated Novartis Protocol template version 4. 
• Title of Section 12.4.1 has been modified to “Definition of primary endpoint(s)” as per 
updated Novartis Protocol template version 4. 
• Title of Section 12.4.3 has been modified to “Handling of intercurrent events of primary 
estimand” as per updated Novartis Protocol template version 4. 
• Title of Section 12.4.5 has been modified to “Sensitivity analyses” as per updated Novartis 
Protocol template version 4. 


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• Title of Section 12.5 has been modified to “Analysis supporting secondary objectives” as 
per updated Novartis Protocol template version 4. 
• In Section 12.5.2 text was modified for vital signs, 12-lead ECG and Clinical laboratory 
evaluations as per updated Novartis Protocol template version 4. 
• Section 13.5 related to Participant Engagement was added as per updated Novartis Protocol 
template version 4. 
• Minor typographical erros corrected allover the document. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes described 
in this amended protocol require IRB/IEC approval prior to implementation. The changes herein 
affect the Informed Consent. Sites are required to update and submit for approval a revised 
Informed Consent that takes into account the changes described in this protocol amendment. 


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Protocol summary 
Protocol number 
CINC280L12301 
Full Title 
A phase III randomized, controlled, open-label, multicenter, global study of capmatinib in 
combination with osimertinib versus platinum - pemetrexed based doublet chemotherapy 
in patients with locally advanced or metastatic NSCLC harboring EGFR activating 
mutations who have progressed on prior EGFR-TKI therapy and whose tumors are T790M 
mutation negative and harbor MET amplification (GEOMETRY-E) 
Brief title 
Study of safety and efficacy of capmatinib in combination with osimertinib compared to 
platinum - pemetrexed based doublet chemotherapy in patients with locally advanced or 
metastatic non-small cell lung cancer harboring EGFR activating mutations, MET 
amplification and T790M negative who have progressed on prior EGFR-TKI therapy  
Sponsor and 
Clinical Phase 
Novartis, Phase III 
Investigation type 
Drug  
Study type 
Interventional  
Purpose  
The purpose of this prospective, randomized, controlled, open-label, multicenter, global 
phase III study is to evaluate the efficacy and safety of capmatinib in combination with 
osimertinib compared to platinum (cisplatin or carboplatin) - pemetrexed based doublet 
chemotherapy as second line treatment in patients with locally advanced or metastatic 
(stage IIIB/IIIC or IV) NSCLC with Epidermal Growth Factor Receptor (EGFR) activating 
mutation (ie. L858R and/or ex19del), T790M negative, MET amplified (defined as Gene 
Copy Number [GCN] ≥ 5 per central Novartis laboratory) who have progressed following 
1st/2nd generation EGFR Tyrosine Kinase Inhibitors (TKIs) treatment, osimertinib or other 
3rd generation EGFR TKIs used per local standard of care.  
Primary 
Objective(s)  
The primary objective of run-in part (part 1) of this study is to confirm the recommended 
dose of capmatinib in combination with osimertinib for the randomized part (part 2). The 
primary objective of the randomized part (part 2) is to compare the efficacy of capmatinib 
in combination with osimertinib as compared to platinum - pemetrexed, by comparing 
progression-free survival (PFS) by blinded independent review committee (BIRC) 
according to Response Evaluation Criteria In Solid Tumors (RECIST 1.1) between 
treatment arms  
Secondary 
Objectives 
Key secondary (randomized part) 
• To compare the overall response rate (ORR) per RECIST 1.1 by BIRC of capmatinib in 
combination with osimertinib as compared to platinum - pemetrexed 
• To compare the overall intracranial response rate (OIRR) by BIRC as per Response 
Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria of capmatinib in 
combination with osimertinib as compared to platinum - pemetrexed, in participants with 
Central Nervous System (CNS) lesions 
Secondary (run-in part) 
• To characterize the safety and tolerability of capmatinib in combination with osimertinib 
based on the incidence, type and severity of adverse events, change in laboratory 
values, vital signs, liver and cardiac assessment 
• To characterize the pharmacokinetics of capmatinib, osimertinib, and osimertinib's 
active metabolites (AZ5104 and AZ7550) in combination setting by assessing plasma 
Pharmacokinetic(s) (PK) concentrations and derived PK parameters  
• To assess the tumor response of capmatinib in combination with osimertinib calculated 
by RECIST 1.1 by investigator 
Other Secondary (randomized part) 
• To assess the anti-tumor activities of capmatinib in combination with osimertinib as 
compared to platinum - pemetrexed (e.g., duration of response (DOR), Time to 
response (TTR), Disease control rate (DCR), all by BIRC per RECIST 1.1) 
• To assess PFS2 (PFS after next-line of treatment) based on local investigator 
assessment 


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• To characterize the pharmacokinetics of capmatinib, osimertinib, and osimertinib's 
active metabolites (AZ5104 and AZ7550) in combination setting by assessing 
plasma PK concentrations  
• To evaluate overall survival (OS) in participants treated with capmatinib in combination 
with osimertinib as compared to platinum - pemetrexed  
• To evaluate the safety profile of capmatinib in combination with osimertinib as compared 
to platinum - pemetrexed 
• To assess the effect of capmatinib in combination with osimertinib as compared to 
platinum-pemetrexed based doublet chemotherapy on patient-reported disease-related 
symptoms, functioning, and health-related quality of life (HRQoL) by evaluating the 
change from baseline in European Organization for Research and Treatment of Cancer 
(EORTC) QLQ-LC13, QLQ-C30, EuroQoL-5 Dimension-5 Level/EQ-5D-5L, and NCCN 
Fact Brain Symptoms Index questionnaires and time to symptom deterioration for 
EORTC QLQ-C30, QLQ-LC13 and NCCN FBrSI questionnaires 
• To assess intracranial anti-tumor activity of capmatinib in combination with osimertinib 
as compared to platinum-pemetrexed in participants with Central Nervous System 
(CNS) lesions at baseline (e.g., Duration of intracranial response (DOIR), time to 
intracranial response (TTIR) and intracranial disease control rate (IDCR), all by BIRC 
as per RANO-BM criteria) 
Study design 
This is a multicenter, open-label, randomized, active-controlled, global phase III study that 
will enroll adult participants with locally advanced or metastatic NSCLC with EGFR 
activating mutation, T790M negative, MET amplified who have progressed following EGFR 
TKIs (EGFR TKIs can be 1st and 2nd generation EGFR TKIs, osimertinib or other 3rd 
generation EGFR TKIs used per local standard of care). Randomization of participants who 
have progressed on prior line with osimertinib will be a minimum of 50% of the planned 
total number of participants) while for the other third generation EGFR TKI will be maximum 
of 10% of the planned total number of participants. 
The study will consist of an initial safety run-in part to evaluate the safety and tolerability of 
capmatinib in combination with osimertinib and to confirm the recommended dose for the 
randomized part, and a randomized part that will evaluate the efficacy and safety of 
capmatinib in combination with osimertinib compared to platinum (cisplatin or carboplatin) 
– pemetrexed based doublet chemotherapy as second line treatment. Participants who 
progressed in the platinum – pemetrexed arm will be allowed to crossover to capmatinib + 
osimertinib therapy.  
The study will enroll approximately 10 to 20 participants in the run-in part and 
approximately 225 participants in the randomized part. Participant's respective treatment 
(either with capmatinib in combination with osimertinib, or with platinum (cisplatin or 
carboplatin) - pemetrexed based doublet chemotherapy) will be continued until participant 
experiences any of the following: documented disease progression by RECIST 1.1 (as 
assessed by the investigator in the run-in part, and as assessed by the investigator 
confirmed by BIRC in the randomization part), withdrawal of consent, pregnancy, lost to 
follow-up, or death. The combination treatment of capmatinib + osimertinib may be 
continued beyond initial disease progression as per RECIST 1.1 if, in the judgement of the 
investigator, there is evidence of clinical benefit, and the participant wishes to continue on 
the study treatment. 
After treatment discontinuation, all participants will be followed for safety evaluations during 
the safety follow-up period 
Rationale 
The rationale for investigating the anti-cancer activity of capmatinib in combination with 
osimertinib is due to the unmet medical need and lack of a current targeted approved 
therapy for MET amplification that is one of the leading mechanisms of resistance to EGFR 
TKI in EGFR mutated NSCLC. Few options to date are available for this population with 
limited benefit, in particular in the T790M negative setting. 
Proof of concept for capmatinib in combination with EGFR TKIs in MET positive EGFR 
mutated post-EGFR TKI NSCLC setting has been demonstrated with both first-generation 
EGFR TKI (gefitinib) and 3rd generation EGFR TKI (EGF816). 


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Study population 
This study will enroll adult male and female participants with EGFR activating mutation 
(i.e., L858R and/or ex19del), T790M negative, advanced (stage IIIB, IIIC or IV) NSCLC 
harboring MET amplification as determined by a Novartis central molecular laboratory and 
who have progressed following 1st/2nd generation EGFR TKIs, osimertinib or other third 
generation EGFR TKIs used per local standard of care.  
Key Inclusion 
criteria 
• Stage IIIB/IIIC (not amenable to curative surgery, chemoradiation or radiation) or stage 
IV NSCLC at the time of study entry 
• Histologically or cytologically confirmed diagnosis of NSCLC with EGFR mutations 
known to be associated with EGFR TKI sensitivity, EGFR T790M negative, and MET 
gene amplification defined as IHC 3+ for the Run-In part (defined as ≥ 50% of cells 
staining with high intensity) and/or MET Gene Copy Number ≥ 5 will be utilized as study 
entry parameters by local test in tissue or blood. For the Randomized part, it should be 
defined as Gene Copy Number (GCN) ≥ 5 per central Novartis designated laboratory 
result from tissue sample test 
• Mandatory provision of a formalin-fixed, paraffin embedded tumor tissue sample (a 
newly obtained tumor sample, or archival tumor block/slides taken after progression on 
prior line of EGFR TKI)  
• Participants must have progressed on one prior line of therapy (either to 1st/2nd 
generation EGFR TKIs, osimertinib, or other 3rd generation EGFR TKIs used per local 
standard of care for advanced/metastatic disease and must be eligible candidates for 
platinum (cisplatin or carboplatin) - pemetrexed based doublet chemotherapy 
• At least one measurable lesion as defined by RECIST 1.1 
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1  
Key Exclusion 
criteria 
• Prior treatment with any MET inhibitor or Hepatocyte Growth Factor (HGF)-targeting 
therapy 
• 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 
• Presence or history of interstitial lung disease or interstitial pneumonitis, including 
clinically significant radiation pneumonitis (i.e., affecting activities of daily living or 
requiring therapeutic intervention) 
• Long QT syndrome, family history of idiopathic sudden death or congenital long QT 
syndrome 
• Treatment with a prior 1st or 2nd generation EGFR TKIs (e.g., erlotinib, gefitinib, afatinib, 
dacomitinib), osimertinib or another third generation EGFR TKIs such as almonertinib 
and furmonertinib, within 14 days or approximately 5x half-life, whichever is shorter, of 
the first dose of study treatment 
• Unable or unwilling to swallow tablets as per dosing schedule 
Study treatment 
Capmatinib (INC280) + osimertinib or platinum - pemetrexed based doublet 
chemotherapy  
Efficacy 
assessments 
• Tumor assessment by RECIST 1.1 performed every 6 weeks for the first 18 months 
starting at C3D1, then every 12 weeks until progressive disease (PD) determined using 
RECIST 1.1 by investigator (run-in part) or by investigator and confirmed by BIRC 
(randomized part) 
• CNS lesions assessed by BIRC based on RANO-BM criteria 
• survival status collected every 12 weeks regardless of treatment discontinuation reason 
(except if consent is withdrawn or participant is lost to follow-up) until death, lost to 
follow-up, or withdrawal of consent for survival follow-up (randomized part only) 
Pharmacokinetic 
assessments  
Blood samples will be collected from all participants who receive capmatinib and 
osimertinib to assess plasma PK of capmatinib, osimertinib and osimertinib's active 
metabolites (AZ5104 and AZ7550) at the following time points: 
• Cycle 1 Day 1 
• Cycle 1 Day 2 and Cycle 1 Day 15 (only for run-in part) 


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• At Day 1 of Cycles 2 (only for randomized part), C3, C4 and C6 (applicable for both run-
in and randomized parts) 
No blood samples will be collected to assess PK for participants in ET period 
Key safety 
assessments 
• Laboratory assessments, including hematology, chemistry, urinalysis, coagulation, 
Human Immunodeficiency virus (HIV) testing (where locally required), pregnancy test 
(for women of child-bearing potential) 
• Physical examination 
• Vital signs 
• Body weight and height 
• Electrocardiogram (ECG) and cardiac imaging Multigated Acquisition Scan (MUGA) 
• Collection of Adverse Events (AE) and Serious Adverse Events (SAE) 
Other 
assessments  
• Patient Reported Outcomes (PRO): EORTC QLQ-C30, QLQ-LC13, NCCN FACT Brain 
Symptom Index and EQ-5D-5L  
Data analysis 
The primary objective is to evaluate whether capmatinib in combination with osimertinib 
prolongs PFS by BIRC according to RECIST 1.1 compared to platinum-based 
chemotherapy.  
The primary endpoint for the safety run-in phase is the incidence of Dose Limiting Toxicity 
(DLT) during cycle 1. The dose recommendation decision will be based on the following 
criteria:  
• At least six evaluable participants treated at this dose and regimen 
• No more than two DLT have been observed out of six evaluable participants 
• It is the dose recommended for participants after review of all clinical data by Novartis 
and Investigators in a dose level review team meeting 
If one of the conditions specified above is not satisfied, dose confirmation cannot be 
declared and a second cohort may be treated at the lower dose level with capmatinib (400 
mg b.i.d.) and osimertinib (40 mg q.d.). The same criteria are applied for this new dose and 
regimen. If dose confirmation cannot be declared on this lower dose, the randomized part 
cannot start and the study will end.  
For randomized part, the primary efficacy analysis to test these hypotheses and compare 
the two treatment groups will consist of the stratified log-rank test at an overall one-sided 
2.5% significance level. The following null and alternative hypothesis will be tested to 
address the primary efficacy objective for PFS based on BIRC as per RECIST 1.1:H01: θ1 
= 1 vs. HA1: θ1 < 1 where θ1 is the PFS hazard ratio (capmatinib in combination with 
osimertinib versus platinum pemetrexed based chemotherapy). The stratification will be 
based on the stratification factors assigned at randomization (presence of brain metastasis 
at baseline (presence vs absence) and previous treatment with 3rd generation EGFR TKIs 
(yes vs no). The PFS distribution will be estimated using the Kaplan-Meier method, and 
Kaplan-Meier curves, medians and 95% confidence intervals of the medians will be 
presented for each treatment group. The hazard ratio for PFS will be calculated, along with 
its 95% confidence interval, from a stratified Cox model using the same stratification factors 
as for the log-rank test  
Key words 
Capmatinib, osimertinib, platinum-pemetrexed, Non-small-cell lung cancer (NSCLC), 
EGFR  


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1 
Introduction 
1.1 
Background 
1.1.1 
Non-small cell lung cancer (NSCLC) treatment landscape 
Lung cancer is the most commonly diagnosed 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 (WHO 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). 
NSCLC accounts for more than 85% of all lung cancer cases, and it includes two major types: 
(1) non-squamous carcinoma (including adenocarcinoma, large-cell carcinoma, other cell 
types); and (2) squamous cell (epidermoid) carcinoma. Adenocarcinoma is the most common 
type accounting 50% of NSCLC and is also the most frequently occurring cell type in non-
smokers (Subramanian and Govindan 2007, Perez-Moreno et al 2012, Novello et al 2016). 
Mechanisms of oncogenesis in lung cancer have been largely deciphered over the past 20 years. 
The concept of “oncogene addiction” refers to tumor-cell dependence on the specific activity 
of an activated or overexpressed oncogene. The main oncogenic drivers in the field of thoracic 
oncology are mutations of EGFR, and ALK (Anaplastic Lymphoma Kinase) rearrangements. 
Activating mutations in EGFR and ALK translocations have been the first molecular drivers 
proving to be strong predictors of response to targeted therapies such as EGFR and ALK 
Tyrosine Kinase Inhibitors (TKIs) showing improved efficacy and better tolerance when 
compared to standard chemotherapy in patients harboring EGFR activating mutations and ALK 
translocations and have become standard of care in both the pretreated and treatment naive 
settings 
(Ettinger 2010, 
Zhou et al 2011, 
Fukuoka et al 2011, 
Shaw et al 2013, 
Rosell et al 2012, Sequist et al 2013, Solomon et al 2014, NCCN 2021). Activating mutations 
in the EGFR gene are observed frequently in patients with lung adenocarcinoma, but are rare 
in squamous cell carcinoma. Approximately 50% of Asian adenocarcinoma patients carry 
EGFR mutations, including 50.2% of Chinese patients (Shi et al 2015), compared with 10–20% 
of Caucasian adenocarcinoma patients (Harrison et al 2020). The most common EGFR 
mutations, also known as the classical mutations, are inframe deletions in exon 19 (del19; 49–
72% of EGFR mutations) and a nucleotide substitution within codon 858 of exon 21 (L858R; 
28–43%). Other EGFR mutations have been detected in 7–23% of patients and include the 
G719X (~30% of uncommon mutations), L861Q (13–35%), and S768I (~5%) mutations. 
Management of NSCLC harboring mutations in the epidermal growth factor receptor (EGFR) 
gene has been transformative in recent years. The next clinical challenge for this disease is to 
overcome or prevent drug resistance. 
Three generations of EGFR TKIs are now approved for use in EGFR mutation-positive 
NSCLC; the first-generation agents erlotinib, gefitinib, and icotinib; the second-generation 
ErbB family blockers afatinib and dacomitinib; and most recently, osimertinib, a third-
generation EGFR TKI. 


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First- and second-generation epidermal growth factor receptor tyrosine kinase inhibitors 
(EGFR-TKIs) are effective as first-line treatment for advanced NSCLC harboring activating 
EGFR mutations (e.g., deletions in exon 19 and the exon 21 L858R mutation). EGFR T790M 
mutation emerges following EGFR-TKI therapy, and accounts for 55% of mechanisms of 
acquired resistance to first- and second-generation EGFR-TKIs (Liao et al 2019). Osimertinib 
monotherapy is currently widely recommended second-line treatment for EGFR T790M 
mutation-positive (T790M-pos) NSCLC, and is also the recommended first-line treatment for 
patients with locally advanced or metastatic EGFR mutation-positive NSCLC (Liao et al 2019). 
Other 3rd generation EGFR TKIs such as almonertinib and furmonertinib have demonstrated 
similar efficacy compared to osimertinib and are expected to be approved in China for the 
treatment of patients with first line EGFR mutated NSCLC. 
In addition, recent results from the Phase III ADAURA trial showed that osimertinib 
demonstrated a statistically significant and clinically meaningful improvement in disease-free 
survival (DFS) in the adjuvant treatment of patients with early-stage (Stage IB, II and IIIA) 
epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) after 
complete tumor resection with curative intent (Wu et al 2018a, Wu et al 2020). 
In the primary endpoint of DFS in patients with Stage II and IIIA disease, adjuvant (after 
surgery) treatment with osimertinib reduced the risk of disease recurrence or death by 83% 
(based on a hazard ratio [HR] of 0.17; 95% confidence interval [CI] 0.12, 0.23; p<0.0001). DFS 
results in the overall trial population, Stage IB through IIIA, a key secondary endpoint, 
demonstrated a reduction in the risk of disease recurrence or death of 79% (based on a HR of 
0.21; 95% CI 0.16, 0.28; p<0.0001) (astrazeneca.com/media-centre/press-releases). 
At two years, 89% of all patients in the trial treated with osimertinib remained alive and disease 
free versus 53% on placebo. 
To date, there are few, limited treatment options for patients in particular for those without the 
T790M mutation who progress on EGFR-TKIs, except chemotherapy or, in some countries, a 
combination of chemotherapy and immunotherapy for fit patients based on a recent subgroup 
analysis of IMpower150 study. Immunotherapy alone seems less effective in this population in 
comparison to other NSCLC subgroups (Reck et al 2019, Liu et al 2020). 
 
 
 
 
 
 
 
 
The small sample size of each subgroup is a limitation of this analysis and has resulted in 
imbalances in mutation type, smoking history, previous TKI use, and potentially other 


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subgroups (Planchard et al 2019). Moreover, the T790M status was not widely available in the 
subjects and the patient number was too small to make conclusions. Overall, the findings of 
these subgroup analyses warrant further investigation. Results from current and future studies 
assessing the combination of chemotherapy and immunotherapy in T790M negative who are 
refractory to EGFR-TKIs will provide additional insights. 
Two ongoing phase III trials, CheckMate722 (NCT02864251) and KEYNOTE789 
(NCT03515837), are testing different immuno checkpoint inhibitors (ICIs) strategies in patients 
with EGFR-mutation-positive, T790M-negative NSCLC who failed treatment with a previous 
EGFR TKI and will help to elucidate the role of ICIs in the therapeutic strategy of these patients 
(Nakagawa et al 2016 , Riely et al 2018). 
Platinum-based doublet chemotherapy is a global recommended standard of care as second-line 
treatment based on the data from the IMPRESS trial, a phase III study comparing gefitinib or 
placebo plus cisplatin-pemetrexed chemotherapy after progression on gefitinib therapy in 
patients with advanced EGFR mutation-positive NSCLC (Engelman et al 2007). Overall, the 
PFS (the primary endpoint) was 5.4 months in both arms, with an inferior OS in the gefitinib 
plus chemotherapy arm (13.4 versus 19.5 months). Among patients with T790M-negative 
disease detected in plasma the PFS was longer in those administered gefitinib plus 
chemotherapy (6.7 versus 5.4 months) while the OS was similar (21.4 versus 22.5 months) 
(Liao et al 2019). 
Due to the few options available and modest treatment outcome, future investigation into the 
optimal management of T790M mutation–negative resistance is warranted. 
T790M-negative NSCLC is seen as a heterogeneous group which comprises different molecular 
alterations identified as resistance mechanisms. Those include bypass pathway activation [e.g. 
MET amplification [MET-amp] and Human Epidermal growth factor Receptor 2 (HER2) 
amplification (HER2-amp)] downstream signaling pathways (e.g., PI3K and BRAF mutations), 
histological transformations [e.g., small cell and epithelial–mesenchymal transition (EMT)], 
but also other unknown mechanisms (Schrock et al 2016, Piotrowska et al 2018).  
MET-amp is present in 5–20% of EGFR mutation-positive NSCLC patients who develop 
acquired resistance to EGFR-TKIs (TCGA 2014, Jia et al 2016). More than 5% of patients with 
EGFR mutation-positive NSCLC who progress on first-generation or second-generation EGFR 
TKIs, and up to 25% who progress on osimertinib, have MET amplification. Patients who 
harbor preexisting MET-amp before EGFR-TKI therapy may have a shorter time to progression 
on EGFR-TKI therapy (Guo et al 2020). MET-amp reactivates the PI3K/AKT pathway 
mediated by ErbB3 transactivation; inhibition of MET signaling could restore the sensitivity of 
lung cancer cells to gefitinib. Overexpression of hepatocyte growth factor (HGF), the ligand of 
MET, is also implicated in inducing resistance to EGFR-TKIs, and high serum levels of HGF 
is a poor prognostic factor in NSCLC patients treated with EGFR-TKIs. Both MET-amp and 
HGF overexpression can occur with or without T790M. Based on these findings, MET 
inhibitors were evaluated to overcome this resistance mechanism (Frampton et al 2015, 
Guo et al 2020, Awad et al 2019, Finocchiaro et al 2015). 


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Combination targeted therapy may overcome genomic heterogeneity of drug resistance. 
Combining EGFR TKI with an agent active on an alternative signaling pathway with a MET 
inhibitor may enhance activity in patients with acquired resistance to EGFR-TKIs, or delay the 
development of subsequent resistance via these alternate routes (Frampton et al 2015). 
In EGFR-positive and MET-positive NSCLC, the combination of EGFR and MET TKIs was 
reported to provide promising results (Wolf et al 2020). The phase Ib TATTON trial, the 
combination of osimertinib and savolitinib in 51 EGFR-mutant NSCLC patients T790M-
negative and acquired MET amplification after first- or second-generation EGFR TKI, reported 
a ORR of 65%; (95% CI, 50–78) and median duration of response (DoR) of 9 months. Likewise, 
the same combination in 69 T790M-negative and acquired MET amplified tumors after 
osimertinib reported an ORR of 30% (95% CI, 20–43) and DoR of 7.9 months (95% CI, 4.0–
10.5) (Sequist et al 2020). In TATTON trial centrally confirmed MET positivity was defined 
by fluorescence in situ hybridization (FISH), with gene copy number [GCN] ≥5, or with MET-
to–centromere chromosome 7 ratio ≥2. Personalized treatment with gefitinib and tepotinib was 
evaluated in 21 patients with EGFR-mutant, T790M-negative NSCLC with MET amplification 
(GCN ≥5 or MET-to–centromere chromosome 7 ratio ≥2) after progression while taking an 
EGFR TKI (not osimertinib), the small molecules combination improved PFS (21.2 versus 4.2 
months [HR = 0.17, 90% CI: 0.05–0.57]) versus that with platinum-pemetrexed, as well as ORR 
(67% versus 43%) (Oxnard et al 2020, Eijkelenboom et al 2019).  
1.1.2 
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 monotherapy is currently approved 
by both Food and Drug Administration (FDA) (US) and The Pharmaceuticals and Medical 
Devices Agency PMDA (Japan) for the treatment of adult patients with metastatic non-small 
cell lung cancer (NSCLC) whose tumors have a mutation that leads to mesenchymal-epithelial 
transition (MET) exon 14 skipping mutation. 
1.1.2.1 
Non-clinical experience 
Capmatinib has potent inhibitory activity against the MET kinase in vitro [inhibitory 
concentration IC50 = 0.6 nM in a biochemical assay], and is highly specific for MET with 
approximately 1,000-fold or greater selectivity over more than 400 other human kinases or 
mutant variants thereof (Baltschukat et al 2019). Potent inhibitory activity has also been 
observed in cell-based assays that measure MET-mediated signal transduction, as well as MET-
dependent cell proliferation, survival, and migration. 
In MET–dependent, mouse tumor models (including lung cancer models), capmatinib exhibits 
dose-dependent antitumor activity and causes tumor regression at well-tolerated doses that 
exceeded IC90 coverage (Liu et al 2011). Importantly, plasma levels of capmatinib correlate 
with both the dose administered and the extent of tumor growth inhibition in vivo. In 
MET/HGF-driven tumor models grown as xenografts in mice, oral dosing of capmatinib 
demonstrated significant in vivo activity in blocking both MET phosphorylation and tumor 
growth. Activation of MET in such responsive models is either due to strong MET 
overexpression (mostly because of gene amplification, e.g., in gastric or hepatocellular 


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carcinoma) or HGF secretion resulting in an autocrine loop (e.g., in glioblastoma) 
(Ha et al 2013). 
For further details, please refer to the latest version of the [capmatinib Investigator’s Brochure] 
(IB). 
1.1.2.2 
Clinical experience 
Capmatinib has been extensively tested in both healthy volunteers and cancer patients. As of 
the safety cut-off date of 28-Sep-2020, more than 780 participants with solid tumors have been 
treated with capmatinib as a single agent, and more than 690 participants have received 
capmatinib in combination with other therapies. The recommended phase II dose (RP2D) for 
capmatinib as a single agent has been determined to be 400 mg b.i.d. in tablet formulation 
[capmatinib Investigator’s Brochure]. The most frequent AEs suspected to be related to 
capmatinib of any grade reported in study [CINC280A2201], reference study for the safety 
profile of capmatinib monotherapy (n=334), across study cohorts and irrespective of MET 
mutational status, were edema peripheral (41.6%), nausea (33.2%), blood creatinine increased 
(19.5%), vomiting (18.9%), fatigue (13.8%), decreased appetite (12.6%) and diarrhea (11.4%), 
and the majority were Grade 1/2. The Grade 3/4 AEs suspected to be related to capmatinib in 
the [CINC280A2201] study included edema peripheral (7.5%) and lipase increased (5.1%), 
alanine aminotransferase increased (4.8%), amylase increased (3.0%), fatigue (3.0%), aspartate 
aminotransferase increased (2.4%), nausea and vomiting (1.8%), decreased appetite (0.9%), 
constipation (0.6%), and diarrhea (0.3%) [capmatinib Investigator’s Brochure]. 
Preliminary efficacy data for capmatinib single agent in MET-dysregulated NSCLC have been 
reported in the phase 1 study [CINC280X2102]: as of 17 July 2017, confirmed partial responses 
were observed in 11/55 (ORR 20%) evaluable NSCLC patients (defined as those with at least 
one post-baseline tumor assessment or have discontinued treatment at the time of the data cut-
off) enrolled in the expansion phase (treated at the RP2D of 400 mg b.i.d. tablet or 600 mg b.i.d. 
capsule) and DCR was 51%. In evaluable patients with MET overexpression 
(Immunohistochemistry IHC 3+), confirmed partial responses were seen in 9/37 patients (ORR 
24%), and the DCR was 62%. In evaluable patients with MET amplification GCN ≥ 6, 
confirmed partial responses were seen in 7/15 patients (ORR 47%), and the DCR was 80%. 
Kaplan–Meier median PFS was 3.7months (95% CI 1.8–7.3) in the total NSCLC population 
while in patients with MET GCN ≥ 6 median, PFS was extended to 9.3 months (95% CI 3.8–
11.9). Four NSCLC patients with MET mutations were identified by retrospective Next 
Generation Sequencing (NGS) analysis: all 4 were IHC3+ and 3/4 had high GCN (GCN ≥ 10) 
while GCN was missing in 1 patient. Confirmed Partial Response (PR) was achieved in 3 
patients while one achieved unconfirmed PR (Schuler et al 2020). Moreover, in the ongoing, 
multicohort, phase 2 GEOMETRY mono-1 study, Capmatinib has demonstrated activity in the 
subset of patients with advanced NSCLC who were either pretreated with 1 or 2 prior lines of 
systemic therapy (cohort 1a) with high-level MET amplified (GCN ≥ 10) NSCLC. ORR was 
29%, median DOR was 8.31 months (20 responders, 95% CI: 4.17–15.44) (Wolf et al 2020).  
Efficacy data for capmatinib single agent in previously treated patients with locally advanced 
or metastatic NSCLC harboring MET 14 exon skipping mutation have been reported in the 
group 4 of phase II GEOMETRY 1 study [CINC280A2201]: as of 15-Apr-2019, Response 
Evaluation Criteria In Solid Tumors (RECIST) 1.1 confirmed major responses (including a 


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complete response [CR]) evaluated by BIRC were observed in 28 out of 69 (ORR 40.6%, [95% 
CI, 28.9-53.1]) evaluable patients (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 
9.72 months [95% CI 5.55-12.98]. Median progression-free survival (mPFS) was 5.42 months 
[95% CI 4.17 - 6.97]. Moreover, intracranial responses were observed in 7 out of 13 evaluable 
patients with brain metastases at baseline. Four patients had complete resolution of lesion 
(Wolf et al 2019). Based on these data, capmatinib received breakthrough therapy designation 
for treatment of treatment-naive and pre-treated NSCLC patients with METΔex14 mutations 
from the US Food and Drug Administration (FDA) and was approved by FDA on 06-May-2020 
for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose 
tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping 
as detected by an FDA-approved test. 
Capmatinib is rapidly absorbed after oral administration with a median time to reach maximum 
drug concentration (Tmax) ranging from 1 to 2 hours for tablets. The elimination half-life 
estimated from study [CINC280X1101] ranged from 3.5 to 6.3 hours across the cohorts. Steady 
state is achieved by day 3 of 400 mg twice daily dosing. Accumulation in capmatinib exposure 
following repeated administration of 400 mg b.i.d. tablets is low, with geometric mean 
accumulation ratio of 1.39-fold in the single agent [CINC280A2201] study. The mean plasma 
exposure increase is roughly dose proportional for capmatinib tablet from 200 to 400 mg b.i.d.  
Capmatinib may be administered with or without food. The PK and safety of capmatinib 
administered with food has been evaluated in cancer patients in study [CINC280A2108]. No 
significant difference in exposure was seen when capmatinib was given under fasted conditions 
or with food. The safety profile was similar to that of study [CINC280A2201], with no Dose 
Limiting Toxicities (DLTs) observed.  
Capmatinib is a moderate Cytochrome P450 Enzymes CYP1A2 inhibitor [CINC280A2103]. 
Therefore, CYP1A2 substrates where minimal concentration changes may lead to serious 
adverse reactions should be avoided. If coadministration is unavoidable, decrease the dosage of 
CYP1A2 substrates in accordance with the approved prescribing information.  
Capmatinib is an inhibitor of P-glycoprotein (P-gp) and BCRP (Breast Cancer Resistance 
Protein) transporter [CINC280A2105]. Coadminstration of capmatinib increased P-gp substrate 
(digoxin) exposure (AUCinf and Cmax by 47% and 74%, respectively) and BCRP substrate 
(rosuvastatin) exposure (AUCinf and Cmax by 108% and 204%, respectively), indicating that 
capmatinib could potentially cause clinically relevant drug-drug interaction (DDI) with P-gp 
and BCRP substrates. For further details, please refer to the latest version of the [capmatinib 
Investigator’s Brochure].  
When coadministered with the strong CYP3A inhibitor itraconazole, capmatinib AUC (Area 
under curve) increased by approximately 40% without any change in Cmax. When 
coadministered with the strong CYP3A inducer rifampicin, capmatinib AUC and Cmax 
decreased by 67% and 56%, respectively [CINC280A2102]. Hence, adverse reactions during 
coadministration of capmatinib with strong CYP3A inhibitors should be closely monitored. In 
addition, strong CYP3A inducers should be avoided in participants treated with capmatinib. For 
further details, please refer to the latest version of the [capmatinib Investigator’s Brochure]. 


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1.1.3 
Overview of osimertinib 
Osimertinib is a potent irreversible inhibitor of both the single EGFR mutation-positive (TKI 
sensitivity conferring mutation) and dual EGFR mutation-positive / T790M+ (TKI resistance 
conferring mutation) receptor forms of EGFR with a significant selectivity margin over wild-
type EGFR (NCCN 2021). Osimertinib is approved as first-line treatment for patients with 
metastatic NSCLC whose tumors have epidermal growth factor receptor (EGFR) exon 19 
deletions or exon 21 L858R mutations, as detected by an approved test, based on FLAURA trial 
data that demonstrated a significant improvement in PFS compared to EGFR TKI comparator 
(gefitinib or erlotinib) with median 18.9 months and 10.2 months, respectively, HR=0.46, 95% 
CI: 0.37, 0.57; P<0.001 (Soria et al 2018). On the basis of positive results of the AURA3 
clinical trial, osimertinib is approved also for the treatment of patients with metastatic T790M-
positive NSCLC who have previously progressed during or after EGFR-TKI therapy 
(Jänne et al 2015). In patients harbouring the T790M-mutation after progressing on a first or 
second-generation EGFR-TKI, osimertinib was superior to platinum doublet chemotherapy 
with a higher response rate (71% vs 31%) and longer progression free survival (10.1 vs 4.4 
months, p<0.001). The median overall survival was 26.8 vs 22.5 months, p = 0.277. It has been 
shown that despite the absence of T790M some activity of osimertinib still is maintained in this 
population. In a phase I study which, in addition to T790M-positive patients, also included 50 
EGFR-TKI pre-treated patients without the T790M-mutation, the latter group demonstrated an 
overall response rate of 28% with 10.7 months duration of response and a median PFS of 5.1 
months. Previous studies in which osimertinib was given as a second-line treatment have shown 
superior 
efficacy 
in 
the 
CNS 
as 
compared 
with 
platinum 
chemotherapy 
(Ramalingam et al 2020). For further information, please refer to local label and prescribing 
information. 
1.1.4 
Capmatinib in combination with EGFR TKI non clinical and clinical 
experience 
Preclinical studies of capmatinib in combination with other kinase inhibitors demonstrated its 
activity to overcome MET-driven resistance. In study [CINC280X2202], a phase Ib/II study 
enrolled EGFR-TKI pretreated, T790M-negative patients to receive gefitinib and capmatinib 
combination therapy, 100 patients received gefitinib (250 mg daily) and capmatinib (400 mg 
twice per day), with ORRs in patients with MET-amp [gene copy number (GCN) ≥ 6, n = 36] 
and MET overexpression (IHC 3+, n = 78) of 47% and 32%, respectively (Wu et al 2018b). 
MET detection by fluorescence in situ hybridization (FISH) using a cutoff value of GCN ≥ 6 
may identify the group of patients who may best benefit from this treatment. Study 
[CINC280X2105C] combines nazartinib (EGF816, a third-generation EGFR-TKI) and 
capmatinib in EGFR mutation-positive NSCLC patients in various treatment settings and 
T790M/MET status (MET+ defined as IHC 3+ and/or gene copy number ≥ 4) (Felip et al 2020). 
As of 05-Feb-2019, 68 EGFR TKI first and second generation pretreated patients (2nd-4th line 
after 1st/2nd generation EGFR TKI) were enrolled in group Group 1 + Ph 1b RP2D (66 had 
known MET status, 23 MET+). An ORR of 43.5% [95% CI 23.2, 65.5] and 27.9% [95% CI 
15.3, 43.7] was reported in the MET+ and MET- group respectively. PFS of 7.7 months [95% 
CI 5.4, 12.2] and 5.4 months [95% CI 3.5, 6.4] were reported in the MET+ and MET- group 
respectively, confirming the role of selective MET inhibition in this selected subset of post 
EGFR TKI pts. The AEs profile confirmed the good tolerability of the combination: most 


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frequent (≥ 30%) any-grade treatment-related adverse events were peripheral edema (50%, 
57.4%), nausea (42.3%, 48.9%) and diarrhea (23.1%, 46.8%). 
The clinical use of capmatinib in combination with osimertinib has been reported within 
capmatinib patient named program. We report a case of a patient NSCLC stage IV with brain 
metastases MET amplified previously progressed to different treatments: erlotinib, osimertinib 
(despite dose increased to 160 mg), chemotherapy with carboplatin and pemetrexed, 
atezolizumab, crizotinib. Patient started capmatinib 400 mg b.i.d. as single agent. When brain 
metastases progressed, osimertinib 160 mg was added to capmatinib, leading to rapid clinical 
improvement and radiological response (Gautschi et al 2020, Rusthoven and Doebele 2016, 
Schuette 2004, Zhang et al 2015, Shin et al 2014). 
1.2 
Purpose 
The purpose of this prospective, randomized, controlled, open-label, multicenter, global phase 
III study is to evaluate the efficacy and safety of capmatinib in combination with osimertinib 
compared to platinum (cisplatin or carboplatin) - pemetrexed based doublet chemotherapy as 
second line treatment in patients with locally advanced or metastatic (stage IIIB/IIIC or IV) 
NSCLC with EGFR activating mutation (e.g., L858R and/or ex19del), T790M negative, MET 
amplified who have progressed following either 1st/2nd generation EGFR TKIs, osimertinib or 
other 3rd generation EGFR TKIs used per local standard of care. The rationale for investigating 
the anti-cancer activity of capmatinib in combination with osimertinib in this population is as 
follows: 
• MET amplification is the leading mechanism of resistance to EGFR TKI in EGFRm 
NSCLC (irrespective of the type of prior EGFR TKI) and is the basis for patient selection 
in the post-EGFR TKI setting. No targeted therapy against MET amplification is currently 
approved. 
• The target population represents a high unmet medical need since to date few options with 
limited benefit are available for the treatment of those patients, in particular in the T790M 
negative setting. 
• Proof of concept for capmatinib in combination with EGFR TKIs in MET positive EGFR 
mutated post-EGFR TKI NSCLC setting has been demonstrated with both first-generation 
EGFR TKI (gefitinib) and 3rd generation EGFR TKI (EGF816). 
2 
Objectives, endpoints and estimands 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
Run-in part 
Run-in part 
• To confirm the recommended dose of capmatinib in 
combination with osimertinib for Part 2 
• Incidence of Dose Limiting Toxicities (DLT) during 
the first 21 days (3 weeks) of treatment for each 
dose level associated with administration of 
capmatinib in combination with osimertinib 
Randomized part 
Randomized part 


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Objective(s) 
Endpoint(s) 
• To compare the progression free survival (PFS) of 
capmatinib in combination with osimertinib as 
compared to platinum-pemetrexed based doublet 
chemotherapy 
• Progression free survival (PFS) per Blinded 
Independent Review Committee (BIRC) according 
to RECIST 1.1. See Section 2.1 for Primary 
Estimands 
Key secondary objective(s) 
Endpoint(s) for key secondary objective(s) 
Randomized part 
Randomized part 
• To compare the overall response rate (ORR) of 
capmatinib in combination with osimertinib as 
compared to platinum-pemetrexed based doublet 
chemotherapy 
• ORR calculated per RECIST 1.1 by BIRC. 
See Section 2.2 for Secondary Estimands 
• To compare the overall intracranial response rate 
(OIRR) 
of 
capmatinib 
in 
combination 
with 
osimertinib as compared to platinum-pemetrexed in 
participants with Central Nervous System (CNS) 
lesions 
• OIRR 
by 
BIRC 
as 
per 
RANO-BM 
criteria. See Section 2.2 for Secondary Estimands 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
Run-in part 
Run-in part 
• To characterize the safety and tolerability of 
capmatinib in combination with osimertinib 
• Safety: Incidence, type, and severity of adverse 
events per Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 including 
changes in laboratory values, vital signs, liver 
assessments 
and 
cardiac 
assessments; 
Tolerability: dose interruptions, reductions, dose 
intensity, and duration of exposure for all drug 
components 
• To 
characterize 
the 
pharmacokinetics 
of 
capmatinib, osimertinib, and osimertinib's active 
metabolites (AZ5104 and AZ7550) in combination 
setting 
• Plasma PK concentrations and derived PK 
parameters 
• To assess the tumor response of capmatinib in 
combination with osimertinib 
• All calculated per RECIST 1.1 by investigator: 
Overall response rate (ORR), Duration of response 
(DOR), Time to response (TTR), Disease control 
rate (DCR), Progression free survival (PFS) 
Randomized part 
Randomized part 
• To assess the anti-tumor activities of capmatinib in 
combination with osimertinib as compared to 
platinum-pemetrexed  
• All calculated by BIRC per RECIST 1.1: Duration of 
response (DOR), Time to response (TTR), Disease 
control rate (DCR) 
• To assess PFS2 (PFS after next line of treatment)  
• PFS2 based on local investigator assessment.  
• To 
characterize 
the 
pharmacokinetics 
of 
capmatinib, osimertinib, and osimertinib's active 
metabolites (AZ5104 and AZ7550) in combination 
setting 
• Plasma PK concentrations 
• To evaluate overall survival (OS) in participants 
treated with capmatinib in combination with 
osimertinib as compared to platinum-pemetrexedv 
based doublet chemotherapy  
• Overall Survival 
• To evaluate the safety profile of capmatinib in 
combination with osimertinib as compared to 
platinum-pemetrexed based doublet chemotherapy 
• Incidence of adverse events and serious adverse 
events, change in vital signs, laboratory results and 
ECG 


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Objective(s) 
Endpoint(s) 
• To assess the effect of capmatinib in combination 
with 
osimertinib as 
compared 
to 
platinum-
pemetrexed on patient-reported disease-related 
symptoms, functioning, and health-related quality of 
life (HRQoL) 
• Change from baseline in European Organization for 
Research and Treatment of Cancer (EORTC) QLQ-
LC13, 
QLQ-C30, 
EuroQoL-5 
Dimension-5 
Level/EQ-5D-5L and NCCN Fact Brain Symptom 
index questionnaires and time to symptom 
deterioration for EORTC QLQ-C30, QLQ-LC13 and 
NCCN FBrSI questionnaires 
• To assess intracranial anti-tumor activity of 
capmatinib in combination with osimertinib as 
compared to platinum-pemetrexed in participants 
with Central Nervous System (CNS) lesions at 
baseline by BIRC 
• Duration of intracranial response (DOIR), time to 
intracranial response (TTIR), intracranial disease 
control rate (IDCR) by BIRC as per RANO-BM 
criteria 
2.1 
Primary estimands 
The estimand is the precise description of the treatment effect and reflects strategies to address 
events occurring during trial conduct which could impact the interpretation of the trial results 
(e.g., premature discontinuation of treatment). 
Part 1 - Run-in part 
Not applicable 


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Part 2 - Randomized part 
The primary estimand for the randomized part is defined as below.  
The primary scientific question of interest is to estimate the treatment effect based on the 
primary endpoint of PFS for the combination of capmatinib and osimertinib compared to 
platinum – pemetrexed based doublet chemotherapy for the target population, prior to receiving 
any post-treatment anti-neoplastic therapies. 
The justification for targeting this treatment effect is that it will enable us to understand the 
treatment effect of capmatinib and osimertinib relative to platinum – pemetrexed based doublet 
chemotherapy in the absence of potentially confounding effect of any post-treatment anti-
neoplastic therapy that is not part of the assigned treatment strategy.  
The primary estimand is characterized by the following attributes: 
1. Population: all randomized patients with locally advanced or metastatic (stage IIIB/IIIC or 
IV) NSCLC with EGFR activating mutation (i.e., L858R and/or ex19del), T790M negative, 
MET amplified who have progressed following 1st/2nd generation EGFR TKIs, osimertinib, 
or other 3rd generation EGFR TKIs used per local standard of care treatment. Further details 
on the population are provided in Section 5. 
2. Treatment: randomized treatment (capmatinib in combination with osimertinib versus 
platinum – pemetrexed based doublet chemotherapy). Further details about the treatment 
are provided in Section 6. 
3. Variable: progression free survival (PFS) defined as the time from the date of randomization 
to the date of the first documented disease progression based on BIRC as per RECIST 1.1 
or date of death due to any cause, whichever occurs first. 
4. Handling of remaining intercurrent events: 
5. Initiation of post-treatment anti- neoplastic therapy before PFS event: PFS events that occur 
after the start of a new post-treatment anti-neoplastic will be censored at the last assessment 
prior to initiation of the new post-treatment anti-neoplastic therapy (hypothetical policy 
strategy) 
6. Discontinuation of study treatment for any reason before PFS event:  
7. PFS will take into account all PFS events irrespective of the study treatment discontinuation 
reasons (treatment policy strategy) 
8. Any Public Health emergency as declared by Local or Regional authorities i.e., pandemic, 
epidemic or natural disaster: PFS will take into account all PFS events irrespective of any 
public health emergency (treatment policy strategy) 
9. Summary measure: hazard ratio (HR) for PFS between the two treatment arms. It will be 
estimated using Cox proportional hazard model stratified by the randomization stratification 
factors. PFS will be tested using the log-rank test stratified by the randomization 
stratification factors. 
Details on how to handle the intercurrent events are provided in Section 12.4.3. 


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2.2 
Secondary estimands 
Part 1- Run-in part  
Not applicable. 
Part 2- Randomized part 
The following two key secondary estimands for efficacy are considered for the randomized part. 
I.The first key secondary estimand is to estimate the treatment effect of the combination of 
capmatinib and osimertinib compared to platinum – pemetrexed based doublet chemotherapy 
based on ORR for the target population regardless of discontinuation of treatments and any 
unforeseen Public Health emergency as declared by Local or Regional authorities i.e., pandemic, 
epidemic or natural disaster, refer to Section 4.6. The estimand is defined by the following 
attributes: 
1) The population is all randomized patients with locally advanced or metastatic (stage IIIB/IIIC 
or IV) NSCLC with EGFR activating mutation (ie., L858R and/or ex19del), T790M negative, 
MET amplified who have progressed following 1st/2nd generation EGFR TKIs, osimertinib, or 
other 3rd generation EGFR TKIs used per local standard of care treatment. 
2) The treatment attribute is randomized treatment (capmatinib in combination with osimertinib 
versus platinum – pemetrexed based doublet chemotherapy).  
3) The variable is best overall response (BOR) defined as the best response recorded from the 
date of randomization until disease progression/recurrence (taking as reference for PD the 
smallest measurements recorded since the treatment started) based on BIRC per RECIST 1.1 
with responses after the use of new anti-cancer therapy considered as non-response. 
4) The summary measure is the difference in ORR (defined as the proportion of participants 
with confirmed best overall response (BOR) of CR or partial response (PR) based on BIRC per 
RECIST 1.1) of the two treatments and its 95% confidence interval from the stratified Miettinen 
and Nurminen’s method (Miettinen and Nurminen 1985) with randomization strata weighting 
by sample size with a single treatment covariate.  
5) The remaining intercurrent events are:  
 Start of new anti-cancer therapy: BOR assessments after the use of new anti-cancer therapy 
will be considered as non-responses and have been accounted for in the variable attribute using 
the composite strategy 
Discontinuation of study treatment for any reason: BOR will take into account all response 
assessments irrespective of the study treatment discontinuation reasons (treatment policy 
strategy) 
Any Public Health emergency as declared by Local or Regional authorities i.e., pandemic, 
epidemic or natural disaster, will be handled by treatment policy strategy. 
II.The second key secondary estimand is to estimate the treatment effect of the combination of 
capmatinib and osimertinib compared to platinum – pemetrexed based doublet chemotherapy 
based on OIRR for the target population with baseline brain metastasis as per RANO-BM 
criteria regardless of discontinuation of treatments and any unforeseen Public Health emergency 


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as declared by Local or Regional authorities i.e., pandemic, epidemic or natural disaster. The 
estimand is defined by the following attributes: 
1) The population is as the subgroup of all randomized participants with locally advanced or 
metastatic (stage IIIB/IIIC or IV) NSCLC with EGFR activating mutation (i.e., L858R and/or 
ex19del), T790M negative, MET amplified who have progressed following1st/2nd generation 
EGFR TKIs, osimertinib or other 3rd generation EGFR TKIs used per local standard of care 
treatment and with baseline brain metastasis as per RANO-BM criteria. 
2) The treatment attribute is randomized treatment (capmatinib in combination with osimertinib 
or platinum – pemetrexed based doublet chemotherapy).  
3) The variable is the best overall intracranial response (BOIR) recorded from the date of 
randomization until disease progression/recurrence (taking as reference for PD the smallest 
measurements recorded since the treatment started) based on BIRC per RANO-BM with 
responses after the use of new anti-cancer therapy considered as non-response.  
4) The summary measure is the difference in OIRR (defined as the proportion of participants 
with confirmed best overall intracranial response (BOIR) of CR or partial response (PR) based 
on BIRC per RANO-BM) of the two treatments and its 95% confidence interval from the 
stratified 
Miettinen 
and 
Nurminen's 
method 
(Miettinen and Nurminen 1985) 
with 
randomization strata weighting by sample size with a single treatment covariate. 
5) The remaining intercurrent events are:  
 Start of new anti-cancer therapy: BOIR assessments after the use of new anti-cancer therapy 
will be considered as non-responses and have been accounted for in the variable attribute using 
the composite strategy 
Discontinuation of study treatment for any reason: BOIR will take into account all response 
assessments irrespective of the study treatment discontinuation reasons (treatment policy) 
Any Public Health emergency as declared by Local or Regional authorities i.e., pandemic, 
epidemic or natural disaster, will be handled by treatment policy strategy. 
3 
Study design 
This is a multicenter, open-label, randomized, controlled, global phase III study that will enroll 
adult participants with locally advanced or metastatic (stage IIIB/IIIC or IV) NSCLC with 
EGFR activating mutation (i.e., L858R and/or ex19del), T790M negative, MET amplified who 
have progressed following 1st/2nd generation EGFR TKIs, osimertinib or other 3rd generation 
EGFR TKI used per local standard of care treatment. Randomization of participants who have 
progressed on prior line with osimertinib will be a minimum of 50% of the planned total number 
of participants while patients who progressed on other 3rd generation EGFR TKI will represent 
a maximum of 10% of the planned total number of participants. The study will consist of an 
initial run-in part to evaluate the safety and tolerability of capmatinib in combination with 
osimertinib and to confirm the recommended dose for the randomized part, and a randomized 
part that will evaluate the efficacy and safety of capmatinib in combination with osimertinib 
compared to platinum (cisplatin or carboplatin) - pemetrexed based doublet chemotherapy as 
second line treatment. 


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The study will enroll approximately 10 to 20 participants in the run-in part and approximately 
225 participants in the randomized part.  
Run-in part: 
Approximately 10 participants will be enrolled and treated with dose level 1 (DL1) of 400 mg 
b.i.d. of capmatinib in combination with 80 mg q.d. of osimertinib, in order to have at least 6 
evaluable participants during the Dose Limiting Toxicity (DLT) period (DLT period defined as 
the first cycle - 1 cycle = 21 days).  
A review meeting to evaluate the safety and tolerability of the DL1 will take place after the 
sixth evaluable participant has been treated for at least 21 days. If DL1 is tolerated, capmatinib 
400 mg b.i.d. in combination with osimertinib 80 mg q.d will be the recommended dose for the 
randomized part. 
If DL1 is not tolerated, a second cohort of approximately 10 participants may be added to have 
at least 6 evaluable patients. This second cohort will be treated at a lower dose level (DL-1) of 
400 mg b.i.d. capmatinib in combination with 40 mg q.d. osimertinib. The same rule utilized 
for the evaluation of DL1 will be utilized to evaluate DL-1. A dose level review team meeting 
will take place after the sixth evaluable participant of that second cohort has been treated for at 
least 21 days. If DL-1 is tolerated, capmatinib 400 mg b.i.d. in combination with osimertinib 40 
mg q.d will be the recommended dose for the randomized part. If DL-1 is not tolerated, the 
randomized part will not open. See also Section 6.5.1. 
Participants participating in the run-in part are not eligible to participate in the randomized part. 


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Figure 3-1 
Part 1: Run-in Part 
 
 
 
 
 
 
 
 
 
Study population/Eligibility 
1.
Adults with Stage IIIB/C or IV NSCLC 
2.
EGFR mutation associated with EGFR TKI sensitivity.  
3.
EGFR T790M negative status for patients who progressed on 1
st or 2
nd generation 
EGFR TKI, or 3
rd generation EGFR TKI other than osimertinib and MET gene 
amplification status.  
4.
Must have progressed one prior line of therapy (either to 1
st/2
nd generation EGFR 
TKIs, osimertinib or other 3
rd generation EGFR TKIs) for advanced/metastatic disease.  
5.
At least one measurable lesion as defined by RECIST v1.1 
Part 1: Run-In, n= ~ 10 pts 
Capmatinib + osimertinib 
Review meeting 
Screening 
End of Treatment  
(Participants in Part 1 are not eligible to participate in part 2) 
Safety follow-up 
Treatment 
Post-treatment FUP 
 
MET amplification status (per local lab) 
Treatment beyond disease progression 
Tumor follow up if End of Treatment is not due to disease progression 


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Randomized Part:  
In the randomized part, approximately 225 participants will be randomized in a 2:1 ratio to 
either capmatinib plus osimertinib (n≈150) or to platinum (cisplatin or carboplatin) - 
pemetrexed based doublet chemotherapy (n≈75). 
Participants will be stratified based on the following factors: 
• Presence of brain metastasis (yes/no) 
• Previous treatment with 3rd generation EGFR TKIs (yes/no) 
Randomization of participants who progressed on prior line with osimertinib will be a 
minimum of 50% of the planned total number of participants while patients who progressed on 
other third generation EGFR TKI will represent a maximum of 10% of the planned total number 
of participants. 
An independent Data Monitoring Committee (DMC) will be monitoring the safety of the 
participants on a regular basis.  
Participants randomized to platinum (cisplatin or carboplatin) - pemetrexed based doublet 
chemotherapy treatment will be allowed to crossover to receive study treatment (capmatinib in 
combination with osimertinib) after blinded independent review committee (BIRC) confirmed, 
RECIST 1.1-defined progressive disease (PD) and after meeting the eligibility criteria outlined 
in Section 6.1.5.2. 
 


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Figure 3-2 
Part 2: Randomized Part 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study population/Eligibility 
• 
Adults with Stage IIIB/C or IV NSCLC 
• 
EGFR mutation associated with EGFR TKI sensitivity.  
• 
EGFR T790M negative status for patients who progressed on 1
st or 2
nd generation 
EGFR TKI, or 3
rd generation EGFR TKI other than osimertinib and MET gene 
amplification status.  
• 
Must have progressed on one prior line of therapy (either to 1
st/2
nd generation 
EGRF TKIs, osimertinib or other 3
rd generation EGFR TKIs) for 
advanced/metastatic disease and must be eligible candidate for platinum-
pemetrexed chemotherapy.  
• 
At least one measurable lesion as defined by RECIST v1.1 
Part II: Randomized (2:1), n= ~ 225 pts  
Stratification: - presence of brain metastasis and previous treatment with 3rd 
generation EGFR TKIs 
Arm 1 ~ 150 pts  
Capmatinib + osimertinib  
End of treatment 
Safety follow up  
Survival follow up  
Arm 2 ~ 75 pts  
Platinum- pemetrexed chemotherapy 
Pre-Screening / Screening 
Treatment 
hh
Post-treatment FUP 
Treatment beyond disease progression 
Tumor and PRO assessments if End of treatment not due to 
disease progression 
ET EOT 
MET amplification status (per central lab)  


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Pre-Screening  
In order to be considered eligible for the study, participants must have written documentation 
of an EGFR activating mutation and, for patients who have progressed on 1st or 2nd generation 
EGFR TKIs, or 3rd generation EGFR TKI other than osimertinib, also EGFR T790M negative 
result by tissue. Participants previously treated with osimertinib are not required to have 
confirmation of EGFR T790M negative tumor status however those with known T790M 
positive tumor status are excluded from the study. 
The results from procedures performed as part of the local standard practices (prior to enrolling 
in the trial) will satisfy the inclusion criteria. Additionally, eligible participants must have MET 
amplification per local results in tissue or blood for the run-in part or as confirmed in tissue by 
a Novartis designated central laboratory for the randomized part. Participants must sign a 
molecular pre-screening Informed Consent Form (ICF) prior to any study specific molecular 
pre-screening evaluations. Refer to Section 8.1 for additional details.  
Screening and Randomization  
Participants must sign the main Informed Consent Form (ICF) prior to any study specific 
screening evaluations. 
For the randomized part only: following completion of all required screening procedures (refer 
to Section 8.1 and Section 8.2) and verifying participant eligibility, the participant will be 
randomized via the Interactive Response Technology (IRT) system. 
Treatment 
Study treatment will begin on Cycle 1 Day 1 with the first administration of study treatment. 
Participants will continue treatment until reasons for discontinuation of study treatment are met 
(Section 9.1.1). 
Participants will be evaluated radiologically at screening/baseline then every 6 weeks for the 
first 18 months after C1D1, then every 12 weeks (+/- 7 days), to assess treatment response until 
PD by RECIST 1.1 (as assessed by the investigator in the run-in part, and as assessed by the 
investigator confirmed by BIRC in the randomization part) 
An end of treatment (EOT) visit will be performed when participants permanently discontinue 
study treatments. 
Participants randomized to the platinum (cisplatin or carboplatin) - pemetrexed based doublet 
chemotherapy arm will be allowed to crossover to receive capmatinib in combination with 
osimertinib therapy after BIRC-confirmed RECIST 1.1-defined PD, and after meeting 
eligibility criteria outlined in Section 6.1.5.2. Such participants must complete the EOT visit 
after permanent discontinuation of platinum (cisplatin or carboplatin) - pemetrexed based 
doublet chemotherapy. The subsequent ET-EOT visit will be performed for participants who 
crossover when they permanently discontinue treatment with capmatinib in combination with 
osimertinib. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e., pandemic, epidemic or natural disaster, that limits or prevents the conduct of 
on-site study visits, special effort should be made for the EOT and ET-EOT visits. If it is not 


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feasible to conduct the EOT and ET-EOT visits on-site, virtual visits or visits to the participant´s 
home should be attempted. 
Follow-Up (Safety, Efficacy and PRO Follow-Up) 
After treatment discontinuation from the capmatinib + osimertinib arm, all participants will be 
followed for safety evaluations as outlined in detail in Section 6.5.5 and Section 9.2 during the 
safety follow-up period. After treatment discontinuation from platinum – pemetrexed 
chemotherapy arm due to PD (confirmed by BIRC), participants are allowed to crossover to 
capmatinib + osimertinib therapy if the criteria in Section 6.1.5.2 are met. In this case, the safety 
follow-up will only occur after discontinuation from ET. 
Participants will be followed for safety up to 30 days after the last dose of study treatment. If a 
new antineoplastic therapy is initiated after study treatment, safety follow-up will focus on 
events suspected to be related to study treatment only. 
In addition to the 30-day safety follow-up, participants who discontinue study treatment without 
prior documented PD, will continue efficacy assessments (Efficacy Follow-up) during the post-
treatment follow-up, irrespective of start of new anti-neoplastic therapy and until documented 
PD by RECIST 1.1 (as assessed by the investigator in the run-in part, and as assessed by the 
investigator confirmed by BIRC in the randomization part), participant withdrawal of consent, 
physician's decision, lost to follow-up, death or if study is terminated by the sponsor as outlined 
in Section 9. For all participants of Part 2 (randomization), patients -reported outcomes will also 
continue to be collected (PRO Follow-up) until documented progression, and at three time 
points following to progression (refer to Section 8.5.1).  
Survival Follow-up (only for randomized part) 
All participants of randomized part will be followed for survival once they discontinue study 
treatment and tumor evaluations. Survival follow-up for participants who crossed over to 
capmatinib + osimertinib therapy will only occur after discontinuation from ET. The 
participant’s survival status will be collected every 12 weeks as part of the survival follow-up 
phase.  
For all participants (either in the run-in or randomized part): 
Participant's respective study treatment (either with capmatinib in combination with osimertinib, 
or with platinum (cisplatin or carboplatin) - pemetrexed based doublet chemotherapy) will be 
continued until participant experiences any of the following: documented disease progression 
by RECIST 1.1 (as assessed by the investigator in the run-in part, and as assessed by the 
investigator confirmed by BIRC in the randomization part), withdrawal of consent, pregnancy, 
lost to follow-up, or death (please refer to Section 9). Study treatment may be continued beyond 
initial disease progression as per RECIST 1.1 (as assessed by the investigator in the run-in part, 
and as assessed by the investigator confirmed by BIRC in the randomization part), if, in the 
judgement of the investigator, there is evidence of clinical benefit, and the participant wishes 
to continue on the study treatment (for additional details please refer to Section 6.1.5.1). 
After treatment discontinuation, all participants will be followed for safety evaluations during 
the safety follow-up period. 


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Participants who discontinued study treatment for reasons other than disease progression, death, 
lost to follow-up, or withdrawal of consent will enter in a post-treatment efficacy follow-up. 
Only in the randomized part, the participant’s survival status will be collected every 12 weeks 
as part of the survival follow-up (for additional details please refer to Section 9).  
For participants who crossed over to capmatinib + osimertinib therapy, safety and survival 
follow-ups will only occur after discontinuation from ET. 
4 
Rationale 
The rationale for investigating the anti-cancer activity of capmatinib in combination with 
osimertinib is due to the unmet medical need and lack of a current targeted approved therapy 
for the MET amplification that is one of the leading mechanisms of resistance to EGFR TKI in 
EGFR mutated NSCLC. Few options to date are available for this population with limited 
benefit, in particular in the EGFR T790M negative setting. 
Proof of concept for capmatinib in combination with EGFR TKIs in MET positive EGFR 
mutated post-EGFR TKI NSCLC setting has been demonstrated with both first-generation 
EGFR TKI (gefitinib) and 3rd generation EGFR TKI (EGF816). 
4.1 
Rationale for study design 
Table 4-1 
Rationale for study design  
Study Design Aspect 
Rationale 
Study population 
The study will enroll adult participants with locally advanced or metastatic 
(stage IIIB/IIIC or IV) NSCLC with EGFR activating mutation (i.e., L858R and/or 
ex19del), T790M negative, MET amplified who have progressed following 
EGFR TKIs either 1st and 2nd generation EGFR TKI, osimertinib or other 3rd 
generation EGFR TKIs used per local standard of care. Randomization 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. 
 Refer to Section 1.1.1. 
Randomization (strata, 
allocation ratio) 
Participants will be randomized with a 2:1 ratio, as the efficacy of standard 
chemotherapy in this setting is currently poor. Therefore, the randomization 2:1 
increases the chances for participants to receive a targeted therapy capmatinib 
in combination with osimertinib, given promising activity observed with the 
combination of capmatinib and other EGFR inhibitors (gefitinib and EGF816) as 
well as other MET inhibitors with osimertinib.Presence of brain metastasis at 
baseline (presence vs absence) and previous treatment with 3rd generation 
EGFR TKIs (yes vs no) were chosen as stratification factors due the expected 
difference in clinical outcome between participants based on this strata. 
Open label 
The trial is open-label for the following reasons: 1) Double blind would require 
i.v. placebo administration in the capmatinib/osimertinib arm, which would pose 
an unnecessary burden for the patient, 2) difference in premedication 
requirements between the two arms, which would pose also an unnecessary 
burden for the participants and 3) varying toxicities between the study 
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Study Design Aspect 
Rationale 
Treatment beyond 
progression 
This is to ensure those participants (in either arm) who have disease 
progression per RECIST 1.1 as determined by investigator (run-in part) and as 
determined by investigator and confirmed by BIRC (randomized part) to 
continue the combination of capmatinib + osimertinib treatment, as long as they 
are clinically stable, tolerate the treatment, and are deriving clinical benefit 
according to investigator judgement. Timely follow-up after the initial PD will 
ensure that participants with confirmed/rapid progression will be discontinued 
and can initiate alternative therapies. 
Crossover 
The possibility to crossover increases the chances for participants treated with 
platinum - pemetrexed based doublet chemotherapy to receive capmatinib in 
combination with osimertinib which has shown preliminary meaningful clinical 
activity in this population of MET amplified NSCLC.  
4.2 
Rationale for dose/regimen and duration of treatment 
Based on the PK and safety data, capmatinib 400 mg b.i.d. in tablet formulation has been 
declared the recommended phase II dose (RP2D) as monotherapy [CINC280X2102]. 
Furthermore, robust efficacy has been demonstrated in both 2nd/3rd line and 1st line MET mutant 
NSCLC patients at this dose level [CINC280A2201]. In addition, sustained target coverage was 
expected at this dose as 96% of patients can maintain capmatinib plasma concentration above 
IC95 for MET inhibition during the dosing interval [Population PK report]. For further details, 
please refer to the latest version of the [capmatinib Investigator’s Brochure]. 
The recommended dose for osimertinib monotherapy is 80 mg once a day until disease 
progression or unacceptable toxicity. Dosing interruption and/or dose reduction may be 
required based on individual safety and tolerability. If dose reduction is necessary, then the dose 
should be reduced to 40 mg taken once daily. For further information on posology and methods 
of administration please refer to the current local prescribing information for osimertinib in this 
disease setting. 
The capmatinib 400 mg b.i.d. and osimertinib 80 mg q.d. were selected as the doses for this 
combination and are justified based on evaluation of potential overlapping toxicities and 
pharmacokinetic drug interactions.  
Regarding drug-drug interaction (DDI) potential, no CYP related DDI is anticipated between 
capmatinib and osimertinib, but transporter related DDI is possible. Capmatinib is a P-gp and 
BCRP inhibitor. Osimertinib and its active metabolites (AZ5104 and AZ7550) are the substrates 
of P-gp and BCRP, therefore, their exposure may be increased when coadministered with 
capmatinib. However, during the dose finding part of the first in Human (FiH) study (AURA 
study, D5160C00001), osimertinib was evaluated with increasing dose levels up to 240 mg (3 
times the recommended dose). The Maximum Tolerated Dose (MTD) was not reached and no 
apparent dose-efficacy relationship was demonstrated over the dose range of 20 mg to 240 mg. 
The exposure of capmatinib is not expected to be affected by osimertinib (Jänne et al 2015).  
In this study, treatment will continue until disease progression or other reasons for drug 
discontinuation. Treatment with capmatinib in combination with osimertinib may be continued 
beyond RECIST 1.1-defined PD (as assessed by the investigator in the run-in part; and as 
assessed by the investigator and confirmed by BIRC for the randomized part) if considered by 
the investigator to be in the best interest of the participant and as long as no new anticancer 
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Treatment beyond progression with capmatinib alone or osimertinib alone is not permitted. 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
There are no current effective recommended targeted therapies for NSCLC patients with 
acquired EGFR-TKI resistance who are T790M negative. Pemetrexed in combination with 
cisplatin is approved worldwide for the treatment of advanced non squamous NSCLC and is 
recognized as a standard of care demonstrating superior OS compared to gemcitabine in 
combination with cisplatin in previously untreated advanced NSCLC patients with non-
squamous histology (adenocarcinoma and large cell carcinoma) in a randomised phase III trial: 
12.6 vs 10.9 and 10.4 vs 6.7 months respectively (Scagliotti et al 2008). Treatment guidelines 
for 2nd line treatment of EGFR mutation-positive, T790M negative NSCLC include using 
platinum based chemotherapy doublet treatment based on the data from the IMPRESS trial 
(Liao et al 2019) (for IMPRESS trial results please refer to Section 1.1). 
Results of the IMpower 150 trial (for the results please refer to Section 1.1), which included 
data on patients with EGFR or ALK genetic alterations who failed prior targeted therapy, could 
support the use of a combination of atezolizumab (anti-PD-L1) and bevacizumab with 
carboplatin and paclitaxel (ABPC) as a therapeutic option in fitting patients with non-squamous 
NSCLC, and a PS of 0–1, in the absence of contraindications to the use of immunotherapy and 
may be an option also in the second-line setting. However, this treatment is not available 
worldwide for the treatment of EGFR mutated NSCLC, particularly in Asian countries where 
most of the participants are expected to be recruited. 
Therefore, pemetrexed in combination with either cisplatin or carboplatin is an appropriate 
control arm treatment in this phase III trial. 
4.4 
Purpose and timing of interim analyses 
To reduce the participant's exposure to potentially non-efficacious treatment, an interim 
analysis (IA) for futility is planned for PFS in this study when approximately 65 events have 
occurred (40% of total PFS events) at approximately 18.5 months from the date of first 
participant randomized in the randomized part of the study. Approximately 130 participants 
(57.8%) are expected to have been enrolled/randomized at the time of interim analysis. 
4.5 
Risks and benefits 
The participants enrolled in this study will have stage IIIB/IIIC or stage IV NSCLC with EGFR 
activating mutation (i.e., L858R and/or ex19del), T790M negative, MET amplified (defined as 
GCN ≥ 5 by central Novartis laboratory) who have progressed following1st/2nd generation 
EGFR TKIs, osimertinib or other 3rd generation EGFR TKIs used per local standard of care 
treatment. Given the clinical and molecular characteristics of MET amplified T790M negative 
NSCLC, participants have few therapeutic options with limited benefit in this study population. 
The safety profile of capmatinib and osimertinib as monotherapy is well characterized (see 
Section 1.1.2 and Section 1.1.3). Although different studies have evaluated capmatinib in 
combination with different EGFR TKI inhibitors (erlotinib, gefitinib, EGF816), experience of 
the combination with osimertinib is limited to patient named program. Therefore, different 


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measures will be taken to reduce the number of participants who could be exposed to unwanted 
toxicity: 
• A safety run-in part in a small cohort of participants is intended to allow an assessment of 
the safety profile of this new combination before enrolling more participants into the 
randomized part. 
• A dose level review team composed of Novartis personnel and the investigators whose sites 
have enrolled participants in the safety run in part, will meet to evaluate potential DLT and 
for the confirmation of the recommended dose for the randomized part. 
• In the randomized part, an independent Data Monitoring Committee (DMC) will be 
monitoring the safety of the participants on a regular basis. Unless otherwise requested by 
the DMC members, the first DMC will convene after the first 10 participants have been 
treated with the combination (capmatinib + osimertinib), as specified in the protocol and 
have completed the first cycle of treatment. The second meeting of the DMC will occur 
approximatly 3 months after the first meeting or when 90 participants are treated, whichever 
occurs first. Further DMC meetings will occur approximately every 6 months. DMC 
members will be consulted to ensure appropriate frequency. 
Moreover, the protocol includes specific eligibility criteria (Section 5), dose-limiting toxicity 
definitions, monitoring visits and assessments, dose modification and stopping rules, and 
recommended guidelines for treatment of expected toxicities, including identification and 
management of study-drug induced adverse events. Recommended guidelines for prophylactic 
or supportive treatment of expected toxicities, including the management of study-drug induced 
adverse events, (e.g., infusion reaction, pneumonitis) are provided in Section 6.5. 
The central MET amplification test used for enrollment is investigational and is being clinically 
validated for selecting participants most likely to benefit from capmatinib as a part of this study. 
Therefore, how well the test performs to identify participants who are most likely to benefit 
from capmatinib or to determine whether the benefits of capmatinib treatment will outweigh 
any potential serious side effects or risks has not been fully established. However, the test is 
sufficiently validated for the purposes of selecting participants with MET amplification in their 
NSCLC tumor sample for enrollment to this study. 
The risk to participants in this trial will be minimized by compliance with the eligibility criteria 
and study procedures, as well as by close clinical monitoring and oversight and MET 
amplification assay monitoring. As with any clinical study, there may be unforeseen risks with 
the study treatment, which could be serious. The specific risks for each compound are discussed 
in Section 4.5.1 and Section 4.5.2. For further details, refer to the toxicity data provided in the 
[capmatinib Investigator’s Brochure] and in the osimertinib local prescribing information. 
Women of child-bearing potential and sexually active males must be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 
study and must agree that in order to participate in the study they must adhere to the 
contraception requirements outlined in the exclusion criteria. If there is any question that the 
participant will not reliably comply, they should not be entered or continue in the study. 
Therefore, the overall safety risk to participants enrolled in the study [CINC280L12301] is 
considered manageable, based on the available clinical safety data for both capmatinib and 


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osimertinib, along with the eligibility criteria and monitoring measures implemented in this 
study. 
Given the unmet medical need in the intended patient population, the lack of well-proven 
treatment options, the preliminary evidence of efficacy with capmatinib in combination with 
EGFR TKI inhibitors in NSCLC EGFRm patient progressing on EGFR TKI (>40% ORR in 
MET+ population) and the well tolerated profile reported in ongoing studies [INC280X2105c] 
and [INC280X2202], it is considered appropriate to assess efficacy and safety of capmatinib in 
combination with osimertinib in a randomised open-label phase III study in 2nd line NSCLC 
versus pemetrexed in combination with cisplatin or carboplatin. 
4.5.1 
Capmatinib 
Based upon the clinical experience with capmatinib to date, the overall risk-benefit assessment 
of capmatinib is considered favorable (see Section 1.2). The data from study 
[CINC280A2201] show that capmatinib is generally well tolerated and has a manageable safety 
profile. The safety profile in the METΔex14 mutated or MET amplified NSCLC population is 
consistent with the safety profile of capmatinib across multiple clinical studies.  
The most frequent safety findings on treatment with capmatinib monotherapy include peripheral 
edema, nausea, increased blood creatinine, vomiting, fatigue, decreased appetite, and diarrhea. 
In addition, pancreatic related events (e.g., amylase and lipase increase), and changes in liver 
blood parameters (Alanine Aminotransferase (ALT) and/or Aspartate Aminotransferase (AST) 
and/or bilirubin increase) have been observed in participants treated with capmatinib. To date, 
a direct toxic effect of capmatinib on pancreas could not be identified. Caution is recommended 
when capmatinib is administered in combination with other drugs with a known risk of 
hepatotoxicity. 
Pneumonitis and Interstitial Lung Disease (ILD) have been reported from both capmatinib 
single agent and combination studies with EGFR TKIs, including events with fatal outcomes. 
Investigators are advised to carefully monitor participants for signs and symptoms of 
pneumonitis/ILD and implement dose modification and follow-up evaluations described in the 
protocol in all capmatinib studies, both single agent and in combination studies. If 
ILD/pneumonitis is diagnosed, capmatinib should be permanently discontinued and appropriate 
treatment initiated as necessary. Reintroduction of capmatinib should be considered only in the 
absence of a diagnosis of ILD/pneumonitis and after careful consideration of the individual 
participant’s benefits and risks. 
Finally, capmatinib has shown photosensitization potential in in vitro and in vivo assays. 
Investigators should recommend the use of precautionary measures against ultraviolet exposure 
to the participants during treatment with capmatinib (e.g., use of sunscreen, protective clothing 
and avoid sunbathing or using a solarium intensively). 
For further information on potential toxicities and Drug-Drug Interaction (DDI), please refer to 
the current [capmatinib Investigator’s Brochure]. 
Assessment of the Benefit/Risk did not reveal any additional risks related to COVID-19 in 
participants treated with capmatinib. Based on the available data, no additional risk has been 
observed in participants who were administered COVID-19 vaccines while on capmatinib. 


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4.5.2 
Osimertinib 
The safety profile of osimertinib is characterized by the majority of adverse events being non-
clinically significant, i.e., diarrhoea and skin rash. Below safety profile is pertaining the data 
from the 1142 patient recruited in FLAURA and AURA trials (Scott 2018). 
 
 
 
 
 
Cardiomyopathy occurred in 2.6% of osimertinib treated patients, 0.1% of cardiomiopathy were 
fatal. Changes in cardiac contractility were reported across clinical trials, Left Ventricular 
Ejection Fraction (LVEF) decreases greater than or equal to 10% and a drop to less than 50% 
occurred in 3.9% of patients treated with osimertinib who had baseline and at least one follow-
up LVEF assessment. 
Severe, life-threatening or fatal Interstitial Lung Disease (ILD) or ILD-like adverse reactions 
(i.e., pneumonitis) have been observed in patients treated with osimertinib in clinical studies. 
Most cases improved or resolved with interruption of treatment. Interstitial Lung Disease (ILD) 
or ILD-like adverse reactions (i.e., pneumonitis) were reported in 3.9% and were fatal in 0.4% 
of the patients who received osimertinib. The incidence of ILD was 10.4% in patients of 
Japanese ethnicity, 1.8% in patients of Asian ethnicity and 2.8% in non-Asian patients. Case 
reports of Stevens-Johnson syndrome (SJS) have been rarely observed in association with 
osimertinib treatment. 
Careful assessment of all participants with an acute onset and/or unexplained worsening of 
pulmonary symptoms (dyspnoea, cough, fever) should be performed to exclude 
ILD/pneumonitis. Treatment with this medicinal product should be interrupted pending 
investigation of these symptoms. If ILD/pneumonitis is diagnosed, osimertinib should be 
permanently discontinued and appropriate treatment initiated as necessary. Reintroduction of 
osimertinib should be considered only in the absee of diagnosis of ILD/pneumonitis and after 
careful consideration of the individual participant’s benefits and risks. 
For further information relating the safety and tolerability of osimertinib, please refer to local 
approved label. 
4.5.3 
Cisplatin, carboplatin and pemetrexed 
Pemetrexed can cause severe myelosuppression resulting in a requirement for transfusions and 
which may lead to neutropenic infection. The risk of myelosuppression is increased in patients 
who do not receive vitamin supplementation. Complete blood count be periodically monitored 
during treatment as required by local standard of practice. The incidence of Grade 3-4 
neutropenia was 15% and 23%, the incidence of Grade 3-4 anemia was 6% and 4%, and 
incidence of Grade 3-4 thrombocytopenia was 4% and 5%, respectively. Pemetrexed can cause 
severe, and sometimes fatal, renal toxicity. The incidences of renal failure in clinical studies in 
which patients received pemetrexed with cisplatin were: 2.1% in renal function should be 
periodically monitored during treatment as required by local standard of practice.  


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Serious and sometimes fatal, bullous, blistering and exfoliative skin toxicity, including cases 
suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis can occur with pemetrexed. 
Serious interstitial pneumonitis, including fatal cases, can occur with pemetrexed. 
Carboplatin/Cisplatin produces severe cumulative nephrotoxicity.  
Appropriate hydration will tend to minimize carboplatin/cisplatin nephrotoxicity, renal function 
should be periodically monitored during treatment as required by local prescribing information. 
Severe cases of neuropathies have been reported. These neuropathies may be irreversible and 
may manifest by paresthesia, areflexia and a proprioceptive loss and a loss of vibration 
perception. A loss of motor function has also been reported.  
Appropriate neurological examination should be carried out at regular intervals as required by 
local prescribing information. Ototoxicity has been observed and is manifested by tinnitus 
and/or hearing loss in the high frequency range (2000 to 8000 Hz). Decreased ability to hear 
conversational tones may occur occasionally. Hearing loss can be unilateral or bilateral and 
tends to become more frequent and severe with repeated doses; however, deafness after initial 
dose of cisplatin has been reported rarely. Careful monitoring by audiometry should be 
performed as required by l local prescribing information. Anaphylactic-like reactions to 
cisplatin have been reported. These reactions have occurred within minutes of administration 
to patients with prior exposure to carboplatin/cisplatin and have been alleviated by 
administration of adrenaline, steroids and antihistamines. Nausea and vomiting may be intense 
and require adequate antiemetic treatment. 
Close supervision must be carried out with regard to ototoxicity, myelosuppression and 
anaphylactic reactions. For further information please refer to the local prescribing information. 
4.6 
Rationale for Public Health Emergency mitigation procedures 
During a Public Health emergency as declared by Local or Regional authorities i.e., pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
are listed in relevant sections. Notification of Public Health emergency should be discussed 
with Novartis prior to implementation of mitigation procedures, and permitted/approved by 
Local or Regional Health Authorities and Ethics Committees as appropriate.  
5 
Study Population 
This study will enroll adult male and female participants with EGFR activating mutation (i.e., 
L858R and/or ex19del), T790M negative, advanced (stage IIIB, IIIC or IV) NSCLC harboring 
MET amplification as determined by a Novartis central molecular laboratory and who have 
progressed following 1st/2nd generation EGFR TKIs, osimertinib or other third generation 
EGFR TKIs used per local standard of care’ for consistency with protocol summary. 
The study will enroll approximately 10 to 20 participants in the run-in part and will enroll 
approximately 225 participants in the randomized part globally. 
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. 


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5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study 
2. Adult ≥ 18 years old at the time of informed consent (≥20 years of age in Japan) 
3. Stage IIIB/IIIC (not amenable to curative surgery, chemoradiation or radiation) or stage IV 
NSCLC at the time of study entry (according to Version 8 of the American Joint Committee 
on Cancer (Chun et al 2018) 
4. Participants must have a life expectancy of at least 3 months 
5. Histologically or cytologically confirmed diagnosis of NSCLC (excluding squamous cell 
carcinoma and histological transformation from NSCLC into small cell lung cancer (SCLC) 
following previous EGFR TKI treatment) with all the following: 
• EGFR mutations known to be associated with EGFR TKI sensitivity. This must be 
assessed as part of the patient standard of care by a validated test for EGFR mutations, 
as per local regulations. Exon19del, 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 of the USA must be documented in the patient source documents before the 
patient can be consented for pre-screening for MET amplification status. 
• EGFR T790M negative status for participants who have progressed on 1st or 2nd 
generation EGFR TKI, or 3rd 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 patient source documents before the patient can be 
randomized. If a local T790M result is not available, T790M status in tissue per central 
Novartis-designated laboratory result is required (only applicable for participants 
joining randomized part).  
• MET gene amplification status, after radiological progression on prior EGFR TKI, 
defined as:  
• Run-in part: IHC 3+ (defined as ≥ 50% of cells staining with high intensity) and/or 
MET Gene Copy Number (GCN) ≥ 5 will be utilized as study entry parameters by 
local test in tissue or blood. 
• Randomized part: GCN≥ 5 per central Novartis-designated laboratory result from 
tissue sample test. 
6. Mandatory provision of a formalin-fixed, paraffin embedded tumor tissue sample (a newly 
obtained tumor sample, or archival tumor block/slides taken after progression on prior line 
of EGFR TKI) in a quantity sufficient to allow the confirmation of MET amplification (and 
EGFR T790M if applicable) status for all participants and potential companion diagnostics 
development. Tumor samples must contain at least 10% tumor content. 
7. Participants must have progressed on one prior line of therapy including either to 1st/2nd 
generation EGFR TKIs, osimertinib or other 3rd generation EGFR TKIs used per local 
standard of care for advanced/metastatic disease (stage IIIB/IIIC [not amenable for curative 
surgery, chemoradiation or radiation or stage IV NSCLC) and must be eligible candidates 
for platinum (cisplatin or carboplatin) - pemetrexed based doublet chemotherapy. Acquired 


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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 1st/ 2nd EGFR TKIs (e.g., 
erlotinib, gefitinib, afatinib, dacomitinib), osimertinib or other 3rd 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. 
8. Participants must have recovered from all toxicities related to prior systemic therapy to 
grade ≤ 1 (CTCAE v 5.0). Exception to this criterion: participants with any grade of alopecia 
and vitiligo are allowed to enter the study. 
9. At least one measurable lesion as defined by RECIST 1.1. A previously irradiated site lesion 
may only be counted as a target lesion if there is clear sign of progression since the 
irradiation. 
10. Participants must have adequate organ function including the following laboratory values 
at the screening visit (as assessed by local laboratory for eligibility of the run-in part 
eligibility, and by central laboratory for eligibility of the randomized part; except for China, 
where local laboratory results can be used for eligibility): 
• Absolute neutrophil count (ANC) ˃ 1.5 x 109/L without growth factor support 
• Platelets ˃ 100 x 109/L 
• Hemoglobin (Hgb) > 9 g/dL 
• Calculated creatinine clearance (using Cockcroft-Gault formula) ˃ 50 mL/min 
• Total bilirubin ≤ 1.5 upper limit of normal (ULN)  
• Aspartate transaminase (AST) ≤ 2.5 x ULN except for participants with liver metastasis, 
who may only be included if AST ≤ 5 x ULN 
• Alanine transaminase (ALT) ≤ 2.5 x ULN except for participants with liver metastasis, 
who may only be included if AST ≤ 5 x ULN 
• Asymptomatic serum amylase ≤ grade 2. 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 
11. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. 
12. Willing and able to comply with scheduled visits, treatment plan and laboratory tests. 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Prior treatment with any MET inhibitor or HGF-targeting therapy. 
2. Participants with symptomatic central nervous system (CNS) metastases who are 
neurologically unstable or have required increasing doses of steroids within the 2 weeks 


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prior to study entry to manage CNS symptoms. If participants are on corticosteroids for 
endocrine deficiencies or tumor-associated symptoms other than CNS related, dose must 
have been stabilized (or decreasing) for at least 5 days before Cycle 1 Day 1. 
3. Carcinomatous meningitis. 
4. Presence or history of a malignant disease other than NSCLC that has been diagnosed and/or 
required therapy within the past 3 years. Exceptions to this exclusion include: completely 
resected basal cell and squamous cell skin cancers, and completely resected carcinoma in 
situ of any type. Participants with histological transformation from NSCLC into small cell 
lung cancer (SCLC) following previous EGFR TKI treatment are also excluded.  
5. 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). 
6. Long QT syndrome, family history of idiopathic sudden death or congenital long QT 
syndrome. 
7. Clinically significant, uncontrolled heart diseases such as: 
• Unstable angina within 6 months prior to screening 
• Myocardial infarction within 6 months prior to screening 
• History of documented congestive heart failure (New York Heart Association 
functional classification III-IV) 
• Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ˃ 160 mm Hg 
and/or Diastolic Blood Pressure (DBP) ˃ 100 mm Hg, with or without antihypertensive 
medication. Initiation or adjustment of antihypertensive medication(s) is allowed prior 
to screening. If white coat syndrome (WHS) is suspected, blood pressure measurements 
may be repeated. 
• Ventricular arrhythmias 
• Supraventricular and nodal arrhythmias not controlled with medication 
• Other cardiac arrhythmia not controlled with medication 
• Fridericia QT correction formula (QTcF) ˃ 470 ms on the screening Electrocardiogram 
(ECG) (as mean of triplicate ECG, and assessed by central ECG) 
8. Thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting Cycle 1 Day 1 or participants 
who have not recovered from radiotherapy-related toxicities. For all other anatomic sites 
(including radiotherapy to thoracic vertebrae and ribs), radiotherapy ≤ 2 weeks prior to 
Cycle 1 Day 1, or participants who have not recovered from radiotherapy-related toxicities. 
Palliative radiotherapy for bone lesions or radio-surgery for isolated brain lesions ≤ 2 weeks 
prior to Cycle 1 Day 1 is allowed. 
9. Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior to 
starting study treatment (2 weeks for resection of brain metastases), or participants who 
have not recovered from the side effects of such procedure. Video-assisted thoracic surgery 
(VATS) and mediastinoscopy for biopsy purpose only will not be counted as major surgery 
and participants can be enrolled in the study ≥1 week after the procedure. 
10. Participants receiving treatment with strong inducers of CYP3A and could not be 
discontinued ˃ 1 week prior to the start of treatment. 


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11. Treatment with a prior 1st or 2nd generation EGFR TKIs (e.g., erlotinib, gefitinib, afatinib, 
dacomitinib) osimertinib or another 3rd generation EGFR TKIs such as almonertinib and 
furmonertinib 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). 
12. 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. 
13. Impairment of Gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of capmatinib or osimertinib (e.g., ulcerative diseases, uncontrolled nausea, 
vomiting, diarrhea, or malabsorption syndrome). 
14. Unable or unwilling to swallow tablets as per dosing schedule. 
15. Substance abuse, active infection or other severe, acute, or chronic medical or psychotic 
conditions or laboratory abnormalities that in the opinion of the investigator may increase 
the risk associated with study participation, or that may interfere with the interpretation of 
study results. 
Active infection is including but not limited to Hepatitis B Virus (HBV), Hepatitis C Virus 
(HCV) and human immunodeficiency virus (HIV). Screening for known chronic conditions 
is not required. 
Participants with known serologic evidence of chronic HBV or HCV infection whose 
disease is controlled under antiviral therapy, according to local regulation are eligible. 
Participants with known history of testing positive for human immunodeficiency virus 
(HIV) infection, and with a history of acquired immunoeficiency 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. 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 
treatment, they should have the disease under control and suppressed viral loads defined as 
per local guideline. HIV participants coinfected with hepatitis virus must also be excluded. 
16. Participants with known hypersensitivity or contraindications to capmatinib or osimertinib 
or carboplatin or pemetrexed or cisplatin, or any excipient of these agents. 
17. Pregnant or nursing (lactating) women. 
18. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception as 
precautions. Those precautions must be used during treatment with capmatinib and 
osimertinib and for at least 6 weeks or following osimertinib local label prescription 
(whichever is longer) after stopping study treatment. In case capmatinib is utilized as single 
agent those precaution should be followed for at least 7 days. 


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For platinum (cisplatin or carboplatin) – pemetrexed based doublet chemotherapy, local 
prescribing information relating the time limits for such precautions and any additional 
restrictions will be followed. 
Highly effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant. Periodic abstinence (i.e., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
• Female bilateral tubal ligation, female sterilization (have had surgical bilateral 
oophorectomy with or without hysterectomy), or total hysterectomy at least six weeks 
before taking study treatment. In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow-up hormone level 
assessment. 
• Male sterilization (at least 6 months prior to screening). For female participants on the 
study, the vasectomized male partner should be the sole partner for that participant. 
• Use of hormonal contraceptives that are not prone to drug-drug interaction 
(levonorgestrel intra-uterine system [IUS; Mirena], medroxyprogesterone injection 
[Depo-Provera] and copper-banded intra-uterine devices. All hormonal methods of 
contraception must be used in combination with the use of condom by the male sexual 
partner for intercourse. Women are considered post-menopausal if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., 
age appropriate history of vasomotor symptoms). Women are considered not of child-
bearing potential if they are post-menopausal or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal 
ligation at least six weeks prior to screening. In the case of oophorectomy alone, only 
when confirmed by follow-up hormone level assessment is considered not of child-
bearing potential. 
19. Sexually active males unless they use a condom during intercourse while taking capmatinib 
and osimertinib for at least 4 months or following osimertinib local label prescription 
(whichever is longer) after stopping study treatment and should not father a child in this 
period. In case capmatinib is utilized as single agent those precaution should be followed 
for at least 7 days after stopping study treatment and should not father a child in this period. 
For male participants treated with platinum (cisplatin or carboplatin) - pemetrexed, they 
should not father a child after the last dose of treatment for a period defined as per the local 
prescribing information. A condom is required for all sexually active male participants to 
prevent them from fathering a child AND to prevent delivery of study treatment via seminal 
fluid to their partner. In addition, male participants must not donate sperm for the time 
period specified above. 
If local regulations are more stringent than the contraception methods listed above to 
prevent pregnancy, local regulations apply and will be described in the ICF. 
20. Participants with known druggable molecular alterations (such as ROS1 translocation or 
BRAF mutation, KRAS mutation etc.) who might be candidates for alternative targeted 
therapies as applicable per local regulations and treatment guidelines. 
21. Participants with a known documented EGFR genetic aberration (e.g., C797S) mediating 
resistance to previous treatment with a 3rd generation EGFR TKI (e.g., osimertinib) or any 


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other known genetic aberration concomitant to MET amplification that could negatively 
impact the treatment outcome of capmatininb in combination with osimertinib. 
22. Participant with known EGFR T790M positive status by either tissue or blood after 
progression on 1st, 2nd or 3rd generation EGFR TKIs including osimertinib. 
23. Participants who received live vaccines (e.g., intranasal influenza, measles, mumps, rubella, 
oral polio, BCG, yellow fever, varicella, TY21a typhoid vaccines and COVID 19 vaccines) 
within 30 days prior to the first dose of study treatment. 
6 
Treatment 
6.1 
Study treatment 
For this study, the investigational drugs are capmatinib and osimertinib. The study treatment 
refers to the combination of capmatinib and osimertinib, or to platinum (cisplatin or carboplatin) 
pemetrexed based doublet chemotherapy. 
Capmatinib will be labeled and provided to sites by Novartis in compliance with legal 
requirements for each country. 
Osimertinib and platinum (cisplatin or carboplatin) - pemetrexed based doublet 
chemotherapy will be procured locally according to local practice and regulation. 
The study treatment begins on Cycle 1 Day 1 with the first administration of either capmatinib 
in combination with osimertinib or platinum (cisplatin or carboplatin) - pemetrexed based 
doublet chemotherapy. For the randomized part (including ET), Cycle 1 Day 1 should occur on 
the day of the randomization or no later than 3 days after randomization. 
All doses prescribed, dispensed to the participant and all dose changes during the study, 
including the reason, must be recorded on the appropriate electronic case report form (eCRF) 
page. 
6.1.1 
Investigational and control drugs 
Table 6-1 
Investigational and control drug 
Investigational/ 
Control Drug  
(Name and 
Strength) 
Treatment Form 
or Pharmaceutical 
Dosage Form 
Route of 
Administration 
Presentation 
Supply (global or 
local) 
Capmatinib 
150 mg or 200 mg 
Film-coated tablet  
Oral use 
Open-label 
participant specific; 
bottles 
Global 
Osimertinib£ 
80 mg or 40 mg 
Tablet 
Oral use 
Open-label 
participant specific; 
bottles or blister 
packs 
Local 
Platinum (cisplatin 
or carboplatin) - 
pemetrexed based 
doublet 
chemotherapy£  
Concentrate 
for solution for 
infusion 
Intravenous use 
Open-label; vials 
Local 


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Investigational/ 
Control Drug  
(Name and 
Strength) 
Treatment Form 
or Pharmaceutical 
Dosage Form 
Route of 
Administration 
Presentation 
Supply (global or 
local) 
£ provided locally by the study site, subsidiary or designee as commercially available, according to local clinical 
practices and local regulations. 
Administration (including related pre-medication schemes for chemotherapy) should follow local prescribing 
information. 
6.1.2 
Additional study treatments 
No other treatment beyond investigational drugs (capmatinib and osimertinib) and control drug 
(platinum -cisplatin or carboplatin- pemetrexed based doublet chemotherapy) are included in 
this trial. 
Platinum (cisplatin or carboplatin) - pemetrexed based doublet chemotherapy (including related 
pre-medication schemes) should follow local prescribing information. 
6.1.3 
Treatment arms/group 
Run-in part 
Up to 2 dose levels of capmatinib in combination with osimertinib may be investigated. The 
starting dose of combination is capmatinib 400 mg orally twice daily (b.i.d) and osimertinib 80 
mg orally once per day (q.d). 
If a dose de-escalation is required following DLTs, a lower dose level is defined as capmatinib 
400 mg orally twice a day (b.i.d) and osimertinib 40 mg orally once per day (q.d.) (see also 
Section 6.5). 
Capmatinib in combination with osimertinib can be taken with or without food. 
A complete cycle of treatment is defined as 21 days of continuous treatment of capmatinib in 
combination with osimertinib. 
Randomized part 
Participants will be randomized to one of the following two treatment arms/groups in a ratio of 
2:1 according to the stratification factors. 
• Arm 1: capmatinib in combination with osimertinib  
• continuous, oral, daily dosing, with or without food.  
• the starting doses will be the recommended doses for the randomized part (including 
ET) confirmed during the run-in part. 
• Arm 2: platinum (cisplatin or carboplatin) - pemetrexed based doublet chemotherapy, 
intravenously (i.v.), following local guidelines as per standard of care and products labels 
(including premedications such as antiemetics, steroids and vitamins)  
• cisplatin 75 mg/m2 - pemetrexed 500 mg/m2, or 
• carboplatin AUC5 -AUC 6 - pemetrexed 500 mg/m2. 
Each treatment cycle is 21 days for both arms. First infusion day defines Cycle 1 Day 1. 
Participants can receive up to 6 cycles of pemetrexed + carboplatin/cisplatin as initial treatment. 
Participants whose disease has not progressed after four cycles of platinum/pemetrexed based 


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doublet chemotherapy initial treatment may receive pemetrexed monotherapy maintenance 
therapy (pemetrexed 500 mg/m2 on Day 1 of every 21 days cycle) i.v. infusion per product label 
and local guidelines (as per standard of care). 
In Arm 2, participants will be allowed to crossover to receive capmatinib in combination with 
osimertinib therapy after BIRC-confirmed RECIST 1.1-defined PD, and after meeting the 
eligibility criteria (see Section 6.1.5.2).  
6.1.4 
Guidelines for continuation of treatment 
Participant should continue to receive the study treatment until one or more criteria for treatment 
discontinuation described in Section 6.5 and Section 9.1 are met. Guidelines on the 
management of common capmatinib-osimertinib and platinum pemetrexed based 
chemotherapy-associated toxicities and dose modification instructions are provided in 
Section 6.5. 
6.1.5 
Treatment duration 
Participants will be treated until they experience any of the following: unacceptable toxicity, 
disease progression per RECIST 1.1 (as assessed by the investigator in the run-in part, and as 
assessed by the investigator confirmed by BIRC in the randomization part), and/or treatment is 
discontinued at the discretion of the investigator or the participant. A complete list of the 
circumstances requiring study treatment discontinuation is provided in Section 9.1.1. 
Participants who do not tolerate the combination treatment because of unaceptable toxicity that 
preclude further treatment and are judged by the investigator still to benefit from the treatment 
could continue to receive either capmatinib or osimertinib as single agent. In such circumstances, 
participants who permanently discontinued one of the two investigational drugs should still 
follow the protocol efficacy and safety assessment as scheduled. After discontinuing the two 
investigational drugs, further treatment is left to the physician’s discretion. 
Participants may continue the combination treatment of capmatinib + osimertinib beyond 
locally confirmed disease progression (run-in part) or BIRC-confirmed disease progression 
(randomized part) if, in the judgment of the investigator, there is evidence of clinical benefit 
and the participant wishes to continue on the study treatment. Criteria for treatment beyond 
progression are described in Section 6.1.5.1. 
In randomized part, participants in the chemotherapy arm will be allowed to crossover to receive 
capmatinib in combination to osimertinib therapy after BIRC-confirmed, RECIST 1.1-defined 
PD. Criteria for crossover to capmatinib in combination to osimertinib therapy are described in 
Section 6.1.5.2.  
At the end of the study, every effort will be made to continue provision of study treatment 
outside this study through an alternative setting to participants who in the opinion of the 
investigator are still deriving clinical benefit, where permitted by and in accordance with local 
laws and regulations. 
6.1.5.1 
Treatment beyond disease progression 
Participants will be permitted to continue the combination treatment of capmatinib + 
osimertinib beyond disease progression per RECIST 1.1 (as assessed by the investigator in the 


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run-in part, and as assessed by the investigator confirmed by BIRC in the randomized part), 
provided they meet all the following criteria: 
• Evidence of clinical benefit assessed by investigator 
• No rapid radiological or clinical progression 
• Tolerance to study treatment 
• Should not jeopardize critical interventions to treat/prevent severe complications, or prevent 
participants from receiving adequate care 
• Participant performance status is stable 
• Participant written consent to continue on the study treatment 
• No new antineoplastic therapy has been initiated 
Treatment beyond progression with capmatinib alone or osimertinib alone is not permitted. 
The treatment beyond disease progression is only allowed for participants previously treated 
with the combination of capmatinib + osimertinib.  
The reasons for the participant continuing treatment beyond progression will be documented in 
the eCRF. 
Participants who meet the above criteria and continue the combination of capmatinib + 
osimertinib treatment beyond initial disease progression per RECIST 1.1 will continue all study 
procedures as outlined in Section 8. Clinical deterioration or suspicion of further disease 
progression will require a follow-up imaging assessment to be performed promptly rather than 
waiting for the next scheduled assessment. Participants who are no longer deriving clinical 
benefit, or who meet other protocol discontinuation criteria must be discontinued. 
Participants who crossed over to capmatinib + osimertinib therapy will also be permitted to 
continue treatment beyond initial disease progression (radiological progression assessed by the 
investigator). 
6.1.5.2 
Crossover to capmatinib in combination with osimertinib therapy 
In the randomized part, participants randomized to the platinum-pemetrexed based doublet 
chemotherapy arm will be allowed to crossover to receive capmatinib in combination with 
osimertinib therapy after BIRC-confirmed RECIST 1.1-defined PD. 
Participants in the platinum-pemetrexed based doublet chemotherapy arm who elect to 
crossover to capmatinib in combination with osimertinib therapy must follow the study 
assessments as per visit schedule in Table 8-3 in the ET part. 
The following eligibility criteria must be confirmed prior to crossing over to capmatinib in 
combinatin with osimertinib arm: 
• Participants must have recovered from all toxicities related to platinum-pemetrexed based 
double chemotherapy to grade ≤ 1 (CTCAE version 5.0). Exception to this criterion: 
participants with any grade of alopecia and vitiligo 
• Participants must not have a history or active medical condition of interstitial lung disease or 
interstitial 
pneumonitis, 
including 
clinically 
significant 
radiation 
pneumonitis 
(i.e., affecting activities of daily living or requiring therapeutic intervention) 


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• Crossover must be performed no later than 84 days of BIRC-confirmed PD. This window 
is intended to allow the resolution to ≤ CTCAE grade 1 of the toxicity related to the prior 
chemotherapy with platinum-pemetrexed based doublet chemotherapy 
• Participants with CNS metastases must be neurologically stable as specified in exclusion 
criterion #2 of Section 5.2 
• Participants must have an ECOG PS of 0-1 
• Participants must not be pregnant 
• Participants must be compliant with the contraception guidelines outlined in Section 5.2 
• Participants must have adequate organ function including laboratory values (per local 
laboratory assessment) within 7 days prior to commencing treatment of capmatinib in 
combination with osimertinib in the ET phase as specified in inclusion criterion #10 of 
Section 5.1  
• Participant must not have clinically significant, uncontrolled heart diseases as specified in 
exclusion criterion #7 of Section 5.2  
• If the participant has not undergone below specified assessment 7 days prior to commencing 
treatment of capmatinib in combination with osimertinib in the ET phase, they must 
complete via an unscheduled visit these following assessments in order to ensure the 
initiation of capmatinib in combination with osimertinib treatment: 
• Vital signs 
• Hematology labs 
• Chemistry labs 
• ECG 
• Cardiac Imaging 
• Adverse events 
• Concomitant medications 
Participants must not have started another systemic anti-cancer therapy at the end of the 
treatment phase. Participants must complete the EOT visit after permanent discontinuation of 
platinum-pemetrexed based doublet chemotherapy. The ET-EOT visit will be performed for 
participants 
who 
crossover 
when 
they 
permanently 
discontinue 
treatment 
with 
capmatinib + osimertinib. Participants in ET will be treated until they experience any of the 
following: unacceptable toxicity, disease progression determined on investigator assessment 
only, and/or treatment is discontinued at the discretion of the investigator or the participant.  
Participants who do not tolerate the combination treatment because of unacceptable toxicity 
that preclude further treatment and are judged by the investigator still to benefit from the 
treatment could continue to receive either capmatinib or osimertinib as single agent. In such 
circumstances, participants who permanently discontinued one of the two investigational drugs 
should still follow the protocol efficacy and safety assessment as scheduled. After discontinuing 
the two investigational drugs, further treatment is left to the physician’s discretion. 
6.2 
Other treatment(s) 
No additional treatment beyond investigational drug is provided in this trial.  


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6.2.1 
Concomitant therapy 
In general, the use of any concomitant medication/therapy deemed necessary for the care of the 
participant (i.e., such as anti-emetics, anti-diarrhea) is permitted, except when specifically 
prohibited (see Section 6.2.2). 
The participant must be told to notify the investigational site about any new medications he/she 
takes after the start of the study treatment. All medications (excluding study treatment and prior 
antineoplastic treatments), blood transfusions, surgeries and procedures (including physical 
therapy) administered within 28 days prior to the first dose administration of study treatment 
through 30 days after the last dose of study treatment will be recorded in the Concomitant 
Medications or Surgical and Medical Procedures eCRF, respectively. Medications include not 
only physician prescribed medications, but also all over-the counter medications, herbal 
medications, food supplements and vitamins. In addition, for participants with CNS lesion who 
will be evaluated by RANO-BM, corticosteroid use will be documented on the appropriate 
eCRF (electronic Case Report Form) until disease progression (as determined by investigator 
and confirmed by BIRC). 
The following restrictions apply during the entire duration of the study: 
• No other investigational therapy should be given to participants 
• No anticancer agents other than the study medication should be given to participants 
Participants are permitted to use the following medications while taking study treatment: 
• Antibiotics 
• Medications to prevent or treat nausea, vomiting or diarrhea 
• Growth factors (e.g., Granulocyte Colony-Stimulating Factor (G-CSF), Granulocyte-
Macrophage Colony-Stimulating Factor (GM-CSF), erythropoietin, platelets growth factors, 
etc.) are allowed per the investigator’s judgement and per local guidelines. 
• Oxygen therapy and blood products or transfusions  
• Nutritional support or appetite stimulant 
• Pain medication 
Each concomitant drug must be individually assessed against all exclusion criteria and 
prohibited medication. If in doubt, the investigator should contact the Novartis medical monitor 
before 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. 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
The following medications should be used with caution when concomitantly used with 
capmatinib and osimertinib in this study: 
• Strong CYP3A inhibitors: Coadministrating capmatinib with strong CYP3A inhibitor 
(itraconazole) increased capmatinib AUCinf by 42%. There was 3% increase in capmatinib 
Cmax. Closely monitor participants for adverse reactions during coadministration of 
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• Moderate CYP3A inducers: Simulations using physiologically-based pharmacokinetic 
(PBPK) models predicted that coadministration of capmatinib with the moderate CYP3A 
inducer efavirenz (600 mg once daily for 20 days) would result in a 44% decrease in 
capmatinib AUC0-12h and 34% decrease in Cmax at steady-state compared to 
administration of capmatinib alone. Caution should be exercised during concomitant use of 
capmatinib with moderate CYP3A inducers. Use an alternative medication with no or 
minimal potential to induce CYP3A during coadministration with capmatinib. 
• CYP1A2 substrates with narrow therapeutic index (NTI): Capmatinib is a moderate 
CYP1A2 inhibitor. Coadministration of capmatinib increased sensitive CYP1A2 probe 
substrate (caffeine) AUCinf by 134%. Avoid coadministration of capmatinib with CYP1A2 
substrates where minimal concentration changes may lead to serious adverse reactions. If 
coadministration is unavoidable, decrease the CYP1A2 substrate dosage in accordance with 
the approved prescribing information. 
• P-gp and BCRP substrates: Coadminstration of capmatinib increased P-gp substrate 
(digoxin) exposure (AUCinf and Cmax by 47% and 74%, respectively) and BCRP substrate 
(rosuvastatin) exposure (AUCinf and Cmax by 108% and 204%, respectively). Avoid 
coadministration of capmatinib with P gp and BCRP substrates where minimal 
concentration changes may lead to serious adverse reactions. If coadministration is 
unavoidable, decrease the P-gp or BCRP substrate dosage in accordance with the approved 
prescribing information. 
• Proton pump inhibitor: Coadministration of capmatinib with proton pump inhibitor 
(rabeprazole) decreased capmatinib AUCinf by 25% and Cmax by 38%. Exercise caution 
during concomitant use of capmatinib with proton pump inhibitors. 
• H2-receptor antagonists and antacids: As an alternative to proton pump inhibitors, an H2-
receptor antagonist or antacid can be taken. Capmatinib should be administered at least 3 
hours before or 6 hours after an H2- receptor antagonist. Capmatinib should be administered 
at least 2 hours before or 2 hours after an antacid. 
Refer to Section 16.3 Appendix for a list of the medications that require caution when 
concomitantly used with capmatinib and osimertinib.  
For cisplatin, carboplatin, pemetrexed, please refer to the local prescribing information with 
regards to warnings, precautions, and contraindications. 
6.2.1.2 
Use of bone modifying agents 
Treatment with bone modifying agents (BMAs, e.g., bisphosphonates, denosumab or receptor 
activator of nuclear factor kappa-B ligand (RANKL) inhibitor) for pre-existing bone metastases 
is permitted, if clinically indicated and at the investigator's discretion following existing local 
guidelines. Treatment with BMAs should preferably begin before the study treatment is 
initiated, but can also be initiated during therapy only if absence of radiological bone disease 
progression is well documented (in this case, the reason for its use must be clearly documented; 
i.e., “pre-existing, non-progressing, bone metastases”). Participants taking BMAs prior to 
entering the study should continue with the same BMA treatment given as per local medical 
practice. 


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No drug-drug interaction is expected between study drugs and BMAs, since they are eliminated 
through different elimination pathways. 
6.2.1.3 
Permitted radiotherapy 
Localized palliative radiotherapy for pre-existing, painful bone/liver metastases is permitted. It 
should not be delivered to a target lesion. If palliative radiotherapy is initiated after start of study 
treatment, the reason for its use must be clearly documented and progression as per RECIST 
1.1 must be ruled out. The study treatment must be interrupted on the days of radiotherapy and 
can be resumed the day after its completion. Caution is advised for radiation to fields that 
include lung tissue. The radiotherapy must be listed on the appropriate eCRF pages. After 
documented progression by RECIST 1.1, radiotherapy is allowed following the same dose 
adjustment guidance in case capmatinib and osimertinib is continued beyond PD. 
6.2.2 
Prohibited medication 
Use of the treatments displayed in this section, Section 16.4 and Section 16.5 are not allowed 
after the start of the study treatment as stated below. 
Drugs with a known risk of Torsades de Pointes (TdP) are prohibited. For identification of drugs 
with known risk of TdP please refer to qtdrugs.org (refer to Section 16.4). 
For participants taking capmatinib and osimertinib, prohibited medications are listed in 
Section 16.5. 
Concurrent 
use 
of 
strong 
CYP3A 
inducers 
is 
prohibited 
(refer 
to Section 16.5). Co-administration of capmatinib with strong CYP3A inducer (rifampicin) 
decreases capmatinib AUCinf by 67% and Cmax by 56% [CINC280A2102], which may decrease 
capmatinib anti-tumor activity.  
For cisplatin, carboplatin, pemetrexed please refer to the local prescribing information with 
regards to warnings, precautions, and contraindications. 
Participants enrolled in this study are not permitted to participate in additional parallel 
investigational drug or device studies while on treatment. 
Live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow 
fever, varicella, TY21a typhoid vaccines and COVID 19 vaccines) should not be administered 
while a participant is on study treatment and for 30 days after the last dose of study treatment. 
There are no prohibited therapies during the post-treatment follow-up period. 
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.  
6.3 
Participant numbering, treatment assignment, randomization 
6.3.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for molecular pre-screening and is retained for the 
participant throughout his/her participation in the trial. A new Participant No. will be assigned 
at every subsequent enrollment if the participant is re-screened. The Participant No. consists of 
the Center Number (Center No.) (as assigned by Novartis to the investigative site) with a 


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sequential participant number suffixed to it, so that each participant’s participation is numbered 
uniquely across the entire database. Upon signing the molecular pre-screening informed consent 
form, the participant is assigned to the next sequential Participant No. available. 
A new ICF will need to be signed if the investigator chooses to re-screen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No.  
The investigator or designated staff will contact the IRT and provide the requested identifying 
information to register the participant 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 (except if case of re-screening, see Section 8.1). If the subject fails to be enrolled 
(safety run-in), fails molecular pre-screening, fails to be randomized or to start treatment for 
any reason, the reason will be entered into the appropriate CRF page. 
IRT must be notified within 2 days if the participant did not start treatment or is not randomized.  
6.3.2 
Treatment assignment, randomization 
Run-in part 
No randomization will be performed in the run-in part of the trial.  
Randomized part 
The randomization will be stratified by presence of brain metastasis at baseline (presence vs 
absence) and prior treatment with 3rd generation EGFR TKIs (yes vs no) and participants will 
be randomized in a 2:1 ratio to either capmatinib in combination with osimertinib or platinum-
pemetrexed based doublet chemotherapy.  
The IRT will assign a randomization number to the participant, which will be used to link the 
participant to a treatment arm and will specify a unique medication number for the first package 
of study treatment to be dispensed to the participant. 
The study treatment phase begins on Cycle 1 Day 1 with the first administration of capmatinib 
in combination with osimertinib or platinum-pemetrexed based doublet chemotherapy. Cycle 1 
Day 1 should occur on the day of randomization or no later than 3 days after randomization. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and investigator staff. A 
participant randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of participant numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the responsibility 
of Novartis Global Clinical Supply (GCS) using a validated system that automates the random 
assignment of medication numbers to packs containing the study treatment. 
The threshold for enrollment of different population of participants will be monitored through 
the IRT system.  
The randomization scheme for participants will be reviewed and approved by a member of the 
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For participants crossing over from platinum-pemetrexed based doublet chemotherapy to ET in 
the randomized phase, the study treatment of ET phase begins on Cycle 1 Day 1 with the first 
administration of capmatinib in combination with osimertinib.  
6.4 
Treatment blinding 
This is an open-label study. Treatment assignment will be open to participants, investigator staff, 
persons performing the assessment and the Novartis team. In order to minimize the potential 
impact of treatment assignment, the randomization list will be kept strictly confidential until 
the primary analysis is conducted. No aggregate statistical analyses (efficacy or safety across 
the study) shall be performed by treatment prior to the primary analysis. 
6.5 
Dose escalation and dose modification 
6.5.1 
Dose De-escalation guidelines 
Information related to Dose Limiting Toxicities (DLTs) is specific to the run-in part of this 
study. 
Information related to dose modification applies to all enrolled participants (run-in and 
randomized parts).  
6.5.1.1 
Starting dose 
In the safety run in part, the starting dose of the combination is capmatinib (400 mg b.i.d.) and 
osimertinib (80 mg q.d.). In case that dose de-escalation is required, a lower dose level is defined 
as capmatinib (400 mg b.i.d.) and osimertinib (40 mg q.d.).  
The recommended dose confirmed in the run-in part will be the starting dose for the randomized 
part and for participants who crossover to ET. 
6.5.1.2 
Provisional dose levels 
Table 6-2 describes the starting dose and the dose levels that may be evaluated during this trial 
in the run-in part. 
Table 6-2 
Provisional dose levels  
Dose level 
Proposed daily dose for 
osimertinib* 
Increment from previous dose 
1 
80 mg q.d. 
(starting dose) 
-1* 
40 mg q.d. 
-50% 
*Dose level -1 represents a new treatment dose for osimertinib from the starting dose level. Capmatinib will be 
administered at 400 mg b.i.d. either at dose level 1 or -1 
6.5.2 
Guidelines for confirmation of recommended dose 
For the purposes of dose confirmation decisions, each cohort will consist of approximately 
10 newly enrolled participants to achieve at least 6 evaluable participants in the dose 
determining set (DDS, see definition in Section 12.1.5). The first cohort will be treated with the 
starting dose of capmatinib (400 mg b.i.d.) and osimertinib (80 mg q.d.). 


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Participants must complete a minimum of 1 cycle (21 days) of treatment with the minimum 
safety evaluation and drug exposure or have had a DLT within the DLT period to be considered 
evaluable for dose recommendation decisions. Dose recommendation decisions will occur when 
the cohort of participants has met these criteria. 
Dose recommendation 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. 
Dose confirmation of capmatinib (400 mg b.i.d.) and osimertinib (80 mg q.d.) will occur if the 
following conditions are met in the safety run-in part: 
• At least six evaluable participants treated at this dose and regimen. 
• No more than two DLTs have been observed out of six evaluable participants. 
• It is the dose recommended for participants after review of all clinical data by Novartis and 
Investigators in a dose level review team meeting (DLRTM). 
If one of the conditions specified above is not satisfied, dose confirmation cannot be declared 
and a second cohort may be treated at the lower dose level with capmatinib (400 mg b.i.d.) and 
osimertinib (40 mg q.d.). The same criteria are applied for this new dose and regimen. If dose 
confirmation cannot be declared on this lower dose, the randomized part cannot start and the 
study will end.  
6.5.2.1 
Implementation of dose De-escalation decisions 
To implement dose confirmation decisions, the available toxicity information (including 
adverse events and laboratory abnormalities that are not DLTs), 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 level review team meeting by teleconference. 
Drug administration at the next lower dose level or in the randomized part 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 either a lower 
dose level or to the randomized part. 
6.5.2.2 
Intra-Participant dose escalation 
Intra-participant dose escalation is not permitted at any time. 
6.5.3 
Definitions of Dose Limiting Toxicities (DLTs) (Run-In Part) 
Dose Limiting Toxicities (DLTs) will be collected and used only in the run-in part of the study. 
A Dose Limiting Toxicity (DLT) is defined as an adverse event or abnormal laboratory value 
assessed as unrelated to disease, progressive disease, inter-current illness, or concomitant 
medications that despite optimal therapeutic intervention occurs within the first 21 days of 
treatment with capmatinib in combination with osimertinib and meets any of the criteria 
included in Table 6-4. Toxicity that is clearly and directly related to the primary disease or 
another aetiology is excluded by this definition. 


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National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) 
version 5.0 will be used for all grading. For the purpose of dose decisions, DLTs will be 
considered. 
Whenever a particpant experiences a DLT, investigator should follow guidance as per 
Section 6.5.4 "dose modifications". The investigator must notify the Sponsor immediately of 
any unexpected CTCAE grade ≥ 3 adverse events or laboratory abnormalities. 
The already characterized toxicity profile of each study drug should be taken into account in 
the decision process. In Table 6-3 below there is a summary of capmatinib and osimertinib 
adverse drug reaction by system organ class underlying potential overlapping toxicities 
(highlighted in bold). 
Table 6-3 
Capmatinib and osimertinib overlapping toxicities 
SOC 
Capmatinib toxicity (Ref: Core 
Data Sheet (CDS)) 
Osimertinib toxicity (Ref: United 
States Prescribing Information 
USPI) 
Blood and lymphatic system 
disorders 
  
Lymphopenia 
Anemia 
Thrombocytopenia 
Neutropenia 
Cardiovascular disorders 
  
QTc Interval Prolongation 
Cardiomyopathy 
Cardiac failure 
Chronic cardiac failure 
Congestive heart failure 
Pulmonary edema 
Decreased ejection fraction 
Congenital, familial and genetic 
disorders 
Embryo-Fetal Toxicity 
Embryo-Fetal Toxicity 
Eye disorders 
  
Keratitis 
Gastrointestinal disorders 
Diarrhoea 
Diarrhoea 
Vomiting 
Vomiting 
Nausea 
Nausea 
Constipation 
Constipation 
Amylase increased 
Stomatitis 
Lipase increased 
  
Acute pancreatitis 
General disorders and 
administration site conditions 
Pyrexia 
Pyrexia 
Fatigue 
Fatigue 
Back pain 
Back pain 
Oedema peripheral 
  
Non-cardiac chest pain 
Weight decreased 
Hepatobiliary disorders 
ALT increased 
ALT increased 
AST increased 
AST increased 
Blood bilirubin increased 
Hyperbilirubinaemia 
Hypoalbuminemia 
  


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Infections and infestations 
Cellulitis 
Upper Respiratory Tract Infection 
Metabolism and nutrition 
disorders 
Decreased appetite 
Decreased appetite 
Hyponatremia 
Hyponatremia 
Hypophosphataemia 
Hyperglycemia 
  
Hypermagnesemia 
Hypokalemia 
Nervous system disorders 
  
Headache 
Respiratory, thoracic and 
mediastinal disorders 
Pneumonitis/ILD 
Pneumonitis/ILD 
Dyspnoea 
Dyspnoea 
Cough 
Cough 
Skin and subcutaneous tissue 
disorders 
Urticaria 
Rash 
Pruritus 
Pruritus 
  
Dry skin 
Nail toxicity 
Renal and urinary disorders 
Blood creatinine increased 
  
Acute kidney injury 
Table 6-4 
Criteria for defining dose-limiting toxicities 
Criteria for defining dose-limiting toxicities 
Blood and lymphatic system 
disorders 
Febrile neutropenia defined as 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. 
Neutropenia grade 4 regardless of duration 
Thrombocytopenia CTCAE Grade ≥ 3 with bleeding 
Thrombocytopenia CTCAE Grade 4 regardless of duration or bleeding 
Any other hematologic toxicity = grade 3, present for > 7 consecutive 
days 
Any other hematologic toxicity ≥ grade 4 present for more than 3 days 
Hepatic 
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 x ULN] OR [AST or ALT > 8.0 x 
ULN], 
whichever is lower, combined with [total bilirubin > 2 x baseline AND > 
2.0 x ULN] 
Gastrointestinal disorders 
Diarrhea ≥ grade 3, nausea or vomiting that DO NOT resolve within 3 
days with appropriate maximal medical intervention 
Electrolytes 
Grade ≥ 3 electrolyte abnormalities that are associated with clinical signs 
or symptoms and are not reversed with appropriate maximal medical 
intervention within 3 days 
Laboratory abnormalities  
≥ grade 3 that result in hospitalization 


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Skin and subcutaneous tissue 
disorder 
≥ grade 3 despite 7 consecutive days of optimal treatment 
Respiratory disorders 
≥ grade 2 pneumonitis or interstitial lung disease (ILD) without infection 
etiology 
General disorders 
grade 3 fatigue not improving within 7 days 
Other adverse events 
Any adverse event grade 4 or grade 3 not improving within 7 days. 
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. 
Any death not clearly related to the underlying disease or extraneous 
causes  
* “Combined” defined as: total bilirubin increase to the defined threshold concurrently with ALT/AST increase to 
the defined threshold 
** “Cholestasis” defined as: ALP (Alkaline Phosphatase) elevation > 2 x ULN 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 5.0 will be used for all grading. 
Participants may receive supportive care (i.e., transfusion of red blood cells) as per local institutional 
guidelines, as long as causality can clearly be established that supportive care is to treat disease related 
events and not related to investigational agent 
6.5.4 
Dose modifications 
For participants who do not tolerate the protocol-specified dosing schedule, dose interruptions, 
and/or reductions are either recommended or mandated in order to allow participants to continue 
the study treatment. 
The following guidelines should be considered: 
Platinum pemetrexed based chemotherapy 
Every attempt should be made to maintain the treatment dosing cycle schedule of every 21 days. 
For participants who are unable to tolerate the protocol-specified dosing schedule, dose 
adjustments are permitted per the local approved label in order to keep the participant on 
treatment. Dose reduction will follow the local prescribing information. 
Capmatinib and osimertinib 
Dose reductions are allowed for capmatinib and osimertinib and should follow the dose 
reduction steps described in Table 6-5 and Table 6-6. For each participant, a maximum of two 
consecutive dose level reductions is allowed for capmatinib and one dose level reduction is 
allowed for osimertinib if starting dose is 80 mg q.d. (no dose level reduction for osimertinib 
will be allowed if starting dose is 40 mg q.d.) after which the participant must be discontinued. 
Dose reductions of capmatinib below 200 mg b.i.d. are not permitted. The lowest dose allowed, 
200 mg b.i.d. in tablets is expected to be pharmacologically active, as the observed steady state 
plasma trough concentrations ([CINC280X1101], [CINC280X2202], n=6) were above the 
concentration associated with full MET inhibition in xenograft mice models (IC90, 120 nM total 
concentration). Dose reductions of osimertinib below 40 mg q.d. are not permitted. 
All dose modifications, interruptions or discontinuations must be based on the worst preceding 
toxicity as graded by the NCI Clinical Toxicity Criteria (NCI-CTCAE version 5.0). Any 
changes must be recorded on the dosage administration eCRF page. 


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A participant must discontinue treatment with capmatinib and/or osimertinib if, after treatment 
is resumed at the lowest allowed dose, the toxicity recurs with the same or worse severity 
despite use of maximal preventive measures as per the institution guidelines for toxicity 
prevention and management. Participants who do not tolerate the combination treatment 
because unacceptable toxicity that preclude further treatment and are judged by the investigator 
still to benefit from the treatment could continue to receive either capmatinib or osimertinib as 
single agent. In such circumstances, participants who permanently discontinued one of the two 
study treatment should still follow the protocol efficacy and safety assessment as scheduled. 
Unless otherwise indicated in Table 6-7 and Table 6-8, for grade 1 and tolerable grade 2 
treatment-related toxicities, participants may continue full doses of capmatinib and/or 
osimertinib. For intolerable grade 2 or grade 3 treatment-related toxicities, dosing should be 
interrupted until at least resolution to grade 1 followed by either dose reduction or re-initiation 
at the same dose level, as described in Table 6-7. For any grade 4 toxicity except for neutropenia, 
febrile neutropenia, anemia and thrombocytopenia, participants should interrupt capmatinib 
and/or osimertinib until resolution to grade 1, followed by either dose reduction or treatment 
discontinuation (refer toTable 6-7). 
If capmatinib and/or osimertinib treatment is withheld because of toxicity for more than 21 
consecutive days (counting from the first day when a dose was interrupted), then that treatment 
should be permanently discontinued (participant may continue on the other treatment alone, 
provided there is a clinical benefit to participant per investigator judgement). When the 
investigator believes that continuing treatment may still derive clinical benefit for the 
participant, study treatment may be resumed. However, the investigator must discuss and 
receive approval from Novartis Medical Lead or designee prior to continuing study treatment 
and rationale should be captured in the source documents. 
Recommendations for dose reduction or dose interruption of capmatinib/osimertinib in the 
management of adverse reactions are summarized in Table 6-7 and Table 6-8. Clinical 
judgement of the treating physician, including confirmation of laboratory values if deemed 
necessary, should guide the management plan of each participant based on individual 
risk/benefit assessment. However, permanent treatment discontinuation is mandatory for 
specific events indicated as such in Table 6-7 and Table 6-8, or listed in Section 6.5.2. 
Deviations to mandatory dose discontinuations are not allowed. 
If capmatinib is permanently discontinued and participant continues osimertinib as 
monotherapy, please refer to the current local prescribing information for dose modifications. 
For confirmed pneumonitis and interstitial lung disease, both capmatinib and osimertinib must 
be permanently discontinued.  
Careful assessment of all participants with an acute onset and/or unexplained worsening of 
pulmonary symptoms (dyspnoea, cough, fever) should be performed to exclude 
ILD/pneumonitis. Study treatment should be interrupted pending investigation of these 
symptoms. If ILD/pneumonitis is diagnosed, study treatment should be permanently 
discontinued and appropriate treatment initiated as necessary. Reintroduction of study treatment 
should be considered only in the absence of a diagnosis of ILD/pneumonitis and after careful 
consideration of the individual participant’s benefits and risks. 
Dose re/escalation of study treatment to previous dose is not allowed. 


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Events not included in the study protocol or the reference guidance documents should be 
managed according to local practices. 
Table 6-5 
Dose reduction steps for capmatinib 
  
Starting Dose level 0  
Dose level -1 
Dose level -2 
capmatinib 
400 mg b.i.d. 
300 mg b.i.d. 
200 mg b.i.d.  
Table 6-6 
Dose reduction steps for osimertinib 
  
Starting dose level 0 
Dose level -1 
Osimertinib 
80 mg q.d. 
40 mg q.d. 
Note: dose reduction should be based on the worst toxicity demonstrated at the last dose. 
If osimertinib starting dose for randomized part is 40 mg q.d. (dose level 0), no dose reduction 
(dose level -1) is permitted. 
Table 6-7 
Dose modifications for capmatinib in combination with osimertinib 
Worst toxicity CTCAEa Grade (value) 
Recommendation 
Investigations (Hematologic) 
Neutropenia (ANC) 
Grade 1 (ANC < lower limit of normal (LLN) - 
1500/mm3; < LLN - 1.5 x 109/L) 
Maintain dose levels of both study drugs. 
Grade 2 (ANC < 1500 - 1000/mm3; < 1.5 - 1.0 x 109/L) 
Maintain dose levels of both study drugs. 
Grade 3 (ANC < 1000 – 500/mm3) 
Omit study treatment until resolved to ≤ grade 2, then 
resume osimertinib at the same dose level.  
• If fully resolved in ≤ 7 days, then resume capmatinib 
at the 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 osimertinib and ↓ 1 dose level of capmatinib, 
omit study treatment until resolved to ≤ grade 2, then 
resume osimertinib 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 toxicity during osimertinib 
monotherapy, omit study treatment until resolved to 
≤ grade 2, then resume osimertinib at ↓ 1 dose level 
• If no recurrence of grade 3 toxicity after 7 days of 
osimertinib monotherapy at ↓ 1 dose level, resume 
capmatinib at same dose level 
Grade 4 (ANC < 500/mm3) 
Omit study treatment until resolved, then resume 
osimertinib at the same dose level.  
• If no recurrence of grade 3 toxicity or higher after 7 
days 
of 
osimertinib 
monotherapy, 
resume 
capmatinib at ↓ 1 dose level  


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Worst toxicity CTCAEa Grade (value) 
Recommendation 
• If recurrence of grade 3 or higher toxicity on 
maintained dose level of osimertinib and ↓ 1 dose 
level of capmatinib, omit study treatment until 
resolved to ≤ grade 2, then resume osimertinib at ↓ 
1 dose level and capmatinib at the same dose level 
(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 
osimertinib monotherapy, omit study treatment until 
resolved to ≤ grade 2, then resume osimertinib at ↓ 
1 dose level 
• If no recurrence of grade 3 or higher toxicity after 7 
days of osimertinib monotherapy at ↓ 1 dose level, 
resume capmatinib at the same dose level 
Febrile Neutropenia  
ANC < 1000/mm3 and a single temperature of > 38.3 
degrees C (101 degrees F) or a sustained 
temperature of ≥ 38 degrees C (100.4 degrees F) for 
more than one hour 
Omit study treatment until resolved, then resume 
osimertinib 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 osimertinib monotherapy, omit 
osimertinib until resolved, then resume osimertinib ↓ 1 
dose leveland capmatinib at ↓ 1 dose level  
Platelet (PLT) count decreased (Thrombocytopenia)  
Grade 1 (PLT < LLN - 75,000/mm3; < LLN - 75 x 
109/L) 
Maintain dose levels of both study drugs. 
Grade 2 (PLT < 75,000 - 50,000/mm3; < 75 - 50 x 
109/L) 
Maintain dose levels of both study drugs. 
Grade 3 (PLT < 50,000 - 25,000/mm3) 
Omit study treatment until resolved to ≤ grade 2, then 
resume osimertinib 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 during osimertinib 
monotherapy, omit study treatment until resolved to 
≤ grade 2, then resume osimertinib at ↓ 1 dose level 
and capmatinib at same dose level 
Grade 4 (PLT < 25,000/mm3) 
Omit study treatment until resolved to ≤ grade 2, then 
resume osimertinib at the same dose level.  
• If no recurrence of grade 3 or higher toxicity after 7 
days 
of 
osimertinib 
monotherapy, 
resume 
capmatinib at ↓ 1 dose level 
• If recurrence of grade 3 or higher toxicity on 
maintained dose level of osimertinib and ↓ 1 dose 
level of capmatinib, omit study treatment until 
resolved to ≤ grade 2, then resume osimertinib 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 4 AE) 


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


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Amended Protocol Version 02 (Clean) 
 
Protocol No. CINC280L12301 
 
Worst toxicity CTCAEa Grade (value) 
Recommendation 
Grade 4 (> 6.0 × ULN) 
Discontinue 
capmatinib 
permanently 
and 
omit 
osimertinib until resolved to ≤ grade 1 or baseline, then 
resume osimertinib at the same dose level  
Investigations (Hepatic) 
Isolated Total Bilirubinb 
Grade 1 (> ULN – 1.5 x ULN) 
Maintain dose levels of both study drugs 
Grade 2 (> 1.5 and ≤ 3.0 × ULN) with ALT or AST ≤ 
3.0 × ULN, in participants with normal isolated total 
bilirubin value at baseline 
Omit study treatment until resolved to ≤ grade 1, then 
resume both study drugs at the same dose level 
Grade 3 (> 3.0 and ≤ 10.0 × ULN) 
Omit study treatment until resolved to ≤ grade 1, then 
resume osimertinib at the same dose level.  
• If no recurrence of grade 3 toxicity after 7 days of 
osimertinib monotherapy, resume capmatinib at ↓ 1 
dose level  
• If recurrence of grade 3 toxicity on maintained dose 
of osimertinib and ↓ 1 dose level of capmatinib, omit 
study treatment until resolved to ≤ grade 1, then 
resume osimertnib 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 
3 AE)  
• If recurrence of grade 3 toxicity during osimertinib 
monotherapy, omit study treatment until resolved to 
≤ grade 1, then resume osimertinib at ↓ 1 dose level 
• If no recurrence of grade 3 toxicity after 7 days of 
osimertinib monotherapy at ↓ 1 dose level, resume 
capmatinib at ↓ 1 dose level  
Grade 4 (> 10.0 × ULN) 
Discontinue 
capmatinib 
permanently 
and 
omit 
osimertinib until resolved to ≤ grade 1, then resume 
osimertinib at the same dose level. Monitor for 
recurrence 7 days after resumption of osimertinib, or 
sooner if clinically indicated.  
• If Grade 3 or higher elevation recurs, omit 
osimertinib until resolved to ≤ grade 1, then resume 
osimertinib at ↓ 1 dose level.  
• If Grade 4 or higher elevation recurs, discontinue 
osimertinib permanently. 
Isolated AST or ALT 
Grade 2 (> 3.0 and ≤ 5.0 × ULN) without total bilirubin 
elevation to > 2.0 × ULN, for participants with normal 
AST/ALT values at baseline 
Maintain dose level of both drugs with Liver function 
test LFTsc monitored per protocol 
Grade ≥3 (> 5.0 × ULN) without total bilirubin 
elevation to > 2.0 × ULN 
Omit study treatment until resolved to ≤ grade 1, then 
resume osimertinib at the same dose level.  
• If no recurrence of grade 3 toxicity after 7 days of 
osimertinib monotherapy, resume capmatinib at ↓ 1 
dose level  
• If recurrence of grade 3 toxicity on maintained dose 
of osimertinib and at ↓ 1 dose level of capmatinib, 
omit study treatment until resolved to ≤ grade 1, then 
resume osimertinib 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 
3 AE)  


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Amended Protocol Version 02 (Clean) 
 
Protocol No. CINC280L12301 
 
Worst toxicity CTCAEa Grade (value) 
Recommendation 
• If recurrence of grade 3 toxicity during osimertinib 
monotherapy, omit study treatment until resolved to 
≤ grade 1, then resume osimertinib at ↓ 1 dose level  
• If no recurrence of grade 3 toxicity after 7 days of 
osimertinib monotherapy at ↓ 1 dose level, resume 
capmatinib at ↓ 1 dose level  
Combinedd,e elevation of AST or ALT and concurrent Total bilirubinf 
For participants with normal baseline ALT or AST or 
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 osimertinib 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 LFTsc, or more frequently if clinically 
indicated, until AST, ALT, or bilirubin have resolved to 
baseline or stabilized over 4 weeks. Following 
resolution of AST, ALT, and bilirubin to ≤ grade 1 (or to 
baseline), osimertinib may be resumed at ↓ 1 dose 
level if considered by the investigator to be in the best 
interest of the patient and following documented 
discussion with Novartis. Monitor LFTs twice weekly for 
two weeks and then weekly for two weeks after 
resumption. 
Investigation (metabolic)g 
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 osimertinib 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 osimertinib 
monotherapy, omit study treatment until resolved to 
≤ grade 2, then resume osimertinib at ↓ 1 dose level 
• If no recurrence of Grade 3 toxicity after 7 days of 
osimertinib 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 
osimertinib until resolved to grade ≤ 2, then resume 
osimertinib at the same dose level.  
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. 
Cardiac Investigations 
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 the 
same dose level and osimertinib at ↓ 1 dose level  


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Amended Protocol Version 02 (Clean) 
 
Protocol No. CINC280L12301 
 
Worst toxicity CTCAEa Grade (value) 
Recommendation 
• If resolved in > 7 days, resume both study drugs at 
↓ 1 dose level  
Grade 4 ([QT/QTc ≥ 501 or > 60 ms change from 
baseline] and [Torsades de pointes or polymorphic 
ventricular tachycardia, or signs/symptoms of serious 
arrhythmia]) 
Permanently discontinue capmatinib and osimertinib. 
Obtain local cardiologist (or qualified specialist) 
consultation and repeat cardiac monitoring as 
indicated until the QTcF returns to < 481 ms. 
Left ventricular ejection fraction decrease 
Asymptomatic, absolute decrease in LVEF of > 10% 
that is also below institutional lower limits of normal 
(LLN) 
Omit osimertinib, maintain capmatinib dose level, 
obtain consultation with Cardiologist, and repeat 
cardiac imaging after 1-2 weeks  
• If improved to 10% or less from baseline and at least 
at institutional LLN within 4 weeks, then resume 
osimertinib at ↓ 1 dose level.  
• Repeat ECHO or MUGA 2, 4, 8, and 12 weeks after 
re-starting osimertinib. If no recurrence of LVEF 
decline and if agreed by Cardiologist, the frequency 
of LVEF monitoring may then be decreased to the 
standard schedule per Table 8-2 and Table 8-3. If 
not improved to 10% or less from baseline and at 
least at institutional LLN within 4 weeks, then 
discontinue osimertinib 
Grade 3 left ventricular systolic dysfunction 
Omit study treatment and obtain consultation with 
Cardiologist. Following resolution of symptoms and 
recovery of the LVEF to the normal range, capmatinib 
may be resumed at the same dose level with repeat 
cardiac imaging 2 weeks after resumption, if agreed by 
Cardiologist. If recovery of LVEF occurred within 4 
weeks and remains normal after 2 weeks of capmatinib 
treatment, osimertinib may be resumed at ↓ 1 dose 
level, if agreed by Cardiologist. Repeat ECHO or 
MUGA 2, 4, 8, and 12 weeks after resumption of 
capmatinib. If no recurrence of LVEF decline and if 
agreed by Cardiologist, the frequency of LVEF 
monitoring may then be decreased to the standard 
schedule per Table 8-2 and Table 8-3. 
Grade 4 left ventricular dysfunction 
Discontinue study treatment and obtain consulation 
with Cardiologist. 
NOTE: Upon discontinuation due to LVEF decrease, closely monitor LVEF until resolution. The same cardiac 
imaging modality (i.e., transthoracic echocardiography (TTE) or multigated acquisition (MUGA) scan) used at 
baseline is to be used for all subsequent assessments. 
Cardiac Biomarkers 
NT-Pro-BNP elevation, any grade 
Maintain the dose of capmatinib. Omit osimertinib and 
evaluate and treat patient per institutional guidelines. 
Evaluate LVEF with TTE or MUGA. Follow NT-Pro-
BNP to resolution per institutional guidelines, or at least 
weekly. 
If no evidence of LVEF decrease from baseline of 10% 
or greater to below institutional LLN on TTE or MUGA, 
then resume dose levels of capmatinib and osimertinib. 
Consult with Cardiologist. 
If evidence of LVEF decrease from baseline of 10% or 
greater to below institutional LLN on TTE or MUGA, 
follow guidelines for LVEF decrease. 


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Protocol No. CINC280L12301 
 
Worst toxicity CTCAEa Grade (value) 
Recommendation 
Troponin I/T elevation, any grade 
Maintain the dose of capmatinib. Omit osimertinib and 
evaluate and treat patient per institutional guidelines. 
Evaluate LVEF with TTE or MUGA. Follow Troponin I/T 
to resolution per institutional guidelines. 
If no evidence of LVEF decrease from baseline of 10% 
or greater to below institutional LLN on TTE or MUGA, 
then resume dose level. Consult with Cardiologist.  
If evidence of LVEF decrease from baseline of 10% or 
greater to below institutional LLN on TTE or MUGA, 
follow guidelines for LVEF decrease. 
Vascular disorders 
Hypertension CTCAE grade 3 for at least 7 days, 
despite treatment 
Omit osimertinib until resolved ≤ grade 1, and 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 osimertinib at ↓ 1 
dose level after 7 days of capmatinib monotherapy, 
resume osimertinib 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 
osimertinib at ↓ 1 dose level 
CTCAE grade 4 
Discontinue patient from capmatinib and osimertinib 
Gastro intestinal 
Diarrheah 
Grade 1 
Maintain dose levels of both study drugs but institute 
anti-diarrheal treatment 
Grade 2 (despite maximal anti-diarrheal medication) 
Omit dose of both study drugs 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 the same dose level  
• If no recurrence of Grade 3 toxicity after 7 days of 
capmatinib monotherapy, resume osimertinib at ↓ 1 
dose level  
• If recurrence of Grade 3 toxicity during capmatinib 
monotherapy, omit study treatment until resolved to 
≤ grade 1, then resume capmatinib at ↓ 1 dose level  
• If no recurrence of Grade 3 toxicity after 7 days of 
capmatinib monotherapy at ↓ 1 dose level, resume 
osimertinib 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 osimertinib at the same dose level 
• If no recurrence of Grade 3 or higher toxicity after 7 
days 
of 
osimertinib 
monotherapy, 
resume 
capmatinibat at ↓ 1 dose level 


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Amended Protocol Version 02 (Clean) 
 
Protocol No. CINC280L12301 
 
Worst toxicity CTCAEa Grade (value) 
Recommendation 
• If recurrence of Grade 3 or higher toxicity during 
osimertinib monotherapy, omit study treatment until 
resolved to ≤ grade 1, then resume capmatinib at ↓ 
1 dose level 
• If no recurrence of Grade 3 or higher toxicity after 7 
days of capmatinib monotherapy at ↓ 1 dose level, 
resume osimertinib at the 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 osimertinib at the same dose level 
• If no recurrence of Grade 3 toxicity after 7 days of 
osimertinib monotherapy, resume capmatinib at ↓ 1 
dose level 
• If recurrence of Grade 3 toxicity during osimertinib 
monotherapy, omit study treatment until resolved to 
≤ grade 1, then resume capmatinib at ↓ 1 dose level 
• If no recurrence of Grade 3 toxicity after 7 days of 
capmatinib monotherapy at ↓ 1 dose level, resume 
osimertinib 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 toxicities  
Stevens-Johnson 
Syndrome 
(SJS) 
or 
Lyell 
syndrome/Toxic Epidermal Necrolysis (TEN) 
Permanently discontinue study treatment and manage 
per institutional guidelines. 
Rash 
Grade 1 Macules/papules covering < 10% BSA (Body 
Surface Area) 
Maintain dose levels of both study drugs 
Grade 2 Macules/papules covering 10 - 30% BSA 
Maintain dose levels of both study drugs 
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 osimertinib at ↓ 1 
dose level 
• If recurrence of Grade 3 toxicity during capmatinib 
monotherapy, omit study treatment until resolved to 
≤ grade 1, then resume capmatinib at ↓ 1 dose level 
• If no recurrence of Grade 3 toxicity after 7 days of 
capmatinib monotherapy at ↓ 1 dose level, resume 
osimertinib at same dose level 
Pneumonitis/Interstitial lung disease 
Grade 1 
Omit 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 study treatment.  


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Protocol No. CINC280L12301 
 
Worst toxicity CTCAEa Grade (value) 
Recommendation 
Only in the absence of a diagnosis of 
ILD/Pneumonitis, study treatment may be resumed at 
the same dose level.  
If recurrence after resumption of study drugs, 
permanently discontinue study treatment.  
Grade 2  
Mandatory: omit study treatment 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 study treatment.  
Only 
in 
the 
absence 
of 
a 
diagnosis 
of 
ILD/Pneumonitis, study treatment may be resumed 
following these guidelines:  
• If resolves to ≤ Grade 1 in ≤ 7 days, resume study 
drugs both at ↓ 1 dose level  
• If fails to resolve to ≤ Grade 1 within 7 days or recur 
after resumption of study drugs at ↓ 1 dose level, 
permanently discontinue study treatment. 
Grade 3 OR Grade 4 
Permanently discontinue study treatment. 
Fatigue/ Asthenia (General disorders and administration site conditions) 
Grade 1 or 2 
Maintain dose levels of both study drugs 
Grade 3 
Omit study treatment until resolved to ≤ grade 1, then 
resume osimertinib at the same dose level.  
• If resolved in ≤ 7 days, then resume capmatinib at 
the same dose level 
• If resolved in > 7 days, then resume capmatinib at ↓ 
1 dose level  
• If recurrence of Grade 3 toxicity during osimertinib 
monotherapy, omit study treatment until resolved to 
≤ grade 1, then resume osimertinib at ↓ 1 dose level  
• If no recurrence of Grade 3 toxicity after 7 days of 
osimertinib monotherapy at ↓ 1 dose level, resume 
capmatinib at the same dose level 
Peripheral edema  
Grade 1 or 2 
Maintain dose levels of both study drugs 
Grade 3 
Omit study treatment until resolved to ≤ grade 1, then 
resume osimertinib at the 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 
osimertinib monotherapy, resume capmatinib at ↓ 1 
dose level 
• If recurrence of Grade 3 toxicity on maintained dose 
of osimertinib 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 osimertinb (i.e., 2 ↓ dose level of 
capmatinib and maintained dose level of osimertinib 
from the initial occurrence of grade 3 toxicity) 
• If recurrence of Grade 3 toxicity during osimertinib 
monotherapy, omit study treatment until resolved to 
≤ grade 1, then resume osimertinib at ↓ 1 dose level 


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Protocol No. CINC280L12301 
 
Worst toxicity CTCAEa Grade (value) 
Recommendation 
• If no recurrence of Grade 3 toxicity after 7 days of 
osimertinib monotherapy at ↓ 1 dose level, resume 
capmatinib at ↓ 1 dose level 
Grade 4 
Permanently discontinue capmatinib and continue 
osimertinib monotherapy 
Metabolic 
Any Grade hypophosphatemia 
Treatment with phosphate supplements as clinically 
indicated and maintain dose levels of both study drugs 
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 
the same dose level and osimertinib at ↓ 1 dose level  
• If resolved in > 14 days, then permanently 
discontinue patient from osimertinib and resume 
capmatinib at the same dose level. 
Grade 4 Uveitis/Retinopathy 
Permanently discontinue osimertinib and refer the 
patient 
to 
an 
ophthalmologist 
for 
monitoring. 
Resumption of osimertinib 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 osimertinib and refer the 
patient 
to 
an 
ophthalmologist 
immediately 
for 
monitoring. Resumption of osimertinib following 
resolution to ≤ grade 1 may be considered if approved 
by ophthalmologist and after documented discussion 
with Novartis. 
Resume capmatinib at the same dose level upon 
resolution to ≤ grade 1. 
Other ocular/visual toxicity 
Grade 1 or 2 
Maintain dose levels of both study 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 
the same dose level and osimertinib at ↓ 1 dose level  
• If resolved in > 14 days, then discontinue patient 
from osimertinib and resume capmatinib at ↓ 1 dose 
level.  
Grade 4 
Permanently discontinue osimertinib, omit capmatinib 
and refer the patient to an ophthalmologist immediately 
for monitoring. Resumption of osimertinib at ↓ 1 dose 
level following resolution to ≤ grade 1 may be 
considered if approved by ophthalmologist and after 
documented discussion with Novartis. 


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Protocol No. CINC280L12301 
 
Worst toxicity CTCAEa Grade (value) 
Recommendation 
Once resolved to ≤ grade 1, resume capmatinib. 
Other adverse events 
Grade 1 or 2 
Maintain dose levels of both study drugs 
Grade ≥ 3 
Omit study treatment until resolved to ≤ grade 1, then 
resume osimertinib at the same dose level and re-
evaluate after 7 days, or sooner if clinically indicated  
• If no recurrence of Grade 3 or higher toxicity after 7 
days 
of 
osimertinib 
monotherapy, 
resume 
capmatinib at ↓ 1 dose level  
• If recurrence of Grade 3 or higher toxicity on 
maintained dose level of osimertinib and ↓ 1 dose 
level of capmatinib, omit study treatment until 
resolved to ≤ grade 1, then resume osimertinib 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 3 AE)  
• If recurrence of Grade 3 or higher toxicity during 
osimertinib monotherapy, omit study treatment until 
resolved to ≤ grade 1, then resume osimertinib at ↓ 
1 dose level  
• If no recurrence of Grade 3 or higher toxicity after 7 
days of osimertinib 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. 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 
transferase (GGT). For isolated elevations of any grade of alkaline phosphatase and/or GGT, maintain dose 
level. d “Combined” defined as: total bilirubin increase 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. g A CT (Computerized Tomography) 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. h Antidiarrheal medication 
is recommended at the first sign of abdominal cramping, loose stools or overt diarrhea. 


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Table 6-8 
Dose modifications for capmatinib (if osimertinib 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 the same 
dose level 
If fully 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 
degrees C (101 degrees F) or a sustained temperature 
of ≥ 38 degrees C (100.4 degrees F) for more than one 
hour 
Omit dose, then: 
If resolved in ≤ 7 days, resume treatment at ↓ 1 dose 
level 
If resolved in > 7 days, permanently discontinue 
participant from capmatinib treatment 
Hemoglobin decreased (Anemia) 
Grade 1 (Hemoglobin [Hgb] < LLN - 10.0 g/dL; < LLN - 
6.2 mmol/L; < LLN - 100 g/L) 
Maintain dose level 
Grade 2 (Hgb < 10.0 - 8.0 g/dL; < 6.2 – 4.9 mmol/L; < 
100 - 80 g/L) 
Maintain dose level 
Grade 3 (Hgb < 8.0 g/dL; < 4.9 mmol/L; < 80 g/L; 
transfusion indicated) 
Omit dose until resolved to ≤ grade 2, then: 
If 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 (Life-threatening consequences; urgent 
intervention indicated) 
Omit dose until resolved to ≤ grade 2 and then resume 
at ↓ 1 dose level 
If grade 3 toxicity recurs, permanently discontinue 
capmatinib treatment. 
RENAL 
Serum creatinine 
Grade 1 (> ULN - 1.5 x ULN) 
Maintain dose level 


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Grade 2 (> 1.5 - 3.0 x ULN) 
Omit dose until resolved to ≤ grade 1 or baseline, then 
resume treatment at the same dose level. 
Grade 3 (> 3.0 - 6.0 x ULN) 
Omit dose until resolved to ≤ grade 1 or baseline, then 
resume 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 the 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: 
[AST or ALT > 3 x baseline] OR [AST or ALT > 8.0 x 
ULN], whichever is lower, combined with [total bilirubin 
> 2 x baseline AND > 2.0 x ULN] without evidence of 
cholestasis or hemolysis 
Mandatory: 
Permanently 
discontinue 
capmatinib 
treatment 
METABOLIC 
Amylase and/or lipase elevation 
Grade 1 (> ULN - 1.5 x ULN) 
Maintain dose level 
Grade 2 (> 1.5 - 2.0 x ULN; > 2.0 - 5.0 x ULN and 
asymptomatic) 
Maintain dose level 
Grade 3 (> 2.0 - 5.0 x ULN with signs or symptoms; > 
5.0 x ULN and asymptomatic) 
Omit the dose until resolved to ≤ grade 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 


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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 fully 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 
the 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 
the 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 
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 resolved in ≤ 7 days, then resume at ↓ 1 dose level 
If resolved in > 7 days (despite appropriate skin toxicity 
therapy), then permanently discontinue capmatinib 
treatment 


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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 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 resumed 
following these guidelines: 
• 
If resolves to ≤ Grade 1 in ≤ 7 days reduce study 
drug by 1 dose level 
• 
If fails to resolve to ≤ Grade 1 within 7 days or recur 
after resumption of 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 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Fatigue/ Asthenia  
Grade 1 or 2 
Maintain dose level 
Grade 3 
Omit dose until resolved to ≤ grade 1, then: 
If resolved in ≤ 7 days, resume at the same dose level 
If resolved in > 7 days, resume at ↓ 1 dose level 
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. 


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For any intolerable grade 2 (e.g., limiting instrumental 
ADL), consider omitting the dose until resolved to ≤ 
grade 1, then resume either at the 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) 
6.5.4.1 
Dose adjustments for QTcF prolongation 
 Please see Table 6-7 and Table 6-8. 
6.5.5 
Follow-up for toxicities 
All participants will be followed for safety until 30 days after the last dose of study treatment. 
Participants whose treatment is temporarily interrupted or permanently discontinued due to an 
AE or abnormal laboratory value must be followed until resolution or stabilization of the event, 
whichever comes first, including all study assessments appropriate to monitor the event. 
Appropriate clinical experts such as ophthalmologists, endocrinologists, dermatologists, 
psychiatrists etc., should be consulted as deemed necessary. 
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 6-9 
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 has 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. 


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TOXICITY 
FOLLOW-UP EVALUATION 
For participants with baseline value > 3.0 x ULN: repeat 
LFTs as soon as possible, preferably within 48-72 hr 
from awareness of the abnormal results; if abnormal 
lab values are confirmed upon the repeat test, then 
monitor LFTs, weekly, or more frequently if clinically 
indicated, until resolved to ≤ 5.0 x ULN. 
For AST/ALT elevation > 10.0 - 20.0 x ULN: 
Repeat LFTs as soon as possible, preferably within 48-
72 hr from awareness of the abnormal results; monitor 
LFTs weekly, or more frequently if clinically indicated, 
until resolved to ≤ baseline. 
AST/ALT CTCAE Grade 4 elevation: 
Repeat LFTs as soon as possible, preferably within 48-
72 hr from awareness of the abnormal results; monitor 
LFTs weekly, or more frequently if clinically indicated, 
until resolved to baseline or stabilization over 4 weeks. 
Combined elevations in ALT and/or AST with 
concurrent total bilirubin increase, in the absence of 
cholestasis or hemolysis 
Combined elevations of AST or ALT and total bilirubin: 
After discontinuing the participant from capmatinib 
permanently, repeat LFTs as soon as possible, 
preferably within 48 hr from awareness of the abnormal 
results, then with weekly monitoring of LFTs, or more 
frequently if clinically indicated, until AST, ALT, or 
bilirubin have resolved to baseline or stabilization over 
4 weeks. 
Core LFTs consist of ALT, AST, GGT, total bilirubin 
(fractionated [direct and indirect], if total bilirubin > 2.0 
x ULN), and alkaline phosphatase (fractionated 
[quantification of isoforms], if alkaline phosphatase > 
2.0 x ULN). 
METABOLIC 
amylase or lipase ≥ CTCAE grade 3 
Test weekly (or more frequently) until ≤ CTCAE grade 
2. 
A CT scan or equivalent imaging procedure to assess 
the pancreas, liver, and gallbladder is recommended 
within 7 days of the first occurrence of any ≥ CTCAE 
grade 3 result, to exclude disease progression or 
potential other liver or pancreatic disease. 
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. 


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TOXICITY 
FOLLOW-UP EVALUATION 
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 
(i.e., discontinuation of concomitant medication, dietary 
modification, treatment of comorbidity). 
The participant should be monitored for signs of 
dehydration 
and 
instructed 
to 
take 
preventive 
measures against dehydration as soon as diarrhea 
occurs. Antidiarrheal medication must be initiated at 
the first sign of abdominal cramping, loose stools or 
overt diarrhea. Concomitant medication for the 
treatment of diarrhea should follow local practice and 
the investigator’s best judgment and may follow “the 
recommended guidelines for the treatment of cancer 
treatment-induced diarrhea” (Benson et al 2004). For 
example: 
For uncomplicated diarrhea (grade 1 or 2 without 
complicating signs or symptoms), loperamide given at 
a standard dose (e.g., initial administration of 4 mg, 
then 2 mg every 2-4 hr, maximum of 16 mg/day), along 
with oral hydration and dietetic measures should be 
considered. Note: complicating signs or symptoms 
include moderate to severe cramping, decreased 
performance status, fever, neutropenia, frank bleeding 
or dehydration. 
For complicated diarrhea (all grade 3 or 4, grade 1-2 
with complicating signs or symptoms), management 
should involve intravenous (IV) fluids, and consider 
treatment with octreotide (at starting dose of 100 to 150 
µg sub-cutaneous tid or 25 to 50 µg/h IV) and 
antibiotics (i.e., fluoroquinolone) should be given 


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TOXICITY 
FOLLOW-UP EVALUATION 
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 (i.e., 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 
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 


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TOXICITY 
FOLLOW-UP EVALUATION 
Symptomatic therapy including corticosteroids if 
clinically indicated (1 to 2 mg/kg/day prednisone or 
equivalent as clinically indicated) b 
CTCAE Grade 3 and Grade 4 
CT scan (high-resolution with lung windows) 
Clinical evaluation and laboratory work-up for infection 
Consult pulmonologist 
Pulmonary function testsa - if < normal, repeat every 8 
weeks until ≥ normal 
Bronchoscopy with biopsy and/or BAL if possiblec 
Treat with IV steroids (methylprednisolone 125 mg) as 
indicated. When symptoms improve to ≤ Grade 1, a 
high dose 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 PFT (Pulmonary function tests) to include: diffusing capacity for carbon monoxide corrected for hemoglobin 
(DLCO); spirometry; resting oxygen saturation. 
Guideline for significant deterioration in lung function: Decrease in spirometry and/or DLCO of 30% and/or 
O2 saturation ≤ 88% at rest on room air. 
b Duration and dose of course of corticosteroids will vary according to circumstances but should be as limited as 
possible. Consider tapering dosage at end. 
c If bronchoscopy is performed, bronchoalveolar lavage (BAL) should be done where possible to exclude alveolar 
hemorrhage, opportunistic infections, cell count + determination lymphocyte CD4/8 count where possible. 
6.5.5.1 
Follow-up on potential drug-induced liver injury (DILI) cases 
Participants with transaminase increase combined with elevations of total bilirubin may be 
indicative of potentially severe DILI, these cases should be considered as clinically important 
and assessed appropriately to establish the diagnosis. The required clinical information, as 
detailed below, should be sought to obtain the medical diagnosis of the most likely cause of the 
observed laboratory abnormalities. 
The threshold for potential DILI may depend on the participant’s baseline AST/ALT and total 
bilirubin value; participants meeting any of the following criteria will require further follow-up 
as outlined below: 
• For participants with normal ALT and AST and total bilirubin value at baseline: AST or 
ALT > 3.0 x ULN combined with total bilirubin > 2.0 x ULN 
• For participants with elevated AST or ALT or total bilirubin value at baseline: [AST or ALT 
>3.0 x baseline] OR [ALT or AST > 8.0 x ULN], whichever occurs first, combined with 
[total bilirubin > 2.0 x baseline AND > 2.0 x ULN] 
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before DILI is assumed to be the cause of liver injury. 
A detailed history, including relevant information such as review of ethanol consumption, 
concomitant medications, herbal remedies, supplement consumption, history of any pre-
existing liver conditions or risk factors, should be collected. 


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Laboratory tests should include ALT, AST, total bilirubin, direct and indirect bilirubin, GGT, 
Glutamate dehydrogenase (GLDH), prothrombin time (PT)/ International Normalized Ratio 
(INR), alkaline phosphatase, albumin, and creatine kinase.  
Evaluate status of liver metastasis (new or exacerbation) or vascular occlusion – e.g., using CT, 
MRI, or duplex sonography. 
Perform 
relevant 
examinations 
(Ultrasound 
or 
MRI, 
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 metastasis, or elevation of the liver-specific ALP isoenzyme 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 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 6-10 provides guidance on specific clinical and diagnostic assessments which can be 
performed to rule out possible alternative causes of observed LFT abnormalities. 
Table 6-10 
Guidance to rule out other alternative causes of observed LFT 
abnormalities 
Disease 
Assessment 
Hepatitis A, B, C, E 
• 
Immunoglobulin IgM anti-HAV; Hepatitis B surface 
antigen (HBsAg), IgM & IgG anti-HBc, HBV DNA; 
anti-HCV, HCV RNA, IgM & IgG anti-HEV 
(Hepatitis E Virus), 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, 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 
Other causes should also be considered based upon participants’ medical history 
(hyperthyroidism / thyrotoxic hepatitis – T3, T4, Thyroid Stimulating Hormone (TSH); CVD 
(Cardio Vascular Diseases) / ischemic hepatitis – ECG, prior hypotensive episodes; Type 1 
diabetes (T1D) / glycogenic hepatitis. 


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Following appropriate causality assessments, as outlined above, the causality of the treatment 
is estimated as “probable” i.e., > 50% likely, if it appears greater than all other possible causes 
of liver injury combined. The term “treatment-induced” indicates probably caused by the 
treatment, not by something else, and only such a case can be considered a DILI case and should 
be reported as an SAE. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant,” and thus, meet the definition of SAE and should be reported as SAE using the term 
“potential treatment-induced liver injury”. All events should be followed up with the outcome 
clearly documented. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
Every time the study treatment is to be administered, IRT needs to be accessed (please refer to 
the IRT manual). The date and time of study treatment administration during the study and any 
deviations from the protocol treatment schedule will be captured on the appropriate study 
treatment dispensing form. The investigator must promote compliance by instructing the 
participant to take the study treatment exactly as prescribed and by stating that compliance is 
necessary for the participant’s safety and the validity of the study. The participant must also be 
instructed to contact the investigator if he/she is unable for any reason to take the study 
treatment as prescribed. 
For treatment with platinum - pemetrexed based doublet chemotherapy: exposure to the study 
treatment will be based on the number of infusions administered. 
For treatment with capmatinib in combination with osimertinib: compliance will be assessed by 
the investigator and/or study personnel at each visit using pill counts and information provided 
by the participant. This information should be captured in the source document at each visit. 
All study treatment dispensed and returned must be recorded in a drug accountability log. 
In the case where study treatment is administered at a remote location by an off-site healthcare 
provider, treatment administration compliance will be assessed by the off-site healthcare 
professional and information provided to the Investigator and/or study personnel. 
6.6.2 
Emergency breaking of assigned treatment code 
Not applicable 
6.7 
Preparation and dispensation 
Each study site will be supplied with study treatment in packaging as described under 
investigational and control drugs (Section 6.1.1). 
Capmatinib 
The investigator or responsible site personnel must instruct the participant or caregiver to take 
the study treatment as per protocol. Study treatment will be dispensed to the participant by 


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authorized site personnel only. All dosages prescribed to the participant and all dose changes 
during the study must be recorded on the study treatment eCRF. 
A unique medication number is printed on the study medication label. 
Investigator staff will identify the study medication kits to dispense to the participant by 
contacting the IRT system and obtaining the medication number(s). The study medication has 
a two-part label (base plus tear-off label). Immediately before dispensing the medication kit to 
the participant, site personnel will detach the outer part of the label from the packaging and 
affix it to the source document. 
Osimertinib 
Preparation and dispensation of osimertinib should follow local guidelines as per standard of 
care and product labels. 
Platinum pemetrexed based doublet chemotherapy 
Preparation and dispensation of cisplatin, carboplatin or penetrexed should follow local 
guidelines as per standard of care and product labels. 
As per Section 4.6 during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
delivery of IMP (capmatinib and osimertinib) directly to a participant’s home is generally 
permitted (if allowed by Local or Regional Health Authorities and Ethics Committees) in the 
event the Investigator has decided that an on-site visit by the participant is no longer appropriate 
or possible, and that it is in the interest of the participant’s health to administer the study 
treatment even without performing an on-site visit. Platinum pemetrexed should be shipped and 
administered in an authorized hospital environment or in a similar structure. The dispatch of 
IMP from the site to the participant’s home remains under the accountability of the Investigator. 
The shipment/provisioning will be for a maximum of 3 months supply. In this case, regular 
phone calls or virtual contacts (every 3 weeks or more frequently if needed) will occur between 
the site and the participant for instructional purposes, drug accountability, safety monitoring 
including safety assessments, investigation of any adverse events, ensuring participants 
continue to benefit from treatment, and discussion of the participant´s health status until the 
participant can resume visits at the study site.  
6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the drug labels and in the [capmatinib Investigator’s Brochure].  
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis CO Quality Assurance. 


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Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number. 
The investigator or designated site staff must maintain an accurate record of the shipment and 
dispensing of study treatment in a drug accountability log. Monitoring of drug accountability 
will be performed by monitors during site visits or remotely and at the completion of the trial. 
The Investigator must provide accountability also for locally sourced materials used for 
administration. If study treatment is administered at home e.g., capmatinib and osimertinib, 
participants will be asked to return all unused study treatment and packaging at the end of the 
study or at the time of discontinuation of study treatment.  
At the conclusion of the study, and as appropriate during the course of the study, the site may 
destroy and document destruction of unused study treatment, drug labels and packagings as 
appropriate in compliance with site processes, monitoring processes, and per local 
regulation/guidelines. Otherwise, the investigator will return all unused study treatment, 
packaging, drug labels, and a copy of the completed drug accountability log to the 
Novartis monitor or to the Novartis address provided in the investigator folder at each site. 
6.7.1.2 
Handling of additional treatment 
Not applicable 
6.7.2 
Instruction for prescribing and taking study treatment 
All kits of study treatment assigned by the IRT will be recorded in the IRT system.  
Table 6-11 
Dose and treatment schedule 
Investigational / Control Drug 
(Name and Strength) 
Dose 
Frequency and/or Regimen 
Capmatinib (INC280) 200 mg or 
150 mg 
400 mg orally 
(2 x 200 mg or 2 x 150 mg [if dose 
is reduced to 300 mg b.i.d.], if 
applicable) 
Twice daily 
Osimertinib 80 mg or 40 mg 
80 mg or 40 mg orally 
Once daily 
Cisplatin/carboplatin pemetrexed 
based doublet 
chemotherapycombination (as per 
local product available) 
pemetrexed 500mg/m2 + 
carboplatin AUC 5-AUC 6 or 
pemetrexed 500mg/m2 + cisplatin 
75mg/m2 administered 
intravenously (i.v.) following local 
guidelines as per standard of care 
and product labels. Participants 
can receive up to 6 cycles of 
pemetrexed + carboplatin/cisplatin 
as initial treatment. Participants 
whose disease has not progressed 
after four cycles of platinum-based 
first-line chemotherapy initial 
treatment may receive pemetrexed 
maintenance therapy (pemetrexed 
500mg/m2 on Day 1 of every 21 
days cycle). i.v. infusion per 
product label and local guidelines 
(as per standard of care) 
Once every 21 days 


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6.7.2.1 
Dose and Treatment Schedule 
6.7.2.1.1 Capmatinib - Osimertinib 
The investigator must instruct the participant to take the study drugs exactly as prescribed. All 
dosages prescribed and dispensed to the participant and all dose changes during the study must 
be recorded on the dosage administration eCRF. A complete cycle of treatment is defined as 21 
days of twice daily treatment with capmatinib and 21 days of once daily treatment with 
osimertinib. 
Capmatinib tablets will be administered orally on a continuous twice daily (b.i.d.) dosing 
schedule, on a flat scale of mg per administration and not individually adjusted by weight or 
body surface area. Osimertinib tablets will be administered orally on a continuous once daily 
dosing schedule, also on a flat scale and at the same time as the morning dose of capmatinib. 
Refer to Table 6-11. 
Each dose of capmatinib or capmatinib plus osimertinib is to be taken with a glass of water (at 
least 8 ounces – approximately 240 mL) and consumed over as short a time as possible (i.e., 
not slower than 1 tablet every 2 minutes). 
Capmatinib and capmatinib plus osimertinib 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 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 days of PK sampling, doses of capmatinib plus osimertinib must be held and taken in the 
clinic, as instructed by study personnel. On these days, capmatinib plus osimertinib will be 
administered at the site in the morning prior to the post-dose PK sample blood draws supervised 
by a member of the research team. The pre-dose PK samples will be taken right before 
capmatinib plus osimertinib administration. The exact time of drug administration must be 
recorded in the appropriate eCRF. Information of whether capmatinib was administered with 
or without food must be recorded in the appropriate eCRF. If a participant vomits within 4 hours 
of capmatinib dosing on the day of post-dose PK blood sampling, PK sample collection is at 
investigator's discretion. If PK sample collection is performed, the time of vomiting should be 
recorded on the eCRF (this does not apply for participants in ET, since no PK sample is 
collected). 
Participants must be instructed not to make up for missed doses or partial doses (i.e., when the 
entire dose is not taken as instructed). A missed or partial dose will be defined as a case when 
the full dose is not taken within 4 hours of the scheduled capmatinib twice daily dosing. If that 
occurs, then the dose (or part remaining dose) should not be taken and dosing should restart 
with the next scheduled dose. If vomiting occurs, no attempt should be made to replace the 
vomited dose before the next scheduled dose. 


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Osimertinib will be supplied locally as commercially available and labeled accordingly to 
comply with legal requirements of each country. Osimertinib administration should follow local 
prescribing information if not differently reported in this protocol. Refer to Table 6-11. 
During the whole duration of treatment with capmatinib plus osimertinib, the participant is 
recommended to use precautionary measures against ultraviolet exposure (i.e., use of sunscreen, 
protective clothing, avoid sunbathing or using a solarium). 
6.7.2.1.2 Platinum premetrexed based doublet chemotherapy 
Cisplatin, carboplatin and pemetrexed will be supplied locally as commercially available and 
labeled accordingly to comply with legal requirements of each country. Chemotherapy 
administration (including related pre-medication schemes) should follow local prescribing 
information. 
6.7.2.2 
Osimertinib 
Osimertinib will be supplied locally as commercially available and labeled accordingly to 
comply with legal requirements of each country. Osimertinib administration should follow local 
prescribing information if not differently reported in this protocol. 
7 
Informed consent procedures 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
If applicable, in cases where the participants's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her level of understanding. If the participant is capable of doing so, he/she 
must indicate agreement by personally signing and dating the written informed consent 
document.  
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representatives will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, privacy and data protection 
requirements, where applicable, and the IRB/IEC or study center. 
Informed consent must be obtained before conducting any study-specific procedures (e.g., all 
of the procedures described in the protocol). A copy of the ICFs must be provided to the 
participant (or the legally authorized representative). The process of obtaining informed consent 
must be documented in the participant source documents. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Participants who are re-screened are required to sign a new ICF. 
Information about common side effects already known about the investigational treatment can 
be found in the [capmatinib Investigator’s Brochure] or in the Core Data Sheet (CDS)/package 
insert for licenced or approved drug. 


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This information will be included in the participant informed consent and should be discussed 
with the participant upon obtaining consent and also during the study as needed. The 
Investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the participant (or the legally authorized representative) and answer all 
questions regarding the study. 
Any new information regarding the safety profile of the investigational drug that is identified 
between IB updates will be communicated as appropriate, for example, via an investigator 
notification or an aggregate safety finding. New information might require an update to the 
informed consent and then must be discussed with the participant. 
The following informed consents are included in this study: 
• Molecular pre-screening consent 
• Main study consent, which also includes a subsection that requires a separate signature for 
the ‘Optional Consent for Additional Research’ to allow future research on data/samples 
collected during this study 
• As applicable, Pregnancy Outcomes Reporting Consent for female participants or the 
female partners of any male participants who took study treatment 
• Treatment beyond progression (only applicable for capmatinib + osimertinib arm, including 
ET)  
• As applicable, Home Nursing consent 
Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements. 
Male participants must be informed that if a female partner becomes pregnant while he is 
enrolled in the study, contact with the female partner will be attempted to request her consent 
to collect pregnancy outcome information. This will be applicable for both arms (capmatinib + 
osimertinib and platinum - pemetrexed arms). 
A copy of the approved version of all consent forms must be provided to Novartis after 
Institutional Review Board (IRB)/ Independent Ethics Committee (IEC) approval. 
Participants might be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e., pandemic, epidemic or natural disaster, that may challenge the ability to obtain 
a standard written informed consent due to limits that prevent an on-site visit, Investigator may 
conduct the informed consent discussion remotely (i.e., telephone, videoconference) if 
allowable by local regulations. 
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (i.e., the presence of an impartial witness, sign/dating separate ICFs 
by trial participant and person obtaining informed consent, etc.). 
In case the situation limits or prevents on-site study visits and if home nursing (as outlined 
in Section 8) is implemented, depending on local regulations and capabilities, a separate Home 
nursing consent must be used in addition to the main Global ICF. 


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8 
Visit schedule and assessments 
The assessment schedule in Table 8-2 and Table 8-3 lists all of the assessments when they are 
performed. All data obtained from these assessments must be supported in the participant’s 
source documentation. The table indicates which assessments produce data to be entered into 
the database (X) or remain in the source documents only (S). The eCRF will not be used as a 
source document. 
Written informed consent must be obtained before any study specific assessments are 
performed, including those at molecular pre-screening and screening. Main screening 
evaluations and baseline radiological tumor assessments should be performed within 28 days 
of treatment start. All visits are to be scheduled according to the appropriate number of calendar 
days from Cycle 1 Day 1 of study treatment administration. 
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-2 and Table 8-3) or as close to the designated day/time as possible. Missed or 
rescheduled visits should not lead to automatic discontinuation. Participants who discontinue 
from study treatment are to return for the end of treatment visit as soon as possible, and attend 
the follow-up visits as indicated in the Assessment Schedule. At this final visit, all dispensed 
investigational product should be reconciled, and the adverse event and concomitant 
medications not previously reported must be recorded on the CRF. 
Participants who discontinue from study or withdraw their consent/oppose the use of their 
data/biological samples should be scheduled for a final evaluation visit if they agree, where all 
of the assessments listed for the final visit will be performed. At this final visit, all dispensed 
investigational product should be reconciled, and the adverse event and concomitant 
medications not previously reported must be recorded on the CRF. 
PRO measure(s) must be completed before any clinical assessments are performed at any given 
visit. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, alternative methods of providing continuing care may be implemented. Phone calls, 
virtual contacts (e.g., teleconsult) or visits by site staff/home nursing service to the participant´s 
home depending on local regulations and capabilities, can replace on-site study visits, for the 
duration of the disruption until it is safe for the participant to visit the site again. 
Please refer to Table 8-1 for the allowable window for visits. 
Table 8-1 
Visit Window 
Visit Name  
Window allowed 
Screening 
-28 days to -1 day from first dose of study treatment 
Cycle 1 Day 1 
Within 3 days after randomization (for randomized 
part) 
Day 1 of all subsequent cycles and ET cycles 
±3 days 
Imaging evaluations 
±7 days 
PRO assessments 
• 
During the treatment and until progression: within 3 
days prior to the visit 


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Visit Name  
Window allowed 
• 
For EOT and post progression time points: ±7 days 
of the visit 
EOT and ET EOT 
≤ 7 days after stopping study treatment for EOT 
30-Day Safety Follow-Up Period (FUP)  
+7 days 
Survival FUP 
± 14 days 
Laboratory assessments performed as part of the screening evaluations will not be required to be repeated on 
the first day of dosing (Cycle 1 Day 1) (except hematology/chemistry, serum pregnancy test, ECG* and 
ECHO/MUGA, if not done within 15 days prior to treatment start) unless deemed clinically necessary by the 
investigator and/or required as per local institutional policies. 
* ECG for run-in part will be required to be repeated at screening and at C1D1 due to multiple ECGs required 
at C1D1. 
Every effort must be made to follow the schedule of assessments (Table 8-2 and Table 8-3) within the windows 
outlined in Table 8-1 or as close to the designated day/time as possible. If a given visit is out of window, the 
next visit should be performed with reference to the day of first dose in order to get the participant back on 
schedule. If an off-schedule imaging assessment is performed, subsequent imaging assessments should be 
performed in accordance with the original imaging schedule. 


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Table 8-2 
Assessment Schedule, Part 1 
Period 
Screening 
Treatment: Capmatinib and osimertinib  
EOT 
Follow-up 
Cycle 
 
Cycle 1 (Cycle 1) 
Cycle 2 (Cycle 2 and beyond)  
 
Visit Name 
Molecular 
pre-
screening 
Screening 
Cycle 1 Day 1 
Cycle 
1 Day 
2 
Cycle 1 
Day 15 Cycle 2 and beyond 
EOT 
30-
Day 
Safety 
FUP 
Tumor and 
PROs FUP 
End of 
post 
treatment 
FUP 
Visit Numbers1 
1 
20 
110 
120 
130 
140 
150 
160 
170 
180 
Days 
- 
-28 to -1 
Day 1 
2 
Day 15 Day 1 
- 
- 
- 
- 
Informed consent for 
molecular pre-
screening 
X 
  
  
  
  
  
  
  
  
  
Informed consent for 
treatment beyond 
progression 
 
 
X (participants who meet the criteria outlined in Section 6.1.5.1) 
 
 
 
 


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Period 
Screening 
Treatment: Capmatinib and osimertinib  
EOT 
Follow-up 
Cycle 
 
Cycle 1 (Cycle 1) 
Cycle 2 (Cycle 2 and beyond)  
 
Visit Name 
Molecular 
pre-
screening 
Screening 
Cycle 1 Day 1 
Cycle 
1 Day 
2 
Cycle 1 
Day 15 Cycle 2 and beyond 
EOT 
30-
Day 
Safety 
FUP 
Tumor and 
PROs FUP 
End of 
post 
treatment 
FUP 
Visit Numbers1 
1 
20 
110 
120 
130 
140 
150 
160 
170 
180 
Days 
- 
-28 to -1 
Day 1 
2 
Day 15 Day 1 
- 
- 
- 
- 
IRT pre-screening 
registration 
X 
 
 
 
 
 
 
  
  
  
Inclusion / Exclusion 
criteria 
X 
X 
 
 
 
 
 
  
  
  
IRT eligibility check 
 
S 
 
 
 
 
 
  
  
  
IRT registration 
 
X 
X 
 
 
X 
X 
  
  
  
Main informed consent 
 
X 
 
 
 
 
 
  
  
  
Demography 
X 
 
 
 
 
 
 
  
  
  
Medical history/current 
medical conditions 
 
X 
  
  
  
  
  
  
  
  
Diagnosis and stage 
of cancer 
X 
 
  
  
  
  
  
  
  
  
Smoking history 
 
X 
  
  
  
  
  
  
  
  
Prior antineoplastic 
therapy (meds, 
surgery, radiation) 
 
X 
  
  
  
  
  
  
  
  


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Period 
Screening 
Treatment: Capmatinib and osimertinib  
EOT 
Follow-up 
Cycle 
 
Cycle 1 (Cycle 1) 
Cycle 2 (Cycle 2 and beyond)  
 
Visit Name 
Molecular 
pre-
screening 
Screening 
Cycle 1 Day 1 
Cycle 
1 Day 
2 
Cycle 1 
Day 15 Cycle 2 and beyond 
EOT 
30-
Day 
Safety 
FUP 
Tumor and 
PROs FUP 
End of 
post 
treatment 
FUP 
Visit Numbers1 
1 
20 
110 
120 
130 
140 
150 
160 
170 
180 
Days 
- 
-28 to -1 
Day 1 
2 
Day 15 Day 1 
- 
- 
- 
- 
Prior/concomitant 
medications 
  
Continuously from 28 days prior to first dose until 30 days after last dose of study treatment 
  
  
Physical examination, 
including neurological 
exams 
  
S 
As clinically indicated 
  
  
  
Targeted physical 
examination 
  
 
S 
 
S 
S 
S 
  
  
  
ECOG performance 
status 
  
X 
X 
 
 
X 
X 
  
  
  
Body Height 
  
X 
 
 
 
 
 
  
  
  
Body Weight 
  
X 
X 
 
X 
X 
X 
  
  
  
Vital Signs 
  
X 
X 
 
X 
X 
X 
  
  
  
HIV history (HIV 
testing where locally 
required) 
  
S 
 
 
 
 
 
  
  
  
Hematology3 
  
X (≤ 72 hr 
before 
C1D1) 
X 
 
X 
X 
X 
  
  
  
Clinical chemistry3 
  
X (≤ 72 hr 
before 
C1D1) 
X 
 
X 
X 
X 
  
  
  
Coagulation panel3 
  
X (≤ 72 hr 
before 
C1D1) 
As clinically indicated 
  
  
  
Urinalysis (dipstick)3 
  
X 
As clinically indicated 
  
  
  
Pregnancy Test 
(serum) 
  
S (≤ 72 hr 
before 
C1D1) 
  
  
  
 
S 
  
  
  


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Period 
Screening 
Treatment: Capmatinib and osimertinib  
EOT 
Follow-up 
Cycle 
 
Cycle 1 (Cycle 1) 
Cycle 2 (Cycle 2 and beyond)  
 
Visit Name 
Molecular 
pre-
screening 
Screening 
Cycle 1 Day 1 
Cycle 
1 Day 
2 
Cycle 1 
Day 15 Cycle 2 and beyond 
EOT 
30-
Day 
Safety 
FUP 
Tumor and 
PROs FUP 
End of 
post 
treatment 
FUP 
Visit Numbers1 
1 
20 
110 
120 
130 
140 
150 
160 
170 
180 
Days 
- 
-28 to -1 
Day 1 
2 
Day 15 Day 1 
- 
- 
- 
- 
Pregnancy test (urine)   
  
 
  
  
S 
  
  
  
  
CT or MRI Chest and 
Abdomen  
 
X 
  
  
  
X Starting at cycle 3 day 1 and 
then every 6 weeks (+/- 7 
days) for the first 18 months 
after C1D1, then every 12 
weeks (+/- 7 days) until PD 
determined using RECIST 1.1 
by local investigator  
X EOT scan 
not required if 
previous scan 
was 
performed ≤ 
28 days 
  
X 
  
Brain CT or MRI 
 
X 
  
  
  
X If brain lesion is present at 
screening, follow the same 
schedule as CT/MRI of the 
chest and abdomen. 
Otherwise, only as clinically 
indicated.  
 X EOT scan 
not required if 
previous scan 
was 
performed ≤ 
28 days 
  
X If brain 
lesion is 
present at 
screening, 
follow the 
same 
schedule as 
CT/MRI of 
the chest 
and 
abdomen. 
Otherwise, 
only as 
clinically 
indicated.  
  


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Period 
Screening 
Treatment: Capmatinib and osimertinib  
EOT 
Follow-up 
Cycle 
 
Cycle 1 (Cycle 1) 
Cycle 2 (Cycle 2 and beyond)  
 
Visit Name 
Molecular 
pre-
screening 
Screening 
Cycle 1 Day 1 
Cycle 
1 Day 
2 
Cycle 1 
Day 15 Cycle 2 and beyond 
EOT 
30-
Day 
Safety 
FUP 
Tumor and 
PROs FUP 
End of 
post 
treatment 
FUP 
Visit Numbers1 
1 
20 
110 
120 
130 
140 
150 
160 
170 
180 
Days 
- 
-28 to -1 
Day 1 
2 
Day 15 Day 1 
- 
- 
- 
- 
CT or MRI of other 
metastatic sites (e.g., 
neck) 
  
X (mandated 
for any 
metastatic 
sites not 
captured by 
CT/MRI of 
chest, 
abdomen, 
and brain) 
  
  
  
X If lesion is present at 
screening, follow the same 
schedule as CT/MRI of the 
chest and abdomen. 
Otherwise, only as clinically 
indicated.  
X EOT scan 
not required if 
previous scan 
was 
performed ≤ 
28 days 
  
X If lesion is 
present at 
screening, 
follow the 
same 
schedule as 
CT/MRI of 
the chest 
and 
abdomen. 
Otherwise, 
only as 
clinically 
indicated 
  
CT or MRI Pelvis 
  
X 
  
  
  
X If pelvic lesion present at 
screening, follow the same 
schedule as CT/MRI of the 
chest and abdomen. 
Otherwise, only as clinically 
indicated.  
X EOT scan 
not required if 
previous scan 
was 
performed ≤ 
28 days 
  
X If pelvic 
lesion 
present at 
screening, 
follow the 
same 
schedule as 
CT/MRI of 
the chest 
and 
abdomen. 
Otherwise, 
only as 
clinically 
indicated.  
  
Whole Body Bone 
scan  
  
X 
If clinically indicated 
  
If clinically 
indicated 
  


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Period 
Screening 
Treatment: Capmatinib and osimertinib  
EOT 
Follow-up 
Cycle 
 
Cycle 1 (Cycle 1) 
Cycle 2 (Cycle 2 and beyond)  
 
Visit Name 
Molecular 
pre-
screening 
Screening 
Cycle 1 Day 1 
Cycle 
1 Day 
2 
Cycle 1 
Day 15 Cycle 2 and beyond 
EOT 
30-
Day 
Safety 
FUP 
Tumor and 
PROs FUP 
End of 
post 
treatment 
FUP 
Visit Numbers1 
1 
20 
110 
120 
130 
140 
150 
160 
170 
180 
Days 
- 
-28 to -1 
Day 1 
2 
Day 15 Day 1 
- 
- 
- 
- 
Localized Bone X-
Ray, CT or MRI 
  
X For 
skeletal 
abnormalities 
identified by 
bone scan at 
screening 
  
  
  
X If skeletal abnormalities 
present at screening, follow the 
same schedule as CT/MRI of 
the chest and abdomen. 
Otherwise, only as clinically 
indicated 
X EOT scan 
not required if 
previous scan 
was 
performed ≤ 
28 days 
  
X If skeletal 
abnormalities 
present at 
screening, 
follow the 
same 
schedule as 
CT/MRI of 
the chest 
and 
abdomen. 
Otherwise, 
only as 
clinically 
indicated 
  
Skin Color 
Photography  
  
X If skin 
lesions are 
present  
  
  
  
X If skin lesion present at 
screening, follow the same 
schedule as CT/MRI of the 
chest and abdomen. 
Otherwise, only as clinically 
indicated 
X EOT scan 
not required if 
previous scan 
was 
performed ≤ 
28 days 
  
X If skin 
lesion 
present at 
screening, 
follow the 
same 
schedule as 
CT/MRI of 
the chest 
and 
abdomen. 
Otherwise, 
only as 
clinically 
indicated 
  


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Page 111 of 235 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CINC280L12301 
 
 
Period 
Screening 
Treatment: Capmatinib and osimertinib  
EOT 
Follow-up 
Cycle 
 
Cycle 1 (Cycle 1) 
Cycle 2 (Cycle 2 and beyond)  
 
Visit Name 
Molecular 
pre-
screening 
Screening 
Cycle 1 Day 1 
Cycle 
1 Day 
2 
Cycle 1 
Day 15 Cycle 2 and beyond 
EOT 
30-
Day 
Safety 
FUP 
Tumor and 
PROs FUP 
End of 
post 
treatment 
FUP 
Visit Numbers1 
1 
20 
110 
120 
130 
140 
150 
160 
170 
180 
Days 
- 
-28 to -1 
Day 1 
2 
Day 15 Day 1 
- 
- 
- 
- 
Electrocardiogram 
(ECG)4 
  
X (≤72 hr 
before 
C1D1) 
X (multiple time 
points) 
  
X 
(multiple 
time 
points) 
X At C4D1 (2 time points) and 
then if clinically indicated  
X 
  
  
  
Cardiac imaging 
(MUGA or ECHO)  
  
X (≤15 days 
before 
C1D1) 
  
  
  
X At C4D1 and then if clinically 
indicated 
X 
  
  
  
Adverse Events 
  
X Continuously from signing of main ICF until 30 days after last dose of study treatment 
  
  
Serious Adverse 
Events 
X 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 
X SAEs related to study 
treatment unless 
otherwise specified by 
local law/regulations 
Capmatinib and 
Osimertinib 
administration 
  
  
X Capmatinib continuous twice daily dosing [b.i.d.] and Osimertinib 
continuous once daily dosing [q.d.] 
  
  
  
  
food consumption5 
  
  
X 
 
X 
  
  
  
  
  
PK blood collection 
(full PK) 
  
  
X (multiple time 
points) 
X 
(one 
time 
point) 
X 
(multiple 
time 
points) 
  
  
  
  
  
PK blood collection 
(Sparse PK) 
  
  
  
  
  
X (at C3D1 then C4D1 and 
C6D1 only). Note: for 
osimertinib at C4D1, two time 
points will be collected 
  
  
  
  
Antineoplastic 
therapies (meds, 
surgery, radiation) 
since discontinuation 
of study drug 
  
  
  
  
  
  
X 
X 
X 
X 
Disposition 
  
X 
 
 
 
 
X 
 
 
X 


Novartis 
 
Confidential 
Page 112 of 235 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CINC280L12301 
 
 
Period 
Screening 
Treatment: Capmatinib and osimertinib  
EOT 
Follow-up 
Cycle 
 
Cycle 1 (Cycle 1) 
Cycle 2 (Cycle 2 and beyond)  
 
Visit Name 
Molecular 
pre-
screening 
Screening 
Cycle 1 Day 1 
Cycle 
1 Day 
2 
Cycle 1 
Day 15 Cycle 2 and beyond 
EOT 
30-
Day 
Safety 
FUP 
Tumor and 
PROs FUP 
End of 
post 
treatment 
FUP 
Visit Numbers1 
1 
20 
110 
120 
130 
140 
150 
160 
170 
180 
Days 
- 
-28 to -1 
Day 1 
2 
Day 15 Day 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 Visit structure given for internal programming purpose only 
 
  
3 By local laboratory 
4 Central ECGs 
5 Capture information of whether capmatinib was administered with or without food.  
 
 


Novartis 
 
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Page 113 of 235 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CINC280L12301 
 
 
Table 8-3 
Assessment Schedule, Part 2 
Period 
Screening 
Treatment: Both arms: 1- 
capmatinib and osimertinib 
arm and 2- platinum-
pemetrexed based doublet 
chemotherapy arm 
EOT 
Extension Treatment (ET) 
for platinum-pemetrexed 
based doublet 
chemotherapy participants 
who crossover to receive 
capmatinib+osimertinib  
ET EOT Follow-up 
Cycle 
 
Cycle 1 
Cycle 2 (and 
beyond) 
 
Cycle 1 
Cycle 2 (and 
beyond) 
 
 
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 
FUP 
Tumor 
and 
PROs 
FUP 
End of 
post 
treatment 
FUP 
Survival 
FUP 
Visit Numbers1 
1 
20 
110 
120 
130 
140 
150 
160 
170 
180 
190 
200 
210 
Days 
- 
-28 to -1 
Day 1 
Day 15 
Day 1 
- 
Day 1 
Day 1 
- 
- 
- 
- 
Every 
12 
weeks 
Informed 
consent for 
molecular pre-
screening 
X 
 
 
 
 
 
 
 
 
  
  
  
  


Novartis 
 
Confidential 
Page 114 of 235 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CINC280L12301 
 
 
Period 
Screening 
Treatment: Both arms: 1- 
capmatinib and osimertinib 
arm and 2- platinum-
pemetrexed based doublet 
chemotherapy arm 
EOT 
Extension Treatment (ET) 
for platinum-pemetrexed 
based doublet 
chemotherapy participants 
who crossover to receive 
capmatinib+osimertinib  
ET EOT Follow-up 


Novartis 
 
Confidential 
Page 115 of 235 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CINC280L12301 
 
 
Period 
Screening 
Treatment: Both arms: 1- 
capmatinib and osimertinib 
arm and 2- platinum-
pemetrexed based doublet 
chemotherapy arm 
EOT 
Extension Treatment (ET) 
for platinum-pemetrexed 
based doublet 
chemotherapy participants 
who crossover to receive 
capmatinib+osimertinib  
ET EOT Follow-up 
IRT pre-
screening 
registration 
X 
 
 
 
 
 
 
 
 
  
  
  
  
Inclusion / 
Exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
  
  
  
  
IRT eligibility 
check 
 
S 
 
 
 
 
 
 
 
  
  
  
  
IRT registration 
 
X 
X 
 
X 
X 
X 
X 
X 
  
  
  
  
Main informed 
consent14  
 
X 
 
 
 
 
 
 
 
  
  
  
  
Informed 
consent for 
treatment 
beyond 
progression 
 
 
 
X (Participants who meet the 
criteria outlined in Section 
6.1.5.1) 
 
 
X (Participants who meet the 
criteria outlined in Section 
6.1.5.1) 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
  
  
  
  


Novartis 
 
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Page 116 of 235 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CINC280L12301 
 
 
Period 
Screening 
Treatment: Both arms: 1- 
capmatinib and osimertinib 
arm and 2- platinum-
pemetrexed based doublet 
chemotherapy arm 
EOT 
Extension Treatment (ET) 
for platinum-pemetrexed 
based doublet 
chemotherapy participants 
who crossover to receive 
capmatinib+osimertinib  
ET EOT Follow-up 
Medical 
history/current 
medical 
conditions 
 
X 
 
 
 
 
 
 
 
  
  
  
  
Diagnosis and 
stage of cancer 
X 
 
 
 
 
 
 
 
 
  
  
  
  
Smoking history 
 
X 
 
 
 
 
 
 
 
  
  
  
  
Prior 
antineoplastic 
therapy (meds, 
surgery, 
radiation) 
 
X 
 
 
 
 
 
 
 
  
  
  
  
Prior/concomita
nt medications 
 
X Continuously from 28 days prior to first dose until 30 days after last dose of study treatment 
 
X3,4 
  
  
IRT 
randomization 
 
 
X 
 
 
 
 
 
 
  
  
  
  
Physical 
examination, 
including 
neurological 
exams 
 
S 
As clinically indicated 
  
  
  
  
Targeted 
physical 
examination 
 
 
S 
S 
S 
S 
S 
S 
S 
  
  
  
  
ECOG 
performance 
status 
 
X 
X 
 
X 
X 
X 
X 
X 
  
X3 
  
  
Body Height 
 
X 
 
 
 
 
 
 
 
  
  
  
  
Body Weight 
 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
Vital Signs 
 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  


Novartis 
 
Confidential 
Page 117 of 235 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CINC280L12301 
 
 
Period 
Screening 
Treatment: Both arms: 1- 
capmatinib and osimertinib 
arm and 2- platinum-
pemetrexed based doublet 
chemotherapy arm 
EOT 
Extension Treatment (ET) 
for platinum-pemetrexed 
based doublet 
chemotherapy participants 
who crossover to receive 
capmatinib+osimertinib  
ET EOT Follow-up 
HIV history (HIV 
testing where 
locally required) 
 
S 
 
 
 
 
 
 
 
  
  
  
  
Hematology5 
 
X (≤ 72 hr 
before 
C1D1) 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
Clinical 
chemistry5 
 
X (≤ 72 hr 
before 
C1D1) 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
Coagulation 
panel5 
 
X (≤ 72 hr 
before 
C1D1) 
As clinically indicated 
  
  
  
  
Urinalysis 
(dipstick)6 
 
X 
As clinically indicated 
  
  
  
  
Pregnancy Test 
(serum) 
 
S (≤ 72 hr 
before 
C1D1) 
 
 
 
S 
 
 
S 
  
  
  
  
Pregnancy test 
(urine) 
 
 
 
 
S 
 
 
S 
 
  
  
  
  


Novartis 
 
Confidential 
Page 118 of 235 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CINC280L12301 
 
 
Period 
Screening 
Treatment: Both arms: 1- 
capmatinib and osimertinib 
arm and 2- platinum-
pemetrexed based doublet 
chemotherapy arm 
EOT 
Extension Treatment (ET) 
for platinum-pemetrexed 
based doublet 
chemotherapy participants 
who crossover to receive 
capmatinib+osimertinib  
ET EOT Follow-up 
CT or MRI chest 
and abdomen  
 
X 
 
 
X Starting at 
C3D1 every 6 
weeks (+/- 7 
days) for the 
first 18 
months after 
C1D1, then 
every 12 
weeks (+/- 7 
days) 
thereafter until 
PD 
determined 
using RECIST 
1.1 by local 
investigator 
and confirmed 
by BIRC 
X EOT 
scan not 
required if 
previous 
scan was 
performe
d ≤ 28 
days 
 
 
 
  
X 
  
  


Novartis 
 
Confidential 
Page 119 of 235 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CINC280L12301 
 
 
Period 
Screening 
Treatment: Both arms: 1- 
capmatinib and osimertinib 
arm and 2- platinum-
pemetrexed based doublet 
chemotherapy arm 
EOT 
Extension Treatment (ET) 
for platinum-pemetrexed 
based doublet 
chemotherapy participants 
who crossover to receive 
capmatinib+osimertinib  
ET EOT Follow-up 
Brain CT or MRI 
 
X 
 
 
X If brain 
lesion is 
present at 
screening, 
follow the 
same 
schedule as 
CT/MRI of the 
chest and 
abdomen. 
Otherwise, 
only as 
clinically 
indicated. 
X EOT 
scan not 
required if 
previous 
scan was 
performe
d ≤ 28 
days 
 
 
 
  
X If 
brain 
lesion 
is 
present 
at 
screeni
ng, 
follow 
the 
same 
schedul
e as 
CT/MRI 
of the 
chest 
and 
abdom
en. 
Otherwi
se, only 
as 
clinicall
y 
indicate
d.  
  
  


Novartis 
 
Confidential 
Page 120 of 235 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CINC280L12301 
 
 
Period 
Screening 
Treatment: Both arms: 1- 
capmatinib and osimertinib 
arm and 2- platinum-
pemetrexed based doublet 
chemotherapy arm 
EOT 
Extension Treatment (ET) 
for platinum-pemetrexed 
based doublet 
chemotherapy participants 
who crossover to receive 
capmatinib+osimertinib  
ET EOT Follow-up 
CT or MRI of 
other metastatic 
sites (e.g., neck) 
 
X 
(mandated 
for any 
metastatic 
sites not 
captured 
by CT/MRI 
of chest, 
abdomen, 
and brain) 
 
 
X If lesion is 
present at 
screening, 
follow the 
same 
schedule as 
CT/MRI of the 
chest and 
abdomen. 
Otherwise, 
only as 
clinically 
indicated. 
X EOT 
scan not 
required if 
previous 
scan was 
performe
d ≤ 28 
days 
 
 
 
  
 X If 
lesion 
is 
present 
at 
screeni
ng, 
follow 
the 
same 
schedul
e as 
CT/MRI 
of the 
chest 
and 
abdom
en. 
Otherwi
se, only 
as 
clinicall
y 
indicate
d. 
  
  


Novartis 
 
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Page 121 of 235 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CINC280L12301 
 
 
Period 
Screening 
Treatment: Both arms: 1- 
capmatinib and osimertinib 
arm and 2- platinum-
pemetrexed based doublet 
chemotherapy arm 
EOT 
Extension Treatment (ET) 
for platinum-pemetrexed 
based doublet 
chemotherapy participants 
who crossover to receive 
capmatinib+osimertinib  
ET EOT Follow-up 
CT or MRI 
Pelvis 
 
X 
 
 
X If pelvic 
lesion is 
present at 
screening, 
follow the 
same 
schedule as 
CT/MRI of the 
chest and 
abdomen. 
Otherwise, 
only as 
clinically 
indicated. 
X EOT 
scan not 
required if 
previous 
scan was 
performe
d ≤ 28 
days 
 
 
 
  
X If 
pelvic 
lesion 
is 
present 
at 
screeni
ng, 
follow 
the 
same 
schedul
e as 
CT/MRI 
of the 
chest 
and 
abdom
en. 
Otherwi
se, only 
as 
clinicall
y 
indicate
d. 
  
  
Whole body 
bone scan  
 
X 
If clinically indicated 
 
 
 
  
If 
clinicall
y 
indicate
d 
  
  
Localized Bone 
X-ray, CT or 
MRI 
 
X If 
skeletal 
abnormaliti
es 
 
 
X If skeletal 
abnormality is 
present at 
screening, 
X EOT 
scan not 
required if 
previous 
 
 
 
  
X If 
skeletal 
abnorm
ality is 
  
  


Novartis 
 
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Page 122 of 235 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CINC280L12301 
 
 
Period 
Screening 
Treatment: Both arms: 1- 
capmatinib and osimertinib 
arm and 2- platinum-
pemetrexed based doublet 
chemotherapy arm 
EOT 
Extension Treatment (ET) 
for platinum-pemetrexed 
based doublet 
chemotherapy participants 
who crossover to receive 
capmatinib+osimertinib  
ET EOT Follow-up 
identified 
by bone 
scan at 
screening 
follow the 
same 
schedule as 
CT/MRI of the 
chest and 
abdomen. 
Otherwise, 
only as 
clinically 
indicated. 
scan was 
performe
d ≤ 28 
days 
present 
at 
screeni
ng, 
follow 
the 
same 
schedul
e as 
CT/MRI 
of the 
chest 
and 
abdom
en. 
Otherwi
se, only 
as 
clinicall
y 
indicate
d. 


Novartis 
 
Confidential 
Page 123 of 235 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CINC280L12301 
 
 
Period 
Screening 
Treatment: Both arms: 1- 
capmatinib and osimertinib 
arm and 2- platinum-
pemetrexed based doublet 
chemotherapy arm 
EOT 
Extension Treatment (ET) 
for platinum-pemetrexed 
based doublet 
chemotherapy participants 
who crossover to receive 
capmatinib+osimertinib  
ET EOT Follow-up 
Skin color 
photography  
 
X If skin 
lesions at 
screening 
 
 
X If skin lesion 
is present at 
screening, 
follow the 
same 
schedule as 
CT/MRI of the 
chest and 
abdomen. 
Otherwise, 
only as 
clinically 
indicated. 
X EOT 
scan not 
required if 
previous 
scan was 
performe
d ≤ 28 
days 
 
 
 
  
X If 
skin 
lesion 
is 
present 
at 
screeni
ng, 
follow 
the 
same 
schedul
e as 
CT/MRI 
of the 
chest 
and 
abdom
en. 
Otherwi
se, only 
as 
clinicall
y 
indicate
d. 
  
  
Electrocardiogra
m (ECG)7 
 
X (≤72 hr 
before 
C1D1) 
 
 
X At C2D1 (2 
time points) 
and then if 
clinically 
indicated 
X 
 
X At C2D1 (2 
time points) 
and then if 
clinically 
indicated 
X 
  
  
  
  
Cardiac imaging 
(MUGA or 
ECHO) 7 
 
X (≤15 
days 
before 
C1D1) 
 
 
X At C4D1 
and then if 
clinically 
indicated 
X 
 
X At C4D1 
and then if 
clinically 
indicated 
X 
  
  
  
  


Novartis 
 
Confidential 
Page 124 of 235 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CINC280L12301 
 
 
Period 
Screening 
Treatment: Both arms: 1- 
capmatinib and osimertinib 
arm and 2- platinum-
pemetrexed based doublet 
chemotherapy arm 
EOT 
Extension Treatment (ET) 
for platinum-pemetrexed 
based doublet 
chemotherapy participants 
who crossover to receive 
capmatinib+osimertinib  
ET EOT Follow-up 
Adverse Events 
 
X Continuously from signing of main ICF until 30 days after last dose of study treatment 
  
  
  
Serious Adverse 
Events 
X 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 
X SAEs related to study 
treatment unless otherwise 
specified by local 
law/regulations 
PROs (EORTC 
QLQ-C30 and 
EORTC LC13)8 
 
 
X 
 
X Starting at 
C3D1 and 
then every 6 
weeks for the 
first 18 
months after 
C1D1, then 
every 12 
weeks 
thereafter until 
PD 
determined 
using RECIST 
1.1 by local 
investigator 
and confirmed 
by BIRC 
X (only if 
EOT is 
due to 
PD) 
 
 
 
 
 
 
 
X at 6, 12 
and 18 
weeks (+/- 7 
days) post 
progression 
from 
platinum – 
pemetrexed 
based 
doublet 
chemotherap
y treatment 13 
 
  
X (only 
if EOT 
is not 
due to 
PD) 
X (only if 
EOT is 
not due to 
PD) 
X For all 
participa
nts at 6, 
12 and 
18 
weeks 
(+/- 7 
days) 
post 
progress
ion13 


Novartis 
 
Confidential 
Page 125 of 235 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CINC280L12301 
 
 
Period 
Screening 
Treatment: Both arms: 1- 
capmatinib and osimertinib 
arm and 2- platinum-
pemetrexed based doublet 
chemotherapy arm 
EOT 
Extension Treatment (ET) 
for platinum-pemetrexed 
based doublet 
chemotherapy participants 
who crossover to receive 
capmatinib+osimertinib  
ET EOT Follow-up 
PROs (NCCN 
Fact Brain 
Symptom Index 
and EQ-5D-5L)8 
 
 
X 
 
X Starting at 
C2D1 and 
then every 6 
weeks for the 
first 18 
months after 
C1D1, then 
every 12 
weeks 
thereafter until 
PD 
determined 
using RECIST 
1.1 by local 
investigator 
and confirmed 
by BIRC 
X (only if 
EOT is 
due to 
PD) 
 
 
 
 
 
 
 
X Optional at 
6, 12 and 18 
weeks (+/- 7 
days) post 
progression 
from 
platinum – 
pemetrexed 
based 
doublet 
chemotherap
y treatment 13 
 
  
X (only 
if EOT 
is not 
due to 
PD) 
X (only if 
EOT is 
not due to 
PD) 
Optional 
for all 
participa
nts at 6, 
12 and 
18 
weeks 
(+/- 7 
days) 
post 
progress
ion13 
Capmatinib and 
Osimertinib 
administration 
(arm 1 and ET) 
 
 
X Capmatinib continuous twice 
daily dosing [b.i.d.] and 
Osimertinib continuous once daily 
dosing [q.d.] 
 
X Capmatinib continuous 
twice daily dosing [b.i.d.] and 
Osimertinib continuous once 
daily dosing [q.d.] 
 
  
  
  
  
Platinum-
pemetrexed 
based doublet 
Chemotherapy 
(arm 2)  
 
 
X 
 
X Day 1 for 
every cycle 9 
 
 
 
 
  
  
  
  
food 
consumption10 
 
 
 
 
X (for C2D1 
only) 
 
 
 
 
  
  
  
  


Novartis 
 
Confidential 
Page 126 of 235 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CINC280L12301 
 
 
Period 
Screening 
Treatment: Both arms: 1- 
capmatinib and osimertinib 
arm and 2- platinum-
pemetrexed based doublet 
chemotherapy arm 
EOT 
Extension Treatment (ET) 
for platinum-pemetrexed 
based doublet 
chemotherapy participants 
who crossover to receive 
capmatinib+osimertinib  
ET EOT Follow-up 
PK blood 
collection - 
capmatinib + 
osimertinib arm 
 
 
X (Pre-
dose 
samples
) 
 
X pre-dose 
samples 
(starting at 
C2D1 then on 
C3D1, C4D1 
and C6D1 
only). Note: 
for C2D1, 
three time 
points will be 
collected for 
capmatinib 
and 
osimertinib 
separately (1 
pre-dose and 
2 post-dose) 
 
 
 
 
  
  
  
  
Antineoplastic 
therapies (meds, 
surgery, 
radiation) since 
discontinuation 
of study drug 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
Disposition 
 
X 
 
 
 
X 
 
 
X 
  
  
X 
  
Survival 
(survival 
information can 
be obtained via 
telephone 
contact) 
 
 
 
 
 
 
 
 
 
  
  
  
X 
Trial Feedback 
Questionnaire11 
 
 
S 
 
S (at Cycle 4 
Day 1 only) 
S 
 
 
 
  
  
  
  


Novartis 
 
Confidential 
Page 127 of 235 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CINC280L12301 
 
 
Period 
Screening 
Treatment: Both arms: 1- 
capmatinib and osimertinib 
arm and 2- platinum-
pemetrexed based doublet 
chemotherapy arm 
EOT 
Extension Treatment (ET) 
for platinum-pemetrexed 
based doublet 
chemotherapy participants 
who crossover to receive 
capmatinib+osimertinib  
ET EOT Follow-up 
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 Visit structure given for internal programming purpose only 
 
 
3 Only for participants with brain metastases at baseline 
4 Steroids collection only  
5 By Central laboratory for treatment arms 1 and 2 (except for China: local laboratory allowed); by local laboratory for ET 
6 Optional assessment for China only 
7 Central ECGs and Cardiac Imaging: applicable for all participants at screening and if clinically indicated. ECGs at C2D1 and Cardiac Imaging at C4D1 and EOT are 
applicable only for participants randomized into capmatinib + osimertinib arm (including ET phase). For ET, an uscheduled ECG will be used as baseline ECG. 
8 During treatment and efficacy follow-up period, questionnaires could be performed either at home on own patient device (within 3 days before the scheduled visit) or on 
site on the day of the scheduled visit before performance of any assessment. For post-progression timepoints, for participant who might not return to the clinic, PRO 
completion can be done either at home on own patient device, or by interview (refer to Section 8.5.1) 
9 Participants whose disease has not progressed after four cycles of platinum-based chemotherapy may receive pemetrexed monotherapy maintenance therapy 
(pemetrexed 500 mg/m2 on Day 1 of every 21 days cycle).  
10 Capture information of whether capmatinib was administered with or without food.  
11 The trial feedback questionnaires are optional. 
 
 
 
 
 
 
 
13 For participants who crossed over to ET, PROs will be collected only post – platinum – pemetrexed based doublet chemotherapy progression. These assessments do 
not have to be performed during survival follow-up if done during ET. 
14 Participants who crossover to ET must be consented under ICF related to Protocol Amendment 02 


Novartis 
Confidential 
Page 128 of 235 
Amended Protocol Version 02 (Clean) 
 
Protocol No. CINC280L12301 
 
 
8.1 
Screening 
Molecular Pre-screening 
In order to be considered eligible for the study, participants must have written documentation 
of EGFR activating mutation and, for participants previously treated with 1st or 2nd generation 
EGFR TKIs, or other 3rd generation EGFR TKI other than osimertinib, must also have tissue 
EGFR T790M negative test results (see Section 5.1). The results from CLIA-certified USA 
laboratory or an accredited local laboratory for sites outside of the USA, using a validated test, 
according to local regulations (prior to enrolling in the trial) will satisfy the EGFR status-related 
inclusion criteria. For the randomized part, if T790M testing is not available locally, a tissue-
based confirmation of negative T790M status at the Novartis-designated central laboratory for 
patients who have progressed on 1st or 2nd generation EGFR TKI or 3rd generation EGFR TKI 
other than osimertinib will be needed. In this case, the tumor and blood samples are collected 
for central T790M testing and should be indicated in the appropriate eCRF and requisition 
forms.  
A blood T790M negative test result is not required for eligibility; however participants with 
known T790M positive tissue or blood status are excluded from the study. 
Participants previously treated with osimertinib do not require mandatory confirmation of 
EGFR T790M negative status, however participants with known T790M positive status are 
excluded from the study. 
Part 1 
For run-in part, participants must be enrolled based on local result for MET amplification status 
by either tissue or blood. A tumor tissue biopsy and a blood sample will need to be sent for 
retrospective analysis and may also be used toward the development of an in vitro diagnostic 
test, such as a companion diagnostic. 
Part 2 
For the randomized part, eligible participants must have MET amplification confirmed by a 
Novartis designated central laboratory prior to randomization. MET amplification will be 
identified using a central FISH test that detects MET amplification via Deoxyribonucleic Acid 
(DNA) derived from formalin fixed, paraffin-embedded human tissue. The central MET 
amplification test is investigational and is being clinically validated for selecting patients most 
likely to benefit from capmatinib as a part of this study. The test is sufficiently validated for the 
purposes of selecting participants with MET amplification in their NSCLC tumor sample. 
If a participant's MET amplification status is known via a local result by tissue or blood, 
participant may commence screening following signature of the main ICF. However, 
confirmation by a Novartis-designated central laboratory is required to confirm eligibility prior 
to randomization. The pre-screening results from central testing for all tested participants 
(whether the participant is eligible or not for the study) will be communicated to the respective 
study center by the Novartis-designated central laboratory.  
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The biopsy sample for MET amplification testing should be performed during or after disease 
progression on prior EGFR TKI therapy is observed (either clinically or radiologically). MET 
testing may be performed while participants are still receiving anti-cancer therapy as long as 
progression on prior EGFR TKI therapy was observed prior to biopsy. The participant can only 
start study therapy once he/she has discontinued the last prior systemic treatment due to disease 
progression, as specified in Section 5.2.  
All participants will be asked to sign and date an IRB/ IEC approved “Molecular pre-screening 
informed consent form” before their tumor sample is sent for testing to the Novartis-designated 
central laboratory. A newly obtained tumor biopsy (preferred) or archival tumor tissue (block 
or slides) should be submitted for all participants to the Novartis-designated laboratory to test 
for MET amplification status and, where applicable in the randomized part only, for EGFR 
T790M testing. The archival tumor tissue must have been obtained after progression on prior 
line of EGFR TKI. If more than one archival tissue sample post EGFR TKI progression is 
available, tissue from the most recent biopsy is preferred. Samples obtained from bone 
metastases and cytology samples are not acceptable. Additionally, a blood sample (2 x 10 mL) 
will be collected at Pre-Screening for potential use towards the development of a liquid biopsy 
in vitro diagnostic test, such as a companion diagnostic. 
If a tumor block or newly obtained biopsy is provided, the remaining tissue from pre-screen or 
screen failure samples will be returned to the site. However, a small amount of any remaining 
tissue will be retained from all participants, under control of Novartis, to support the potential 
development of an in vitro diagnostic test(s), such as a companion diagnostic test(s) with a 
method such as NGS, FISH, or PCR. If the participant is enrolled, the remaining block will be 
sent to the Novartis-designated vendor. 
 
Additional tissue may be requested, retrospectively, if 
available, to support potential development of companion diagnostic test(s) if the remaining 
tissue sample is insufficient for analysis.  
 The sample collection information must be entered on the appropriate sample collection 
log eCRF page(s) and requisition form(s). Details on the collection, shipment of samples and 
reporting of results by the central laboratory are provided to investigators in a separate 
Laboratory Manual. 
Participants who crossover to capmatinib + osimertinib treatment do not have to re-confirm 
eligibility regarding their molecular testing. 
Main screening  
The study IRB/IEC approved informed consent form must be signed and dated before any 
screening procedures are performed, except for laboratory and radiological evaluations which 
were performed as part of the participant’s clinical standard of care within the acceptable 
screening window. 
Participants will be evaluated against study inclusion and exclusion criteria and safety 
assessments (refer to Table 8-2 and Table 8-3). Screening assessments must be repeated if 


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performed outside of the specified screening window (Table 8-1). Participants must meet all 
inclusion and none of the exclusion criteria at screening in order to be eligible for the study. 
Laboratory assessments performed as part of the screening evaluations will not be required to 
be repeated prior to dosing (except hematology/chemistry and serum pregnancy test if not done 
within 72 hours prior to treatment start) unless deemed clinically necessary by the investigator 
and/or required as per local institutional policies. Laboratory test result(s) or symptoms that do 
not satisfy the eligibility criteria may be repeated or treated during the screening visit window. 
In the event that the repeated laboratory test(s) cannot be performed within 28 days from the 
original screening visit, or do not meet the eligibility criteria, or other eligibility criteria have 
changed and are not met anymore, the participant is considered a screening failure. 
Re-screening of a participant who has failed screening may be allowed. In such cases, a new 
ICF must be signed. A new participant number will be assigned to the participant. 
All required screening assessments must be repeated if they do not meet the allowed time 
window for screening when the participant is re-screened for participation in the study. Samples 
already collected for pre-screening visit are not required to be re-collected in case of re-
screening. An individual participant can only be re-screened once for the study. 
Once the number of participants screened and enrolled is likely to ensure target enrollment, the 
Sponsor may close the study to further screening. In this case, the participants who screen failed 
will not be permitted to re-screen. 
Participants who are screened and eligibility confirmed in IRT system, but fail to start treatment, 
e.g., participants confirmed in IRT in error, will be considered as early terminations. The reason 
for early termination should be recorded on the appropriate eCRF. 
8.1.1 
Eligibility screening 
When all screening procedures are completed and once the participant’s eligibility has been 
checked and confirmed (i.e., all inclusion/exclusion criteria have been verified), the key 
eligibility criteria checklist will be completed prior to the first dose of study treatment in the 
IRT system by the investigator or designee. The eligibility check will be embedded in the IRT 
system. Please refer to Section 6.3.2 for further details on treatment assignment/randomization 
as well as comply with detailed guidelines in the IRT manual. 
8.1.2 
Information to be collected on screening failures 
Both participants who sign a molecular pre-screening informed consent form but are a 
molecular pre-screening failure, as well as participants who sign the main informed consent 
form and subsequently found to be ineligible prior to randomization will be considered a screen 
failure and data will be handled in the same manner. The reason for screen failure should be 
recorded on the appropriate eCRF page. 
The following eCRF pages must be completed for screening failure 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) 


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• 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 serious adverse event (SAE) during the screening phase 
(see SAE section for reporting details). For molecular pre-screening failures, only SAEs 
possibly related to a study procedure will be reported (i.e., tumor biopsy collection) will be 
reported to the Novartis Safety group. 
The IRT must be notified within 2 days of the screen fail. 
For Run-in Part: participants who sign an informed consent and are considered eligible but fail 
to be started on treatment for any reason will be considered an early terminator. The reason for 
early termination should be captured on the appropriate disposition eCRF. 
For Randomized Part 2: participants who are randomized and fail to start treatment, i.e., 
participants randomized in error, will be considered an early terminator. The reason for early 
termination should be recorded on the appropriate eCRF. 
8.2 
Participant demographics/other baseline characteristics 
Data to be collected on participant characteristics at screening include: 
• Demography 
(age, 
gender, 
race 
and 
ethnicity, 
or 
as 
allowed 
by 
local 
regulations). Participant race and ethnicity are collected and analyzed to identify variations 
in safety or efficacy due to these factors as well as to assess the diversity of the study 
population as required by Health Authorities  
• Other background or relevant medical history (including smoking history) / 
(serious) adverse events 
• Cancer characteristics including diagnosis, history, extent of cancer, baseline 
tumor mutation / amplification / protein expression status (EGFR, T790M, MET and PD-
L1), prior antineoplastic therapies (medications, radiation, surgeries), and date of 
progression prior to study entry 
• Tumor imaging assessments 
• Other assessments to be completed for the purpose of determining eligibility (ECOG 
PS, complete physical examination, vital signs, hematology, blood chemistry, 
coagulation studies, urinalysis, HIV testing where locally required [only recorded in 
source documentation], serum pregnancy test for women of child-bearing potential 
[only recorded in source documentation], 12-Lead ECG and Cardiac Imaging) 


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• Prior and current concomitant medications and surgical and medical procedures 
Data to be collected on C1D1 pre-dose include: 
• Patient Reported Outcomes (PROs) (applicable only for randomized part). 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with the eCRF. 
8.3 
Efficacy 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, the collection of images (i.e., change of imaging center or imaging frequency) may be 
modified by Novartis and will be communicated to the investigator.  
8.3.1 
Tumor imaging assessment 
Participants should have at least one documented measurable lesion at study entry as per 
RECIST 1.1. The imaging assessment collection plan is presented in Table 8-4. 
For part 1 (run-in part): tumor response will be assessed locally only, according to the 
Novartis guideline version 3.2 (Section 16.1) based on RECIST 1.1 (Eisenhauer et al 2009). 
For part 2 (randomized part): tumor response will be assessed locally and centrally according 
to 
the 
Novartis 
guideline 
version 
3.2 
(Section 16.1) 
based 
on 
RECIST 
1.1 
(Eisenhauer et al 2009). In addition, CNS lesions will be assessed by BIRC based on Response 
Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria Novartis guidelines 
(Section 16.2). 
The central review of the scans will be carried out in a blinded fashion. Further details of the 
central review process will be described in the BIRC charter. 
Imaging data will be centrally collected and checked for quality by an imaging Contract 
Research Organization (CRO) designated by Novartis. The results of the central evaluations 
will be used for primary analysis and secondary analysis purposes of the randomized part. The 
local investigator’s assessment will be used for the supportive analysis and for treatment 
decision making. Details regarding collection and shipment of additional information required 
for imaging assessment including RANO-BM assessment by BIRC will be described in the 
imaging manual provided by the designated CRO. 
Table 8-4 
Imaging Assessment Collection Plan 
Procedure 
Screening/Baseline 
During Treatment/Follow-up 
Chest 
and 
abdomen 
CT 
or 
Magnetic Resonance Imaging MRI 
(with 
intravenous 
contrast 
enhancement) 
Mandated 
Mandated 
Starting at C3D1: every 6 weeks 
(+/- 7 days) for the first 18 months 
after C1D1, then every 12 weeks 
(+/- 
7 
days) 
thereafter 
until 
PD determined using RECIST 1.1 
by investigator (run-in part) or by 
investigator and confirmed by BIRC 
(randomized part) 


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Procedure 
Screening/Baseline 
During Treatment/Follow-up 
At End of Treatment if not done 
within 28 days. 
Post 
Treatment 
Follow-Up: 
participants with EOT reason other 
than 
disease 
progression, 
withdrawal of consent, opposition to 
use data or death will continue 
collect imaging and follow the same 
schedule of every 6 weeks (+/- 7 
days) for the first 18 months after 
C1D1, then every 12 weeks (+/- 7 
days) thereafter 
until 
PD determined 
using RECIST 
1.1 by investigator (run-in part) or 
by investigator and confirmed by 
BIRC (randomized part). 
Pelvis CT or MRI (with intravenous 
contrast enhancement) 
Mandated 
Only if lesions were documented at 
baseline or if clinically indicated; 
follow the same schedule as 
CT/MRI of chest and abdomen 
Brain CT or MRI (with intravenous 
contrast enhancement) 
Mandated 
Only if lesions were documented at 
baseline or if clinically indicated; 
follow the same schedule as 
CT/MRI of chest and abdomen. 
Whole body bone scan 
(Per institutional standard of care 
[e.g., Tc-99 bone scan, whole body 
bone 
MRI, 
Fluorodeoxyglucose 
positron emission 
tomography (FDG-PET) or sodium 
fluoride (NaF) PET]) 
Mandated 
If clinically indicated 
Localized bone CT, MRI, or x-ray 
Mandated for any lesions identified 
on the whole body bone scan that 
are not visible on the chest, 
abdomen and pelvis CT or MRI 
Only if lesions were documented at 
baseline or if clinically indicated; 
follow the same schedule as 
CT/MRI of chest and abdomen 
Skin 
color 
photography 
(with 
scale/ruler) 
Mandated for any skin lesions 
present 
Only if lesions were documented at 
baseline or if clinically indicated; 
follow the same schedule as 
CT/MRI of chest and abdomen 
CT or MRI of other metastatic sites 
(e.g., neck) 
If 
other 
metastatic 
sites 
are 
suspected 
Only if lesions were documented at 
baseline or if clinically indicated; 
follow the same schedule as 
CT/MRI of chest and abdomen 
8.3.1.1 
Baseline imaging assessment 
Imaging assessments will be performed at screening/baseline within 28 days of start of 
treatment (Day -28 to Day -1 prior to Cycle 1 Day 1) as per Table 8-2, Table 8-3 and Table 8-4. 
Any imaging assessments already completed during the regular work-up of the participant 
within 28 days prior to start of treatments for the whole body bone scan, including before 
signing the main study ICF, can be considered as the baseline images for this study. Any 
imaging assessments obtained after randomization cannot be considered baseline images. 


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If a participant is known to have a contraindication to CT intravenous (IV) contrast media or 
develops a contraindication during the trial, a non-contrast CT of the chest (MRI is not 
recommended due to respiratory artifacts; however, if CT is not feasible per local regulations, 
MRI can be performed instead) plus a contrast-enhanced MRI (if possible) of the abdomen and 
pelvis should be performed. 
Contrast enhanced brain MRI must be completed for all participants unless MRI contrast is 
contraindicated. If MRI contrast is contraindicated, then MRI without contrast or CT 
with/without contrast is acceptable. 
A whole body bone scan should be performed per institutional standard of care [i.e., Tc-99 bone 
scan, whole body bone MRI, Fluorodeoxyglucose positron emission tomography (FDG-PET), 
or sodium fluoride (NaF) PET]. Localized CT, MRI, or X-rays should be acquired for all 
skeletal lesions identified on the screening whole body bone scan, which are not visible on the 
chest, abdomen and pelvis CT/MRI. 
If clinically indicated, CT or MRI of other areas (i.e., neck) of disease as appropriate should be 
performed. 
If skin lesions are present at screening, color photography should be acquired using a digital 
camera in clear focus, including a scale/ruler, in such a way that the size of the lesion(s) can be 
determined from the photograph. 
Combined PET/CT may be used only if the CT is of similar diagnostic quality as a CT 
performed without PET, including the utilization of i.v. contrast media. At the discretion of the 
investigators, FDG-PET scans may be performed to document PD per RECIST 1.1 
(Section 16.1). 
Any potentially measurable lesion that has been previously treated with radiotherapy should be 
considered as a non-measurable lesion. However, if a lesion previously treated with 
radiotherapy has clearly progressed since the radiotherapy, it can be considered as a measurable 
lesion. 
Chest x-rays and ultrasound should not be used to measure tumor lesions. 
8.3.1.2 
Post-baseline imaging assessment 
Imaging assessments as described in Table 8-4 should be performed at the time points specified 
using the same imaging modality used at baseline, irrespective of study treatment interruption 
or actual dosing (see Table 8-1). Imaging assessments for response evaluation will be 
performed starting at C3D1 every 6 weeks (+/- 7 days) for the first 18 months after C1D1, then 
every 12 weeks (+/- 7 days) thereafter until disease progression, death, lost to follow-up, or 
withdrawal of consent/opposition to use data/biological samples. Imaging assessments should 
be scheduled using the date of first dose of study treatment as the reference date (not the date 
of the previous tumor assessment) and should be respected regardless of whether treatment with 
study treatment is temporarily withheld or unscheduled assessments performed. If an 
unscheduled imaging assessment is performed because progression is suspected, subsequent 
imaging assessments should be performed in accordance with the original imaging schedule. 
Additional imaging assessments may be performed at any time during the study at the 
investigator’s discretion to support the efficacy evaluations for a participant, as necessary. 


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Clinical suspicion of disease progression at any time requires a physical examination and 
imaging assessments to be performed promptly rather than waiting for the next scheduled 
imaging assessment. 
Each lesion that is measured at baseline must be measured by the same method (either same 
imaging method or by photography, including a metric ruler) and when possible, the same local 
radiologist/physician throughout the study so that the comparison is consistent. 
For the randomized part only: all study imaging (including any off-schedule study imaging) 
should be submitted to the designated imaging CRO for quality control and review by BIRC, 
promptly after acquisition. 
If participants start on a new antineoplastic therapy before documented progression, every effort 
should be made to continue to collect tumor assessment according to the planned schedule.  
8.3.1.3 
Confirmation of disease progression (for randomized part only) 
Time points at which progression is determined locally 
All participants who have disease progression determined by the local investigator require an 
expedited central review. Rapid image transmission to the imaging CRO may be accomplished 
by transferring the images electronically, e.g., via the Internet. In all instances, the process at 
the imaging CRO will ensure that the central reviewers remain blinded to the results of the local 
assessment and the expedited nature of the review. The investigator seeking an expedited review 
must indicate this request to the imaging CRO on a designated form or by alternative means. 
Further details of the central review process will be described in the BIRC charter.  
The imaging will undergo expedited central review (within 5 business days from the time of 
image receipt at the imaging CRO and once all applicable queries are resolved) and the results 
of the central review will be communicated to the site. While the investigator is awaiting the 
results of the central review, it is preferable that the participant continue on study treatment. 
However, during this time, the investigator should do whatever is medically necessary for 
his/her participant. 
If the central review determines disease progression, then the participant will discontinue study 
treatment and subsequent tumor assessments are no longer required (not applicable to treatment 
beyond disease progression. Refer to Section 6.1.5.1). 
If the central review does not determine disease progression, the participant should continue 
receiving the study treatment until disease progression has been determined by the BIRC or, as 
a minimum requirement, until at least one additional tumor assessment has been completed, 
unless there is a medical need (i.e., rapid progression or clinical deterioration) for an immediate 
change in therapy. 
Participants will continue to have imaging performed as per protocol (Table 8-4) until the 
central review determines disease progression. 
Time points without locally determined progression 
All imaging time points without locally determined progression will be read on an ongoing, 
non-expedited basis as detailed in the imaging manual to be provided by the designated imaging 


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CRO and independent review charter. Results of these readings will not be communicated to 
the sites. 
For participants who crossover to capmatinib in combination with osimertinib treatment, the 
disease progression will be determined based on investigator assessment only. Imaging 
assessment should be performed according to local practice and institutional guidelines. Reason 
for discontinuation and date of disease progression will be captured in the eCRF. 
Treatment beyond disease progression 
Following determination of disease progression, if the investigator believes the participant may 
derive benefit from continuing study treatment, the participant will be permitted to continue 
treatment beyond initial disease progression as per RECIST 1.1. Please see Section 6.1.5.1 for 
additional information. 
8.3.1.3.1 Progression on next line of therapy (PFS2) - applicable to both Run-In and 
Randomized parts 
For PFS2, the disease progression will be determined based on investigator assessment of 
progression on next-line therapy. For this purpose, subsequent antineoplastic therapies 
including start/end date, reason for discontinuation and date of disease progression will be 
captured in the appropriate eCRF. 
8.3.1.4 
Efficacy Follow-up Imaging Assessment - applicable to both run-in 
and randomized parts 
For participants who discontinue treatment for reasons other than initial disease progression as 
per RECIST 1.1 (either by investigator assessment - run-in part - or by investigator and 
BIRC assessement - randomized part-), tumor assessments must continue to be performed as 
outlined in Table 8-2 and Table 8-3, regardless if participants start on new antineoplastic 
therapy before documented disease progression. Please refer to Section 9.2 for additional 
information. 
8.3.2 
Appropriateness of efficacy assessments 
Tumor assessments every 6-12 weeks of chemotherapy are consistent with the standard clinical 
practice. Different guidelines for advanced NSCLC recommend response assessment every  
6-12 weeks after first line therapy.  
Based on available data (Mok et al 2017) and the negative prognostic impact of the MET 
dysregulation and T790M negative population, the median PFS in the control arm (platinum - 
pemetrexed based doublet chemotherapy) is expected to be around 4.5 months or 
18 weeks. Conducting tumor evaluations more than 6 weeks apart may expose a participant to 
an unnecessary treatment if the disease progression event takes place between the infrequent 
assessments or prevent from early identification of progression lesions and appropriate 
treatment. 


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8.3.3 
Overall survival 
Run-in part: 
Survival follow-up is not applicable 
Randomized part:  
All participants will enter the survival follow-up period once they complete the safety follow-
up and efficacy follow-up after treatment discontinuation (whichever is longer). Survival status 
will be collected every 12 weeks (+/- 14 days) regardless of treatment discontinuation reason 
(except if consent is withdrawn or participant is lost to follow-up) until death, lost to follow-up, 
or withdrawal of consent/opposition to use data/biological samples for survival follow-up. 
Additional survival assessments may be performed outside the 12 weeks follow-up schedules 
if a survival update is required for an interim assessment to meet safety or regulatory needs. 
Survival information can be obtained via phone, and information will be documented in the 
source documents and relevant eCRFs. Information on the therapies received for NSCLC, if 
any, after study treatment has been completed will be collected. 
8.4 
Safety 
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, the method of collection of safety assessments may be modified. See Section 10 for more 
details. 
For details on AE collection and reporting, refer to AE Section 10.1. 
Table 8-5 
Physical Assessments 
Assessments 
Specification 
Physical examination 
Significant findings that were present prior to the signing of informed consent 
must be included as medical history on the participant’s eCRF. Significant new 
findings that begin or worsen after informed consent must be recorded as an 
adverse event on the appropriate eCRF. 
Physical examination 
At screening, a complete physical examination will be performed including the 
examination of general appearance, skin, neck (including thyroid), eyes, ears, 
nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular, 
and neurological systems. More frequent examinations may be performed at 
the discretion of the investigator and if medically indicated. Information about 
the physical examination must be present in the source documentation. 
Targeted physical examination 
A targeted physical exam will be performed at all visits as indicated in 
Table 8-2 and Table 8-3 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 exams will be performed. 


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Assessments 
Specification 
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. 
Vital signs 
Vital signs include blood pressure (supine position preferred when ECG is 
collected), pulse measurement, repiratory rate, and body temperature. 
They will be measured at screening and at subsequent time points as specified 
in Table 8-2 and Table 8-3.  
Height and weight 
Height will be measured at screening. 
Body weight (in indoor clothing, but without shoes) will be measured at 
screening and at subsequent time points as specified in Table 8-2 and 
Table 8-3. 
Performance status 
The performance status will be assessed according to the Eastern Cooperative 
Oncology Group (ECOG) Performance Status Scale as specified in Table 8-6 
following the schedule given in Table 8-2 and Table 8-3. 
Table 8-6 
ECOG Performance Status 
Grade 
ECOG status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
8.4.1 
Laboratory evaluations 
For the run-in part, no central laboratory will be used - All laboratory analysis will be 
performed locally, inclusive of assessment for participants' eligibility. 
For the randomized part: a central laboratory will be used for analysis of all specimens 
collected, except urinalysis, pregnancy testing and HIV testing (where locally required), which 
will be performed locally. Details on the collections, shipment of samples and reporting of 
results by the central laboratory are provided to investigators in the [Laboratory Manual]. For 
China only, local laboratories can be used for all specimens collected (ie: central laboratory 
assessments not mandatory). 
For the ET part: no central laboratory will be used. All laboratory analysis will be perfomed 
locally. 
Local laboratory assessments may be performed instead of central laboratory assessments if 
medically indicated or when the treating physician cannot wait for central laboratory results for 
decision making. In this particular situation, the blood sample obtained at the same time point 
should be submitted to the central laboratory for analysis in parallel with local analysis. 
In case of off-site visits, samples that can be collected remotely will be collected and analyzed 
in line with the [Laboratory Manual].  


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The results of the local laboratory will be recorded in the CRF if the following criteria are met: 
• a treatment decision was made based on the local results, or 
• there are no concomitant central results available 
For assessment of participants’ eligibility to the randomized part of study, only laboratory 
results from the central laboratory will be used. Clinically significant abnormalities must be 
recorded as either medical history / current medical conditions or adverse events as appropriate. 
Table 8-7 
Clinical laboratory parameters collection plan 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Platelets, White blood cells, Red blood cells, Differential 
[Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands*, Other. Absolute 
value preferred, %s are acceptable unless indicated otherwise] 
Chemistry 
Albumin, Alkaline phosphatase, ALT, AST, Gamma-glutamyl-transferase (GGT), 
Calcium, Magnesium, Phosphate, Sodium, Potassium, Creatinine, Creatine kinase, 
Creatinine Clearance, Total Bilirubin, Direct Bilirubin (only if total bilirubin is ≥ grade 2), 
Blood Urea Nitrogen (BUN) or Urea 
Amylase, Lipase, Glucose (fasting) (non-fasting allowed post-baseline) 
Bicarbonate, Chloride, Uric Acid at screening and thereafter if clinically indicated 
Urinalysis 
Local laboratory: Macroscopic Panel (Dipstick)* (Color, Bilirubin, Blood, Glucose, 
Ketones, Leukocytes esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen) 
If dipstick is abnormal then perform local laboratory Microscopic Panel (Red Blood Cells, 
White Blood Cells, Casts, Crystals, Bacteria, Epithelial cells) 
Coagulation 
Prothrombin time (PT) or Quick Test (QT), International normalized ratio [INR]), 
Pregnancy Test 
At screening (and/or Cycle 1 Day 1) a serum pregnancy test is to be performed within 72 
hr before the first dose, while during the study (Day 1 of each cycle) urine pregnancy 
tests are sufficient. An End of Treatment serum pregnancy test is also required to be 
performed. 
For women considered to be post-menopausal and not of child-bearing potential, 
pregnancy testing is not required. 
If a serum pregnancy test is required as per local practice at day 1 of every cycle, the 
urine pregnancy test does not need to be repeated. 
Infection markers 
HIV testing (where locally required) 
* Assessements are optional for China only 
8.4.1.1 
Hematology 
Hematology tests are to be performed according to the Visit Schedules outlined in Table 8-2 
and Table 8-3. For details of the hematology panel refer to Table 8-7. Hematology should be 
assessed on the actual scheduled day, even if study treatment is being withheld. 
Laboratory assessment done ≤ 3 days of first dose of study treatment are permitted to be used 
as Cycle 1 Day 1 labs and do not need to be repeated. 
More frequent hematology testing may also be performed as medically necessary. Additional 
results from unscheduled hematology lab evaluations should be recorded on the appropriate 
unscheduled visit eCRF. 
8.4.1.2 
Clinical chemistry 
Clinical chemistry tests are to be performed according to the visit schedule outlined in 
Table 8-2 and Table 8-3. 


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For details of the biochemistry panel see Table 8-7. Biochemistry should be assessed on the 
actual scheduled day, even if study treatment is being withheld. 
Chemistry lab tests done as part of screening assessments ≤ 3 days prior to the first dose of 
study treatment do not need to be repeated. 
More frequent chemistry testing may also be performed as medically necessary. Additional 
results from unscheduled chemistry lab evaluations should be recorded on eCRF as unscheduled 
visit. 
8.4.1.3 
Urinalysis 
Urinalysis Dipstick measurements will be performed as per Table 8-7 and according to the 
schedule of assessments (Table 8-2 and Table 8-3). Any significant findings on dipstick will be 
followed up with microscopic evaluation. 
8.4.1.4 
Coagulation 
Coagulation tests outlined in Table 8-7 will be performed according to the visit schedule 
outlined in Table 8-2 and Table 8-3, as applicable. 
8.4.2 
Electrocardiogram (ECG) 
In both parts (run-in and randomized part, including ET), ECGs will be evaluated centrally. 
Triplicate 12 lead ECGs are to be collected with ECG machines supplied by the central ECG 
laboratory. ECGs will be performed at the time points indicated in Central ECG collection plan 
(Table 8-8 and Table 8-9). 
For participants who crossover to ET, an unscheduled ECG has to be performed within 3 days 
prior to ET-C1D1 which will serve as baseline ECG. 
Electrocardiograms (ECGs) must be recorded after 10 minutes rest in the supine position. The 
preferred sequence of cardiovascular data collection during study visits is ECG collection first, 
followed by vital signs, and blood sampling. 
The individual ECGs should be recorded approximately 2 minutes apart. The Fridericia QT 
correction formula (QTcF) should be used for clinical decisions. The mean QTcF value for each 
visit will be calculated from the triplicate ECGs for each participant. 
For any ECGs with participant safety concerns, two additional ECGs must be performed to 
confirm the safety finding and copies forwarded to the central ECG laboratory for assessment. 
A monitoring or review process should be in place for clinically significant ECG findings 
throughout the study and especially at baseline before administration of study treatment. 
Any identifier details must be redacted e.g., subject initials, date of birth, where local 
regulations require it. 
In the event that a clinically significant ECG abnormality is identified at the site (e.g., severe 
arrhythmia, conduction abnormality of QTcF > 500 ms), a copy of the assessment is sent to the 
central ECG laboratory for expedited review, and the ECG is repeated to confirm the diagnosis. 
If the participant is hemodynamically compromised, the investigator or a medically qualified 
person must initiate appropriate safety procedures without delay (for example cardioversion). In 


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case of off-site visits, ECGs will be recorded remotely and transmitted electronically or in paper 
version to the central ECG laboratory, in line with instructions included in the protocol. 
Clinically significant abnormalities must be recorded on the eCRF as either medical 
history/current medical conditions or adverse events as appropriate. 
Interpretation of the tracing must be made by a qualified physician and documented on the 
appropriate eCRF. Each ECG tracing should be labeled with the study number, participant 
initials (where regulations permit), participant number, date, and kept in the source documents 
at the study site. 
Clinically significant findings must be discussed with Novartis prior to dosing (run-in part) or 
randomizing the participant in the study. New or worsened clinically significant findings 
occurring after informed consent must be recorded as adverse events. 
Clinically significant ECG abnormalities present at screening should be reported on the 
appropriate CRF. New or worsened clinically significant findings occurring after informed 
consent must be recorded as adverse events. 
All ECGs must be recorded using the machines supported by the central ECG laboratory 
and transmitted electronically to the central ECG laboratory to be centrally reviewed 
by an independent reviewer. Any original ECG not transmitted electronically to the central 
ECG laboratory should be forwarded for central review. 
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated, and transmitted electronically to the central 
ECG laboratory as unscheduled timepoints. Local cardiologist ECG assessment may also be 
performed at any time during the study at the discretion of the investigator. 
All ECGs, including unscheduled triplicate safety ECGs with clinically relevant findings, 
collected during the study should be transmitted to the central ECG laboratory for review. 
The results of the centrally assessed ECGs are automatically transferred into the clinical 
database. 
Table 8-8 
Central ECG (run-in part) collection plan  
Cycle 
Day 
Time 
ECG Type 
Screening 
Anytime (≤ 72 hr before 
C1D1) 
12 Lead, triplicate 
1 
1 
Pre-dose 
Post-dose 2 h (within 15 
min prior to PK) 
Post-dose 4 h (within 15 
min prior to PK) 
Post-dose 6 h (within 15 
min prior to PK) 
Post-dose 8 h (within 15 
min prior to PK) 
12 Lead, triplicate 
1 
15 
Pre-dose 
Post-dose 2 h (within 15 
min prior to PK) 
12 Lead, triplicate 


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Cycle 
Day 
Time 
ECG Type 
Screening 
Anytime (≤ 72 hr before 
C1D1) 
12 Lead, triplicate 
Post-dose 4 h (within 15 
min prior to PK) 
Post-dose 6 h (within 15 
min prior to PK) 
Post-dose 8 h (within 15 
min prior to PK) 
4 
1 
Pre-dose (within 15 min 
prior to PK) 
12 Lead, triplicate 
Post-dose 6 h (within 15 
min prior to PK) 
EOT 
  
Anytime 
12 Lead, triplicate 
Unscheduled ECG 
Anytime if clinically 
indicated 
12 Lead, triplicate 
Table 8-9 
Central ECG (randomized part and ET part) collection plan  
Cycle 
Day 
Time 
ECG Type 
Screening (applies for all participants) 
Anytime (≤ 72 hr before 
C1D1) 
12 Lead, triplicate 
2 (applies only for 
participants randomized 
into the capmatinib + 
osimertinib arm and 
participants who 
crossover to ET) 
1 
Pre-dose (within 15 min 
prior to PK*) 
12 Lead, triplicate 
Post-dose 6 h (within 15 
min prior to PK*) 
EOT (applies only for 
participants randomized 
into the capmatinib + 
osimertinib arm and 
participants who 
crossover to ET) 
  
Anytime 
12 Lead, triplicate 
Unscheduled ECG (applies for all participants) ** 
Anytime if clinically 
indicated 
12 Lead, triplicate 
* In ET, ECGs will be collected without PK sample collection 
** An uscheduled ECG which will serve as baseline ECG is required for participants who crossover to ET within 3 days prior 
to ET-C1D1 
8.4.2.1 
MUGA (multiple gated acquisition) scan or echocardiogram 
An Echocardiogram or MUGA scan to assess LVEF will be performed at screening (within 15 
days prior to study medication/C1D1), at C4D1 (only for participants in the capmatinib + 
osimertinib arm, including ET), and as clinically indicated, and at end of treatment visit (only 
for participants in the capmatinib + osimertinib arm, including ET).  
In the run-in and randomization parts, assessment will be performed locally. The modality of 
the cardiac function assessments must be consistent throughout ie, if echocardiogram is used 
for the screening assessment then echocardiogram should also be used for subsequent scans. 
The participant should also be examined using the same machine and operator whenever 
possible. 


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8.4.3 
Pregnancy and assessments of fertility 
Participants are required to use highly effective methods of contraception during the study and 
for the follow-up time period as specified in Section 5.2. For a definition of highly effective 
contraception, assessment of fertility (males and females), and the definition of postmenopausal, 
please refer to Section 5.2. 
All women of child-bearing potential will have a serum pregnancy test within 72 hours prior to 
the first dose of study treatment. hCG may also be considered a tumor marker, therefore if hCG 
levels are detected, another blood sample at least 4 days later must be taken to assess the kinetics 
of the increase, and a transvaginal ultrasound must be performed to rule out pregnancy. Urine 
pregnancy tests will be required to be performed on Day 1 of every cycle beginning with Cycle 
2, followed by serum pregnancy test at the end of treatment visit. Women of child-bearing 
potential will be instructed to contact the site immediately at any time during the study (on-
treatment or during follow-up) should they have a positive pregnancy test. 
In case of positive urine pregnancy testing, additional testing must be performed to confirm the 
pregnancy, and, if confirmed, follow the reporting requirements as described in Section 10.1.4. 
A positive pregnancy test requires immediate discontinuation of study treatment. If a positive 
pregnancy test is performed in between study visits, the participant must immediately notify the 
investigator. Male participants must notify the investigator in case their partner is confirmed 
with positive pregnancy test results during the treatment period. See Section 10.1.4 for 
pregnancy reporting. 
Local pregnancy test and associated results will not be collected on the eCRF. 
If participants cannot visit the site to have serum pregnancy tests 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, 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. 
8.4.3.1 
Assessment of fertility 
A woman is considered of child-bearing potential from menarche and until becoming post-
menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy and bilateral oophorectomy. Medical documentation of oophorectomy, 
hysterectomy, or tubal ligation must be retained as source documents. A post-menopausal state 
is defined as no menses for 12 months without an alternative medical cause and an appropriate 
clinical profile. 
In absence of the medical documentation confirming permanent sterilization, or if the post-
menopausal status is not clear, the investigator should use his/her medical judgement to 
appropriately evaluate the fertility state of the woman and document it in the source document. 
For both treatment arms, when non-child-bearing potential status is determined during the study, 
further pregnancy testing will not be continued. For further details on the assessment of fertility, 
please refer to the study exclusion criteria in Section 5.2. 
If local requirements dictate otherwise, local regulations should be followed. 


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8.4.4 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/participant population. 
8.5 
Additional assessments 
8.5.1 
Clinical Outcome Assessments (COAs) 
Patient reported outcomes (PRO) (Randomization part only) 
A PRO is a measurement based on a report that comes from the participant (i.e., study 
participant) about the status of a participant’s health condition without interpretation of the 
participant’s report by anyone else. Symptoms or other unobservable concepts known only to 
the participant (e.g., pain severity or nausea) can only be captured by PRO measures. PROs can 
also assess the participant perspective on functioning or activities that may also be observable 
by others. 
This study will implement the following PROs: 
• The European Organization for Research and Treatment of Cancer’s core quality of life 
questionnaire EORTC (QLQ-C30) 
• The Lung Cancer module of the EORTC’s quality of life questionnaire EORTC (QLQ-
LC13) 
• NCCN FACT-Brain Symptom Index version 2.0 (FBrSI) 
• The EuroQoL 5-level instrument (EQ-5D-5L, tablet version) 
The EORTC QLQ-C30 and QLQ-LC13 are frequently used in clinical trials of participants with 
advanced or metastatic lung cancer (Aaronson et al 1993, Bergman et al 1994).  
The EORTC QLQ-C30 is a questionnaire developed to assess the quality of life of cancer 
patients which has been translated and validated into 81 languages and has been used in more 
than 3,000 studies worldwide. The questionnaire contains 30 items and is composed of both 
multi-item scales and single-item measures based on the patients experience over the past week. 
These include five scales (physical, role, emotional, cognitive and social functioning), three 
symptom scales (fatigue, nausea/vomiting, and pain), six single items (dyspnea, insomnia, 
appetite loss, constipation, diarrhea and financial impact) and a global health status/QoL scale. 
All of the scales and single-item measures range in score from 0 to 100. A high scale score 
represents a higher response level. Thus, a high score for a functional scale represents a high / 
healthy level of functioning; a high score for the global health status / QoL represents a high 
QoL, but a high score for a symptom scale / item represents a high level of 
symptomatology/problems. All scoring will follow the scoring procedures defined by the 
EORTC Scoring Manual (Aaronson et al 1993, Fayers 2001). 
The QLQ-LC13 is used in conjunction with the EORTC QLQ-C30 and provides information 
on an additional 13 items specifically related to lung cancer. The five domains of the LC13 
include pain, dyspnea, coughing and hemoptysis, and are based on their presence over the past 
week. All but the pain domain are scored on a 4 point Likert scale ranging from “not at all” to 
“very much”. Pain is score based on its presence, hence yes or no. A higher score indicates a 
higher presence of symptoms (Bergman et al 1994). 


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The NCCN FACT-Brain Symptom Index version 2.0 (FBrSI) symptom module will be used to 
explore changes in symptoms associated with potential BM in this study. The FBrSI was 
adapted from the previously developed FACT-Brain module. The symptoms module contains 
12 items with a recall period of the past 7 days. The participant responds to 12 statements and 
indicates to what extent it applies to them on a 5-point Likert response scale from “not at all” 
to “very much.” (Lai et al 2014). The 24 statements address three sub-scales: disease related 
symptoms (which includes 12 physical symptoms and 5 emotional symptoms), treatment side 
effects (5 items), and function/well-being (2 items).  
The EQ-5D-5L is a standardized measure of health status developed by the EuroQol Group in 
order to provide a simple, generic measure of health for clinical and economic appraisal (The 
EuroQol Group 1990). The EQ-5D 5L is designed for self-completion by respondents and takes 
only a few minutes to complete. Instructions to respondents are included in the questionnaire. 
The EQ-5D-5L consists of 2 pages – the descriptive system and the EQ visual analogue scale 
(EQ VAS) (Herdman et al 2011). The descriptive system comprises 5 dimensions (mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression), each with 5 levels: no 
problems, slight problems, moderate problems, severe problems, and extreme problems. The 
participant is asked to indicate his/her health state by ticking (or placing a cross) in the box 
against the most appropriate statement in each of the 5 dimensions. This decision results in a 1-
digit number expressing the level selected for that dimension. The EQ VAS records the 
participant’s self-rated health on a 20 cm vertical, visual analogue scale with endpoints labeled 
‘the 
best 
health 
you 
can 
imagine’ 
and 
‘the 
worst 
health 
you 
can 
imagine’ (Rabin and de Charro 2001). 
During treatment period and efficacy follow-up period, PRO questionnaires will be collected 
by self-report using electronic devices. Participants may also be given the possibility to 
complete PRO questionnaires at home on their own device before arriving at the site on 
scheduled visit days. Completion at home must be performed within 3 days before the 
scheduled visit (for more details, refer to vendor manual). 
For post-progression timepoints, for participant who might not return to the clinic, 
PRO completion can be done either at home on own patient device, or by interview over the 
phone provided the interviewer has received the appropriate training on recordingthe 
participant's responses. 
All PRO assessments should be administered in the participant’s most familiar language and 
according to the visit schedule in Table 8-3, prior to any tests, treatments or receipt of results 
from any test to avoid biasing the participant’s perspective. 
The EORTC QLQ C-30 and LC-13 questionnaires should be completed on Cycle 1 Day 1 (or 
within 3 days prior to this visit), Cycle 3 Day 1 (- 3 days), then every 6 weeks (- 3 days) for the 
first 18 months after C1D1 and every 12 weeks (- 3 days) thereafter, until End of Treatment 
(EOT) visit. For the other two PRO questionnaires, following the first administration, they will 
be completed at alternate visits i.e., the NCCN FACT Brain Symptom Index and EQ-5D-5L 
questionnaires should be completed on Cycle Day 1 (or within 3 days prior to this visit), Cycle 
2 Day 1 (-3 days) then very 6 weeks (-3 days) for the first 18 months after C1D1 and every 12 
weeks (-3 days) therafter, until End of treatment (EOT) Visit. Following this: 


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• for participants who discontinued treatment due to BIRC-Confirmed RECIST 1.1 defined 
progression and enter the safety survival follow-up period, PROs (all four set of questions) 
will be collected at EOT (+/- 7 days) and at 6, 12 and 18 weeks (+/- 7 days) post progression. 
• for participants who discontinued treatment for any other reason than BIRC-Confirmed 
RECIST 1.1 defined progression and enter the efficacy follow-up period, PROs will be 
collected at the same timepoints as imaging assessments until BIRC-Confirmed 
RECIST 1.1 progression. Following progression, PROs will then be collected within 7 days 
of the progression and again at 6, 12 and 18 weeks (+/- 7 days) post progression. 
• during the survival follow-up period, the NCCN FACT Brain Symptom Index and EQ-5D-
5L questionnaires are optional. 
For participants who discontinue platinum – pemetrexed based doublet chemotherapy treatment 
and enter extension treatment, PROs will be collected at 6, 12 and 18 weeks (± 7 days) post-
chemotherapy treatment progression only. These assessments do not have to be performed 
during survival follow-up if done during ET. 
All PRO questionnaires will also be accessible during unscheduled visits and can be completed 
at investigator/site team discretion. 
The participant must be given the PRO measure(s) to be completed at the scheduled visit (if not 
completed at home on own patient device) before any clinical assessments are conducted and 
should be given sufficient space and time to complete the PRO measure(s). 
Participant’s refusal to complete all or any part of a PRO measure should not be captured as a 
protocol deviation. 
The site personnel should check PRO measure(s) for completeness and ask the participant to 
complete any missing responses. The responses stored electronically in the database will be 
considered the source file. 
The participant should be made aware that responses of the completed measure(s) are not 
reviewed by the investigator/ study personnel and that they should report any discomfort, 
unusual symptoms or medical problems directly to the Investigator/ study personnel. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
participants could complete the questionnaires at home on their own device or study site staff 
may administer the questionnaires to the participants via interview over the phone regardless of 
the study phase (for more details, refer to the vendor manual). 
Trial Feedback 
This study is including an optional questionnaire, the “Trial Feedback Questionnaire” for trial 
participants to provide feedback on their clinical trial experience in adherence to local 
regulations and guidelines. Individual trial participant responses will not be reviewed by 
investigators. Responses may be used by Novartis to understand where improvements can be 
made in the clinical trial process. This questionnaire asks questions about trial experience. It 
does not ask questions about the trial participant's disease, symptoms, treatment effect, or AEs, 
and, therefore is not considered as trial data. 


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8.5.2 
Pharmacokinetics 
Serial blood samples will be collected from all participants in the run-in and those who are 
randomized to receive capmatinib and osimertinib to assess plasma PK of capmatinib, 
osimertinib and osimertinib's active metabolites (AZ5104 and AZ7550). Time points of blood 
sample collection for run-in part and randomization part are outlined in Table 8-10 to 
Table 8-13. 
No PK samples will be collected in the ET phase. 
Complete dosing information, including the date and time of actual blood draw and time of the 
last study drug dose prior to the sampling, must be obtained on all sampling days and recorded 
on the PK eCRF and/or CRO requisition form(s). 
An additional unscheduled PK blood sample will be collected if a participant experiences an 
AE suspected to be related to study treatment that results in an unscheduled visit or fits the 
criteria of an SAE (unless participant has interrupted capmatinib and osimertinib for 7 days or 
more). 
 
 
8.5.2.1 
Pharmacokinetic sampling for run-in part 
PK blood samples will be collected for all participants in the run-in part, as outlined in 
Table 8-10 and Table 8-11. Extensive PK samples will be collected on Cycle 1 Day 1, Cycle 1 
Day 2 (only for osimertinib) and Cycle 1 Day 15. 
Table 8-10 
Pharmacokinetic blood collection log for capmatinib (run-in part)  
Cycle 
Day 
Scheduled 
Time Point 
Dose Reference ID 
PK Sample 
No 
Sample 
Volume 
(mL) 
1 
1 
Pre-dose (0 
hour) 
11 
101 
2 
1 
1 
Post-dose 
0.5 h (± 5 
min) 
11 
102 
2 
1 
1 
Post-dose 1 
h (± 10 min) 
11 
103 
2 
1 
1 
Post-dose 2 
h (± 15 min) 
11 
104 
2 
1 
1 
Post-dose 3 
h (± 15 min) 
11 
105 
2 
1 
1 
Post-dose 4 
h (± 20 min) 
11 
106 
2 
1 
1 
Post-dose 6 
h (± 30 min) 
11 
107 
2 
1 
1 
Post-dose 8 
h (± 60 min) 
11 
108 
2 
1 
15 
Pre-dose 
12 
121a 
109 
2 


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Cycle 
Day 
Scheduled 
Time Point 
Dose Reference ID 
PK Sample 
No 
Sample 
Volume 
(mL) 
1 
15 
Post-dose 
0.5 h (± 5 
min) 
12 
110 
2 
1 
15 
Post-dose 1 
h (± 10 min) 
12 
111 
2 
1 
15 
Post-dose 2 
h (± 15 min) 
12 
112 
2 
1 
15 
Post-dose 3 
h (± 15 min) 
12 
113 
2 
1 
15 
Post-dose 4 
h (± 20 min) 
12 
114 
2 
1 
15 
Post-dose 6 
h (± 30 min) 
12 
115 
2 
1 
15 
Post-dose 8 
h (± 60 min) 
12 
116 
2 
3 
1 
Pre-dose 
13 
131a 
117 
2 
4 
1 
Pre-dose 
14 
141a 
118 
2 
6 
1 
Pre-dose 
15 
151a 
119 
2 
Unscheduled 
Anytime 
  
1001+ 
2 
aDose reference IDs with three digits refer to the dose administered and dosing time of the last dose prior to 
collection of the corresponding PK sample 
Table 8-11 
Pharmacokinetic blood collection log for osimertinib, AZ5104 and 
AZ7550 (run-in part) 
Cycle 
Day 
Scheduled 
Time Point 
Dose Reference ID 
PK Sample 
No 
Sample 
Volume 
(mL) 
1 
1 
Pre-dose (0 
hour) 
21 
201 
3 
1 
1 
Post-dose 
0.5 h (± 5 
min) 
21 
202 
3 
1 
1 
Post-dose 1 
h (± 10 min) 
21 
203 
3 
1 
1 
Post-dose 2 
h (± 15 min) 
21 
204 
3 
1 
1 
Post-dose 3 
h (± 15 min) 
21 
205 
3 
1 
1 
Post-dose 4 
h (± 20 min) 
21 
206 
3 
1 
1 
Post-dose 6 
h (± 30 min) 
21 
207 
3 
1 
1 
Post-dose 8 
h (± 60 min) 
21 
208 
3 
1 
2 
Post-dose 24 
h (± 120 min) 
/ pre-C1D2 
am dose 
21 
211 
209 
3 
1 
15 
Pre-dose 
22 
221a 
210 
3 


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Cycle 
Day 
Scheduled 
Time Point 
Dose Reference ID 
PK Sample 
No 
Sample 
Volume 
(mL) 
1 
15 
Post-dose 
0.5 h (± 5 
min) 
22 
211 
3 
1 
15 
Post-dose 1 
h (± 10 min) 
22 
212 
3 
1 
15 
Post-dose 2 
h (± 15 min) 
22 
213 
3 
1 
15 
Post-dose 3 
h (± 15 min) 
22 
214 
3 
1 
15 
Post-dose 4 
h (± 20 min) 
22 
215 
3 
1 
15 
Post-dose 6 
h (± 30 min) 
22 
216 
3 
1 
15 
Post-dose 8 
h (± 60 min) 
22 
217 
3 
3 
1 
Pre-dose 
23 
231a 
218 
3 
4 
1 
Pre-dose 
24 
241a 
219 
3 
4 
1 
Post-dose 6 
h (± 30 min) 
24 
  
220 
3 
6 
1 
Pre-dose 
25 
251a 
221 
3 
Unscheduled 
Anytime 
  
2001+ 
3 
aDose reference IDs with three digits refer to the dose administered and dosing time of the last dose prior to 
collection of the corresponding PK sample 
8.5.2.2 
Pharmacokinetic sampling for randomization part 
PK blood samples will be collected for all participants randomized to the capmatinib plus 
osimertinib arm as outlined in Table 8-12 and Table 8-13. PK blood samples will not be 
collected from participants randomized to the platinum-pemetrexed chemotherapy arm.  
Table 8-12 
Pharmacokinetic blood collection log for capmatinib (randomization 
part) 
Cycle 
Day 
Scheduled 
Time Point 
Dose Reference ID 
PK Sample 
No 
Sample 
Volume 
(mL) 
1 
1 
Pre-dose (0 
hour) 
31 
301 
2 
2 
1 
Pre-dose 
32 
321a 
302 
2 
2 
1 
Post-dose 1-
4 hours 
32 
  
303 
2 
2 
1 
Post-dose 6 
h (± 30 min) 
32 
  
304 
2 
3 
1 
Pre-dose 
33 
331a 
305 
2 
4 
1 
Pre-dose 
34 
341a 
306 
2 
6 
1 
Pre-dose 
35 
351a 
307 
2 
Unscheduled 
Anytime 
  
3001+ 
2 
aDose reference IDs with three digits refer to the dose administered and dosing time of the last dose prior to 
collection of the corresponding PK sample 


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Table 8-13 
Pharmacokinetic blood collection log for osimertinib, AZ5104 and 
AZ7550 (randomization part) 
Cycle 
Day 
Scheduled 
Time Point 
Dose Reference ID 
PK Sample 
No 
Sample 
Volume 
(mL) 
1 
1 
Pre-dose (0 
hour) 
41 
401 
3 
2 
1 
Pre-dose 
42 
421a 
402 
3 
2 
1 
Post-dose 1-
4 hours 
42 
  
403 
3 
2 
1 
Post-dose 6 
h (± 30 min) 
42 
  
404 
3 
3 
1 
Pre-dose 
43 
431a 
405 
3 
4 
1 
Pre-dose 
44 
441a 
406 
3 
6 
1 
Pre-dose 
45 
451a 
407 
3 
Unscheduled 
Anytime 
  
4001+ 
3 
aDose reference IDs with three digits refer to the dose administered and dosing time of the last dose prior to 
collection of the corresponding PK sample 
8.5.2.3 
Pharmacokinetic blood collection and handling 
Blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in 
a forearm vein at specified time points described in Table 8-10 to Table 8-13. 
All sampling is relative to the ingestion of capmatinib and osimertinib. On days and time points 
where blood PK samples are to be drawn, the PK sample must be drawn first. The exact date 
and time of dosing, as well as the date and actual time of blood sampling must be recorded on 
the appropriate eCRF. 
If vomiting occurs within 4 hours following capmatinib administration, post dose PK sample 
collection is at investigator’s discretion. If PK sample collection is done, the clock time of 
vomiting must be recorded in the dosage administration PK eCRF page. 
Refer to the [Laboratory Manual] for detailed instructions for the collection, handling, and 
shipment of PK samples. 
8.5.2.4 
Analytical method 
Plasma concentrations of capmatinib, osimertinib, AZ5104, and AZ7550 will be measured 
using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay with a 
lower limit of quantification (LLOQ) of 1.0 ng/mL, 0.4 ng/mL, 0.4 ng/mL, and 0.4 ng/mL for 
capmatinib, osimertinib, AZ5104 and AZ7550, respectively, by Novartis Bioanalytics. 
Concentrations below the LLOQ will be reported as 0.00 ng/mL and missing samples will be 
labelled accordingly. 
 
 
 
 
 
 


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9 
Study discontinuation and completion 
9.1 
Discontinuation and completion 
9.1.1 
Discontinuation from study treatment and from study  
Discontinuation from study treatment 
Discontinuation of study treatment for a participant occurs when study treatment is permanently 
stopped for any reason (prior to the planned completion of study drug administration, if any) 
and can be initiated by either the participant or the investigator. 
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being. 
Discontinuation of study treatment is required under the following circumstances: 
• Participant/guardian decision 
• Investigator decision 
• Pregnancy (see Section 10.1.4) 
• Any situation in which continued study participation might result in a safety risk to the 
participant 
• Disease progression per RECIST 1.1 (as assessed by the investigator in the run-in part, and 
as assessed by the investigator confirmed by BIRC in the randomization part). In some 
circumstances, participants may be allowed to continue to receive study treatment beyond 
disease progression as per RECIST 1.1. These participants will continue assessments as 
outlined in Table 8-2 or Table 8-3, as applicable, and will complete the EOT visit only after 
permanent discontinuation of study treatment (see Section 6.1.4) 
• Adverse event requiring permanent discontinuation of study treatment (see Table 6-7) 
• Protocol deviation that results in a significant risk to participant's safety 


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• Withdraw of consent (see Section 9.1.2) 
• Study is terminated by the sponsor (see Section 9.1.4) 
• Death 
• Lost to follow-up 
If discontinuation from study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s discontinuation from study treatment and 
record this information. 
Participants who discontinue from study treatment agree to return for the end of treatment and 
follow-up visits indicated in the Assessment Schedule (refer to Section 8).  
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be done according to the study visit schedule. 
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact: 
• New / concomitant treatments 
• Adverse Events / Serious Adverse Events 
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
For participants who discontinue from study treatment for reasons other than documented 
disease progression, death, lost to follow-up, or withdrawal of consent/opposition to use 
data/biological samples, tumor assessments must continue to be performed every 6 weeks for 
the first 18 months, then every 12 weeks until documented disease progression per RECIST 1.1 
as determined by investigator and confirmed by BIRC, death, lost to follow-up, discontinuation 
from study or withdrawal of consent/opposition to use data/biological samples. 
In some circumstances, participants may be allowed to continue to receive study treatment 
beyond disease progression as per RECIST 1.1 criteria. These participants will continue 
assessments as outlined in the assessments section, and will complete the EOT visit only after 
permanent discontinuation of study treatment. 
Discontinuation from study 
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason. 
If the participant agrees, a final evaluation at the time of the participant’s study discontinuation 
should be made as detailed in the assessment table (refer to Section 8). 
9.1.1.1 
Replacement policy 
Run-in part 
Participants will not be replaced on study. However, if a participant is considered as non-
evaluable for the Dose-Determination Set (DDS), a new participant will be enrolled until at 
least the minimum number of 6 evaluable subjects is achieved within each treatment cohort. 


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Randomized part 
No replacements will be needed. 
9.1.2 
Withdrawal of informed consent/Opposition to use data/biological 
samples 
Withdrawal of consent/opposition to use of data and/or biological samples occurs in countries 
where the legal justification to collect and process the data is consent and when a participant: 
• Explicitly requests to stop use of their data 
and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study-related contacts) 
This request should be in writing (depending on local regulations) and recorded in the source 
documentation. 
Withdrawal of consent impacts ability to further contact the participant, collect follow-up data 
(e.g., respond to data queries) and potentially other country-specific restrictions. It is therefore 
very important to ensure accurate recording of withdrawal vs discontinuation based on the 
protocol definitions of these terms. 
In this situation, the investigator should make a reasonable effort (e.g., telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw his/her 
consent/exercise data privacy rights and record this information. The investigator shall clearly 
document if the participant has withdrawn his/her consent for the use of data in addition to a 
study discontinuation. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/exercise data privacy rights should be made as detailed in the assessment table (refer 
to Section 8). 
Further details on withdrawal of consent or the exercise of participants’ data privacy rights are 
included in the corresponding informed consent form. 
9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits or fail to 
respond to any site attempts to contact them without stating an intention to discontinue from 
study treatment or discontinue from study or withdraw consent (or exercise other participants’ 
data privacy rights), the investigator must show "due diligence" by documenting in the source 
documents steps taken to contact the participant, e.g., dates of telephone calls, registered letters, 


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etc. A participant should not be considered as lost to follow-up until due diligence has been 
completed. 
9.1.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination: 
• Unexpected, significant, or unacceptable safety risk to 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 early termination be necessary, participants must be seen as soon as possible and treated 
as a participant who discontinued study treatment. The investigator may be informed of 
additional procedures to be followed in order to ensure that adequate consideration is given to 
the protection of the participant’s interests. The investigator or sponsor depending on local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial. 
9.2 
Study completion and post-study treatment 
For individual participant  
Study completion is defined when participant completes all post-treatment follow-up (including 
30-day safety follow-up and tumor assessment until PD, whichever is longer). The appropriate 
disposition eCRF must be completed, giving the date and reason of post-treatment follow-up 
discontinuation. After this, participant can enter survival follow-up. 
For the study 
Study completion is defined as the earliest occurrence of one of the following: 
• All participants have discontinued study treatment and completed the safety follow-up 
and approximately 80% of the participants have died, withdrawn consent or are lost to 
follow-up. 
• Another clinical study becomes available that can continue to provide capmatinib in this 
participant population, and all participants ongoing are transferred to that clinical study. 
Note: For participants who transfer to another clinical study or an alternative treatment 
option to continue provision of study treatment, the follow-up for safety, disease progression 
and survival will not be performed. 
If the primary analysis of PFS does not demonstrate treatment benefit, the follow-up for OS 
will end, in this case the end of the study will be when all participants have discontinued 
treatment and completed the safety follow-up, or have withdrawn consent or are lost to follow-
up. 
At the end of the study, every effort will be made to continue provision of study treatment 
outside this study through an alternative setting to participants who in the opinion of the 
investigator are still deriving clinical benefit. 


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Details on the timing of the primary analysis and final reporting of data are provided in 
Section 12. 
9.2.1 
Follow-up for safety evaluations 
Regardless of the reason for discontinuation from study treatment (see Section 9.1.1), 
participants will be contacted for a safety follow-up 30 days after the last dose of study treatment. 
At this time, the investigator will record any AEs/SAEs that may have occurred after 
discontinuation of study treatment and/or follow on resolution of ongoing AEs. 
If the participant begins any post-treatment antineoplastic medication before the 30-day safety 
follow-up period is complete, the collection of new SAEs and AEs unrelated to capmatinib will 
stop, and, thereafter, only suspected AEs and suspected SAEs will continue to be collected up 
to day 30. Suspected SAEs will continue to be collected beyond the 30-day safety follow-up. 
AEs, concomitant medications and antineoplastic therapies since discontinuation of study 
treatment will be recorded on the appropriate eCRFs during this follow-up period. 
9.2.2 
Efficacy follow-up and PROs 
All participants who discontinue study treatment for reasons other than disease progression as 
per RECIST 1.1 as determined by investigator and confirmed by BIRC, withdrawal of consent 
or lost to follow-up will continue to have tumor assessments and PROs collection as per their 
current schedule until disease progression is confirmed by BIRC, withdrawal of consent, lost to 
follow-up or study terminated by the Sponsor. 
When a participant discontinued from efficacy follow-up, the appropriate disposition eCRF 
must be completed, giving the date and reason of discontinuation, as per Table 8-2. 
Information on new antineoplastic therapy initiated since discontinuation of study treatment 
will be collected on the appropriate eCRF during this follow-up period. 
9.2.3 
Survival follow-up 
Participants will enter the survival follow-up period once they complete the 30-day safety 
follow-up and efficacy follow-up (if applicable) after treatment discontinuation (whichever is 
longer). Participants from randomized part will then be contacted by telephone every 12 weeks 
to follow-up on their survival status. Any new antineoplastic therapies that have been started 
since the last contact date will also be collected during these phone calls. At this time, the 
investigator will record any SAEs that may have occurred after discontinuation of study 
treatment if the investigator suspects a causal relationship to study treatment. 
PRO questionnaires will also be collected in the survival follow-up period at 3 time points (6, 
12 and 18 weeks (+/-7 days)) post progression. For participants crossing over to the ET, those 
three time points (6, 12 and 18 weeks (+/- 7 days)) should be collected during the ET phase.  
Every effort should be made to comply with the survival follow-up schedule and ensure 
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10 
Safety monitoring, reporting and committees 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
regular phone or virtual contact will occur at least every 3 weeks (± 3 days) as per the visit 
scheduled, or more frequently if needed for safety monitoring and discussion of the participant´s 
health status until the participant can again visit the site. Events qualifying for being reported 
in the case report form (i.e., AE, infection) should be entered as appropriate. 
If participants can not visit the site to have serum pregnancy tests done, urine pregnancy test 
kits may be shipped or provided directly to participants (i.e., together with the study drug). 
Relevant participants can perform the urine pregnancy test at home and report the result to the 
site. It is important that participants are instructed to perform the urine pregnancy test first and 
only if the test result is negative proceed with the administration of the study treatment. A 
communication process will be established with participants so that the site is informed and can 
verify the pregnancy test results (i.e., following country specific measures). 
Depending on local regulations and capabilities, study site staff or Home Nursing Services may 
visit the participant at home to draw blood/ urine samples if needed. Alternatively, safety lab 
tests performed locally will be allowed as appropriate. 
ECG, echocardiogram or MUGA performed locally (i.e., by the participant´s general 
practitioner or at another facility) will be allowed as appropriate. Alternatively, depending on 
local regulations and capabilities, Home Nursing Services or study site staff may visit the 
participant at home for ECG collection. 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign, including abnormal laboratory findings, symptoms or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
For participants who sign the molecular pre-screening ICF, AEs which occur after signature of 
this consent will only be captured if they meet the definition of serious as outlined in 
Section 10.1.2 and are reported to be causally related with study procedures (i.e., an invasive 
procedure such as biopsy). Once the main study ICF is signed, all AEs per the descriptions 
below will be captured as adverse events. 
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 


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by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments. 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. Adverse events will be assessed and graded according to the Common Terminology Criteria 
for Adverse Events (CTCAE V5.0). If CTCAE grading does not exist for an adverse event, the 
severity of mild, moderate, severe, life-threatening, and fatal corresponding to grades 1 - 5, will 
be used. Information about any deaths (related to an Adverse Event or not) will also be collected 
through a Death form. 
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression of 
underlying illness (i.e., progression of the study indication) the assessment of causality will 
usually be ‘Not suspected’. The rationale for this guidance is that the symptoms of a lack of 
efficacy or progression of underlying illness are not caused by the trial drug, they happen in 
spite of its administration and/or both lack of efficacy and progression of underlying disease 
can only be evaluated meaningfully by an analysis of cohorts, not on a single participant. 
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not recovered/ not 
resolved must be reported. 
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met. 
5. Action taken regarding study treatment. All adverse events must be treated appropriately. 
Treatment may include one or more of the following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/withdrawn 
6. Its outcome: not recovered/not resolved, recovered/resolved, recovered/resolved with 
sequelae, fatal, unknown  
If the event worsens, then the event should be reported a second time in the CRF noting the start 
date when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement 
to a lower grade is determined a new entry for this event should be reported in the CRF noting 
the start date when the event improved from having been Grade 3 or Grade 4. 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. Adverse 
event monitoring should be continued for at least 30 days following the last dose of study 
treatment. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (i.e., continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 


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Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST 1.1 criteria for solid tumors), should not be reported as a 
serious adverse event, except if the investigator considers that progression of malignancy is 
related to study treatment. 
Adverse events separate from the progression of malignancy (i.e., deep vein thrombosis at the 
time of progression or hemoptysis concurrent with finding of disease progression) will be 
reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug. 
Information about adverse drug reactions for capmatinib can be found in the [capmatinib 
Investigator's Brochure]. Information about adverse drug reactions for the other drugs could be 
found in the respective local labels. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease. 
10.1.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the participant’s 
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• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, 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 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the  
[ICH-E2D Guidelines]). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occured. 
10.1.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days following the last administration of study 
treatment must be reported to Novartis safety immediately, without undue delay but under no 
circumstance later than within 24 hours of obtaining knowledge of the events (Note: if more 
stringent, local regulations regarding reporting timelines prevail). Detailed instructions 
regarding the submission process and requirements are to be found in the investigator folder 
provided to each site. Information about all SAEs is collected and reported on the Serious 
Adverse Event Report Form in the eCRF (paper forms will only used as backup); all applicable 
sections of the form must be completed in order to provide a clinically thorough report. 
For participants who undergo molecular pre-screening procedures, SAE collection will start 
upon signing the molecular pre-screening ICF and will only be reported if the event is suspected 
to be causally related to a study procedure as assessed by the investigator (i.e., 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 (i.e., molecular screen failure), 
SAE collection ends 30 days after the last study related procedure. 
For participants who do not need to undergo molecular pre-screening procedure, SAE collection 
starts at the time of main study informed consent whether the participant is a screen failure or 
not and will be reported regardless of relationship to study procedure. 
For participants who failed the molecular pre-screening or screening, SAEs will be collected 
until the time the subject is deemed a molecular screening or screen failure. 


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For participants treated and/or randomized, SAEs will be collected until 30 days after the 
participant has discontinued or stopped study treatment. 
Any SAEs experienced after the 30 days period following the last administration of the study 
treatment should only be reported to Novartis if the investigator suspects a causal relationship 
to the study treatment, unless otherwise specified by local law/regulations. 
Progression of malignancy (including fatal outcomes) should not be reported as a serious 
adverse event, except if the investigator considers that the progression is related to study 
treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay but under no circumstances later than 24 hours of the 
investigator receiving the follow-up information (Note: if more stringent, local regulations 
regarding reporting timleines prevail). An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event. 
If the SAE is not previously documented in the [capmatinib Investigator’s Brochure] or Package 
Insert (new occurrence) and is thought to be related to the study treatment, a CMO & PS 
Department associate may urgently require further information from the investigator for health 
authority reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees (EC) in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
10.1.4 
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 the pregnancy consent form. This consent form is 
necessary to allow the Study Doctor to collect and report information regarding the pregnancy. 
To ensure participant safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up at 1, 3 (for a live birth only) and 12 (for a live birth only) months after the estimated 
date of delivery to determine outcome, including spontaneous or voluntary termination, details 
of the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications. 
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment and 
pregnancy outcome. Any SAE experienced during pregnancy must be reported. 
If a female partner of a male trial participant who took study treatment in this study becomes 
pregnant, pregnancy outcome should also be collected. Consent to report information regarding 
these pregnancy outcomes should be obtained from the mother. 


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Pregnancy reporting applies to all study participants for both arms (capmatinib + osimertinib 
and platinum-pemetrexed arms) as well as for ET.  
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
CRF (Yes/No) 
Document in AE eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with an 
AE 
Only if associated with an 
SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
10.2 
Additional Safety Monitoring 
10.2.1 
Data Monitoring Committee 
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will assess at defined intervals the progress 
of a clinical trial, safety data, and critical efficacy variables and recommend to the sponsor 
whether to continue, modify, or terminate a trial. 
Specific details regarding composition, responsibilities, data monitoring, and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate charter that is established between the sponsor and the DMC. 
10.2.2 
Steering Committee 
A Steering Committee (SC) will be established comprising investigators participating in the 
trial and/or key opinion leaders in NSCLC (i.e., not being DMC members), and Novartis 
representatives from the Clinical Trial Team. 


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The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC may review 
protocol amendments as appropriate. Together with the Clinical Trial Team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the SC will be defined in the Steering Committee charter. 
11 
Data Collection and Database management 
11.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (entered into eCRF) is 
complete, accurate, and that entry and updates are performed in a timely manner. The 
investigator must certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
11.2 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes and data about all study treatment(s) dispensed to the participant and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines. 
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. 


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11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e., eCRFs) with the 
investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and GCP (Good Clinical Practice) compliance and the quality/integrity of the sites’ 
data. The field monitor will visit the site to check the completeness of participant records, the 
accuracy of data capture / data entry, the adherence to the protocol and to GCP, the progress of 
enrollment, and to ensure that study treatment is being stored, dispensed, and accounted for 
according to specifications. Key study personnel must be available to assist the field monitor 
during these visits. Continuous remote monitoring of each site’s data may be performed by a 
centralized Novartis CRA organization. Additionally, a central analytics organization may 
analyze data & identify risks & trends for site operational parameters, and provide reports to 
Novartis clinical teams to assist with trial oversight. 
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
participant's file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 
12 
Data analysis and statistical methods 
The primary efficacy and safety analyses will be performed after observing approximately 162 
PFS events as assessed by BIRC. 
Data from participating centers in this protocol will be combined, so that an adequate number 
of participants will be available for analysis. Data will be summarized using descriptive 
statistics (continuous data) and/or contingency tables (categorical data) for demographic and 
baseline characteristics, and efficacy, safety and pharmacokinetic measurements. Study data 
will be analyzed and reported in a primary clinical study report (CSR) based on all participants’ 
data up to the time of the data cut-off date determined for the primary efficacy analysis. Any 
additional data for participants continuing to receive study treatment past the data cut-off date 
for the primary CSR, as allowed by the protocol, or continuing in the follow-up parts will be 
reported at completion of the study in a final CSR. All summaries, listings, figures and analyses 
will be performed by treatment arms (unless otherwise specified). Screen failure participants, 
as described in Section 8.1.2, and the reasons for not being randomized will be reported in a 
listing, but will not be included in any analyses. 


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Details of the statistical analysis and data reporting will be provided in the Statistical Analysis 
Plan (SAP). 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
12.1 
Analysis sets 
A participant is considered to be enrolled into the study if they have signed the main study 
informed consent. Only participants who have signed main study informed consent will be 
included in the analysis data sets. 
12.1.1 
Full analysis set 
For the safety run-in part, the Full Analysis Set (FAS) comprises all participants that received 
any component of the study drug. According to the intent to treat principle, participants will be 
analyzed according to the treatment(s) received. 
For the randomized part, the Full Analysis Set (FAS) comprises all participants to whom study 
treatment has been assigned by randomization, regardless of whether or not the treatment was 
administered. According to the intent to treat principle, participants will be analyzed according 
to the treatment and strata they have been assigned to during the randomization procedure. 
12.1.2 
Full analysis set brain metastases 
The Full Analysis Set – Brain Metastases (FAS-BM) comprises all participants in the FAS who 
have measurable and/or non-measurable brain metastases at baseline based on randomization 
strata. 
12.1.3 
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 actually received, i.e., either capmatinib in combination with 
osimertinib or platinum-pemetrexed based doublet chemotherapy. The actual treatment 
received is defined as the randomized/assigned treatment if the participant took at least one dose 
of that treatment or the first treatment received if the randomized/assigned treatment was never 
received. 
12.1.4 
Pharmacokinetic analysis set 
The Pharmacokinetic Analysis Set (PAS) includes all participants who provided at least one 
evaluable PK concentration. For a concentration to be evaluable, participants are required to: 
• Have received at least one dose of capmatinib + osimertinib 
• For steady state trough samples (pre-dose samples) on or after Cycle 2 Day 1 (C2D1), have 
taken the consistent dose of capmatinib + osimertinib for at least 5 consecutive days prior 
to sampling except for Cycle 1 Day 1 (C1D1) 
• A PK sample is considered as non-evaluable if it is collected after a participant has vomited 
within 4 hours post-dose. 


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The definition of an evaluable PK concentration profile will be further specified in the SAP. 
12.1.5 
Dose-Determining Set (DDS) 
The Dose-Determining Set (DDS) includes all participants from the FAS (safety run in parts) 
who met the minimum exposure criterion and had sufficient safety evaluations, or experienced 
a Dose Limiting Toxicity (DLT) during cycle 1 (the first 21 days of dosing). 
A participant has met the minimum exposure criterion if the participant takes during the first 
21 days of dosing at least 75% of the planned doses for each of the combination drugs (i.e., ≥ 
16 out of 21 daily doses for capmatinib and ≥ 16 out of 21 daily doses for osimertinib) and at 
least 50% of the planned combination doses of the two drugs administered together (i.e., ≥ 11 
out 21 daily doses). 
Participants who do not experience a DLT during cycle 1 (the first 21 days of dosing) are 
considered to have sufficient safety evaluations if they have been observed for ≥ 21 days 
following the first dose, and are considered by both the sponsor and investigators to have 
enough safety data to conclude that a DLT did not occur. Participants will be analyzed according 
to the study treatment received as defined for FAS. 
12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be summarized 
descriptively by treatment arm for the FAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class, preferred term, and by treatment arm. 
12.3 
Treatments 
The Safety Set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented. The exposure related analyses will 
be presented by dosing regimen for the safety run-in part and by treatment group for the 
randomized part. 
The duration of exposure in weeks to study treatment and for each study drug (capmatinib, 
osimertinib, and platinum-pemetrexed chemotherapy) as well as the dose intensity (computed 
as the ratio of actual cumulative dose received and actual duration of exposure) and the relative 
dose intensity (computed as the ratio of dose intensity and planned dose intensity) will be 
summarized by means of descriptive statistics using the safety set. 
The number of participants with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized by treatment arm, and all dosing data will 
be listed. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized according to the Anatomical Therapeutic Chemical (ATC) 
classification system, by treatment arm. 


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12.4 
Analysis supporting primary objectives 
The primary objective of randomized phase is to evaluate whether capmatinib in combination 
with osimertinib prolongs PFS by BIRC according to RECIST 1.1 compared to platinum-
pemetrexed based doublet chemotherapy. The analysis will be performed on the FAS. 
12.4.1 
Definition of primary endpoint(s) 
Safety run-in part 
The primary endpoint for the safety run-in part is incidence of Dose Limiting Toxicities (DLT) 
during Cycle 1 of treatment for each dose level associated with administration of capmatinib in 
combination with osimertinib.  
Randomized part 
The primary estimand for the randomized phase is defined as in Section 2.1. For the primary 
estimand, the endpoint PFS is defined as the time from the date of randomization to the date of 
the first documented disease progression based on BIRC as per RECIST 1.1, or date of death 
due to any cause, whichever occurs first. In the primary analysis, PFS will be censored at the 
date of the last adequate tumor assessment if no PFS event is observed prior to the analysis cut-
off date. Clinical deterioration without objective radiological evidence will not be considered 
as documented disease progression. PFS will be assessed by BIRC according to RECIST 1.1. 
Censoring conventions (i.e., handling of missing values, censoring, and discontinuations) are 
provided in Section 12.4.4. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
Run-in part 
The primary endpoint for the safety run-in phase is the incidence of DLT during cycle 1. The 
dose recommendation decision will be based on the following criteria:  
• At least six evaluable participants treated at this dose and regimen. 
• No more than two DLT have been observed out of six evaluable participants. 
• It is the dose recommended for participants after review of all clinical data by Novartis 
and Investigators in a dose level review team meeting. 
If one of the conditions specified above is not satisfied, dose confirmation cannot be declared 
and a second cohort may be treated at the lower dose level with capmatinib (400 mg b.i.d.) and 
osimertinib (40 mg q.d.). The same criteria are applied for this new dose and regimen. If dose 
confirmation cannot be declared on this lower dose, the randomized part cannot start and the 
study will end.  
DLTs will be listed, and their incidence summarized by primary system organ class, preferred 
term and worst grade (CTCAE v5.0). Listings and summaries will be based on the DDS. 
Randomized part 
The primary efficacy analysis to test the hypotheses and compare the two treatment groups will 
consist of the stratified log-rank test at an overall one-sided 2.5% significance level. The 
following null and alternative hypothesis will be tested to address the primary efficacy objective 
for PFS based on BIRC as per RECIST 1.1: 


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H01: θ1 = 1 vs. HA1: θ1 < 1 where θ1 is the PFS hazard ratio (capmatinib in combination with 
osimertinib versus platinum-pemetrexed based chemotherapy). The stratification will be based 
on the stratification factors assigned at randomization (presence of brain metastasis at baseline 
(presence vs absence) and prior treatment with 3rd generation EGFR TKIs (yes vs no). 
The primary efficacy variable, PFS, will be analyzed at the interim analysis and final analysis 
of a group sequential design (Section 12.7). Analyses will be based on the FAS population 
according to the randomized treatment group and strata assigned at randomization. The PFS 
distribution will be estimated using the Kaplan-Meier method, and Kaplan-Meier curves, 
medians and 95% confidence intervals of the medians will be presented for each treatment 
group. The hazard ratio for PFS will be calculated, along with its 95% confidence interval, from 
a stratified Cox model using the same stratification factors as for the log-rank test. Sensitivity 
analysis using PFS by investigator assessment will be performed using the same method. 
Further details will be provided in the SAP. 
Multiplicity 
In order to conserve the overall type-1 error (one-sided level of significance α=0.025), a 
graphical gate-keeping approach (Bretz et al 2009, Bretz et al 2011) is used. The primary 
endpoint of PFS will be tested with α=0.025. If the test is successful, the key secondary 
endpoints of ORR and OIRR will each be tested with an alpha split following a graphical gate-
keeping approach as shown in Figure 12-1. If one of the key secondary endpoint ORR or OIRR 
is successful, then the 1.25 % alpha assigned to the statistically significant endpoint will be 
transferred to the other key secondary endpoint and will be tested at a one-sided 2.5% level of 
significance. 
Figure 12-1 
Graphical gate-keeping procedure to test the key secondary 
endpoints in order to control overall type 1 error 
  
12.4.3 
Handling of intercurrent events of primary estimand 
The intercurrent events for the primary estimands and handling strategies are described in 
Section 2.1. The handling of the intercurrent events will allow the inclusion of PFS events in 
the primary analysis prior to inititation of new antineoplastic therapy and is targeting the 
treatment effect based on the primary endpoint of PFS due to any cause for the combination 
capmatinib and osimertinib compared to platinum-pemetrexed based doublet chemotherapy for 


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the target population and any unforeseen intercurrent Public Health emergency as declared by 
Local or Regional authorities i.e., pandemic, epidemic or natural disaster. 
12.4.4 
Handling of missing values not related to intercurrent event 
Part 1- Run-in part 
Participants who are ineligible for the DDS will be excluded from the primary analysis of DLT 
although their data will be used for all remaining analyses. Other missing data will simply be 
noted as missing on appropriate tables/listings. 
Part 2- Randomized part 
Participants whose disease has not progressed or died by the date of the analysis cut-off will 
have their PFS censored at the time of the last adequate tumor evaluation performed on or before 
the cut-off date. Clinical deterioration will not be considered as documented disease progression. 
PFS events will be included in the analysis if it occurs after one missing assessment. PFS will 
be censored at the last adequate tumor assessment if a participant didn’t have an event or the 
event occurred after two or more consecutive missing tumor assessments. 
As per Section 4.6 during a Public Health emergency as declared by Local or Regional 
authorities i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, the number of missing measurements for the primary endpoint PFS may increase and the 
potential to recover information from intermediate measurements that have been dropped from 
the visit schedule may decrease. This may affect the power of tests and the precision of 
estimates for this study. Since it is due to pandemic/epidemic, a reduced visit schedule can be 
considered to be caused by independent external factors as long as the latter is applied uniformly 
across the two arms. 
12.4.5 
Sensitivity analyses  
In the randomized part, the following sensitivity analyses for the primary endpoint of PFS will 
be performed: 
PFS by investigator assessment using a stratified Cox model, with the same analysis 
conventions as for the primary efficacy analysis. The treatment effect will be summarized by 
the hazard ratio with its 95% confidence interval. Kaplan-Meier curves, medians and 95% 
confidence intervals of the medians will be presented for each treatment group. 
12.4.6 
Supplementary analysis 
As supplementary analyses performed in the FAS, the hazard ratio and 95% confidence interval 
for PFS per BIRC review will be obtained from: 
1. an unstratified and covariate unadjusted Cox model. 
2. a stratified and covariate adjusted Cox model. A final list of covariates will be defined in 
the SAP. 
Furthermore, a supplementary analysis in the FAS will be performed for PFS by BIRC where 
PFS will take into account all PFS events regardless of study treatment discontinuation or start 
of new antineoplastic therapy (treatment policy strategy). 


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12.4.7 
Supportive analyses 
As supportive analyses, if the primary analysis is statistically significant, subgroup analyses to 
assess the homogeneity of the treatment effect across demographic and baseline disease 
characteristics will also be performed. Important subgroups will be specified in the Statistical 
Analysis Plan (SAP). 
12.5 
Analysis supporting secondary objectives 
12.5.1 
Efficacy endpoint(s) 
For the run-in part, the secondary efficacy endpoints are below: 
• ORR, DOR, time to response (TTR), and disease control rate (DCR), by 
investigator assessment per RECIST 1.1. 
• PFS by investigator assessment as per RECIST 1.1. 
For the randomized part, the key secondary estimands are defined in Section 2.2 for the key 
secondary endpoints of ORR and OIRR. Other secondary efficacy endpoints are described as 
the following: 
• DOR, time to response (TTR), and disease control rate (DCR), by BIRC as per RECIST 
1.1. 
• PFS2 (PFS after next-line of treatment) based on local investigator assessment 
• Overall Survival 
• Duration of intracranial response (DOIR), time to intracranial response (TTIR), and 
intracranial disease control rate (IDCR) by BIRC as per RANO-BM criteria 
 
 
 
  
 
12.5.1.1 Key secondary endpoints 
Overall response rate (ORR) 
The secondary estimand for ORR is defined in Section 2.2. ORR is defined as the proportion of 
participants with confirmed best overall response (BOR) of CR or partial response (PR), and 
will be assessed by BIRC review and according to RECIST 1.1. The following null and 
alternative hypothesis will be tested using stratified Miettinen and Nurminen’s 
method (Miettinen and Nurminen 1985) to address the key secondary efficacy objective for 
ORR based on BIRC as per RECIST 1.1: 
H01: θ1 - θ2 ≤ 20 % vs. HA1: θ1 - θ2 > 20 %, where θ1, θ2 are the ORR for the treatment 
(capmatinib in combination with osimertinib) and control (platinum-pemetrexed based doublet 
chemotherapy) arms respectively. ORR will be calculated based on the data from the FAS and 
strata assigned at randomization. The stratification will be based on the stratification factors 


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assigned at randomization (presence of brain metastasis at baseline (presence vs absence) and 
previous treatment with 3rd generation EGFR TKIs (yes vs no)).  
The difference in ORR and its 95% confidence interval from the stratified Miettinen and 
Nurminen's method with strata weighting by sample size with a single treatment covariate will 
be reported. 
As a supportive analysis, ORR per local investigators will be analyzed using the same method 
as ORR by BIRC.  
Further details will be provided in the SAP.  
Overall intracranial response rate (OIRR) 
The secondary estimand for OIRR is defined in Section 2.2. OIRR is defined as the proportion 
of participants with confirmed best overall intracranial response (BOIR) of CR or partial 
response (PR), and will be assessed by BIRC review. The following null and alternative 
hypothesis 
will 
be 
tested 
using 
stratified 
Miettinen 
and 
Nurminen’s 
method (Miettinen and Nurminen 1985) to address the key secondary efficacy objective for 
OIRR based on BIRC: 
H01: θ1 - θ2 ≤ 30 % vs. HA1: θ1 - θ2 > 30 %, where θ1, θ2 are the OIRR for the 
treatment (capmatinib in combination with osimertinib) and control (platinum-pemetrexed 
based chemotherapy) arms respectively. OIRR will be calculated based on the data from the 
FAS and strata assigned at randomization. The stratification will be based on the stratification 
factor assigned at randomization (previous treatment with 3rd generation EGFR TKIs (yes vs 
no)). 
The difference in OIRR and its 95% confidence interval from the stratified Miettinen and 
Nurminen's method with strata weighting by sample size with a single treatment covariate will 
be reported. 
As a supportive analysis, OIRR per local investigators will be analyzed using the same method 
as OIRR by BIRC. 
Handling of intercurrent events for the key secondary estimands  
The intercurrent events for the key secondary estimands and handling strategies are described 
in Section 2.2. The handling of the intercurrent events will allow the inclusion of all BOR and 
BOIR in the analysis and is targeting the treatment effect based on ORR and OIRR due to any 
cause for the combination of capmatinib and osimertinib compared to platinum-pemetrexed 
based doublet chemotherapy for the target population irrespective of study treatment 
discontinuation and any Public Health emergency as declared by Local or Regional authorities 
i.e., pandemic, epidemic or natural disaster. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, the number of missing measurements for the key secondary endpoints (ORR and 
OIRR) may increase and the potential to recover information from intermediate measurements 
that have been dropped from the visit schedule may decrease. Since it is due to 


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pandemic/epidemic, a reduced visit schedule can be considered to be caused by independent 
external factors as long as the latter is applied uniformly across the two arms. 
The BOR and BOIR assessments after the use of new anti-cancer therapy will be considered as 
non-responses and have been accounted for in the variable attribute using the composite strategy. 
12.5.1.2 Other secondary efficacy endpoints 
Duration of response (DOR) 
DOR by BIRC is a secondary endpoint. DOR only applies to participants whose BOR is CR or 
PR according to RECIST 1.1 based on tumor response data. DOR is defined as the time from 
the date of first documented response (CR or PR) to the first documented progression per 
RECIST 1.1 or death due to any cause. If a participant has not had an event, DOR is censored 
at the date of last adequate tumor assessment. Participants who never achieved a BOR of CR or 
PR will be excluded from the analysis. The distribution function of DOR will be estimated using 
the Kaplan-Meier method. Definition of last adequate tumor assessment is provided in 
Section 16.1. DOR will be analyzed based on the data from the FAS. Median DOR, with 
corresponding 95% CI, and 25th and 75th percentiles (Brookmeyer and Crowley 1982, 
Klein and Moeschberger 1997) will be presented. DOR will be also assessed by local review 
and will be analyzed with the same method as supportive analysis.  
Kaplan-Meier (KM) estimates for DOR proportions (by BIRC and by investigator) at specific 
time points, along with 95% CI (Greenwood’s formula, Kalbfleisch and Prentice 2002) will 
also be provided. 
Time to response (TTR) 
TTR is defined as the time from the date of randomization to the first documented response of 
either CR or PR, which must be subsequently confirmed (date of initial response is used, not 
date of confirmation), according to RECIST 1.1 (see Section 16.1). TTR by BIRC will be 
presented as the secondary analysis. The analysis of TTR by investigator assessment will also 
be presented as a supportive analysis. 
Participants without a confirmed CR or PR will be censored at the study-maximum follow-up 
time (i.e., LPLV−FPFV) for participants with a PFS event, or at the date of the last adequate 
tumor assessment for participants without a PFS event. TTR will be summarized using the 
Kaplan-Meier (KM) method, based on data from the FAS. Median TTR, with corresponding 
95% 
CI, 
and 
25th 
and 
75th 
percentiles 
(Brookmeyer and Crowley 1982, 
Klein and Moeschberger 1997) will be presented. KM estimates for TTR proportions at specific 
time points, along with 95% CI (Greenwood’s formula, Kalbfleisch and Prentice 2002) will 
also be provided. 
Disease control rate (DCR) 
DCR is defined as the proportion of participants with a BOR of confirmed CR, PR and stable 
disease (SD) according to RECIST 1.1 (Section 16.1). DCR will be assessed by local review as 
well as by BIRC. DCR by BIRC will be presented as the secondary analysis and DCR by 
investigator assessment will be provided as supportive analysis. 


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DCR will be calculated based on the data from the FAS and the corresponding 95% confidence 
intervals based on the exact binomial distribution (Clopper and Pearson 1934) will be presented. 
Progression-free survival 2 (PFS2) 
PFS2 is defined as time from date of randomization to the first documented progression on the 
next line therapy or death from any cause, whichever occurs first. The PFS2 distribution will 
be estimated using the Kaplan-Meier method for each treatment arm. The hazard ratio for PFS2 
will be calculated, along with its 95% confidence interval, using a Cox model stratified by 
randomization stratification factors. PFS2 analysis will be performed using data from FAS. 
Overall survival (OS) 
OS is defined as the time from the date of randomization to the date of death due to any cause. 
If a participant is alive at the date of the analysis cut-off or lost to follow-up, then OS will 
be censored at the last contact date prior to data cut-off date. OS will be summarized using the 
KM method, based on data from the FAS. 
Median 
OS 
with 
corresponding 
95% 
CI, 
and 
25th 
and 
75th percentiles 
(Brookmeyer and Crowley 1982, Klein and Moeschberger 1997) will be presented. 
The hazard ratio for OS will be calculated, along with its 95% confidence interval, from a 
stratified Cox model using the same stratification factors as for PFS analysis. 
The analysis of OS will be performed at the time of the analysis for the primary endpoint of 
PFS. 
Final analysis of OS will be performed at the end of the study as defined in Section 9.2. 
There is no hypothesis testing for OS and thus it is not included in the group sequential testing 
procedure. 
Sensitivity analyses for OS may be performed and further details will be provided in the SAP. 
Duration of intracranial response (DOIR) 
DOIR only applies to participants whose confirmed BOIR is CR or PR per RANO-BM criteria 
as assessed by BIRC review. DOIR is defined as the time from the date of first documented 
intracranial response of either CR or PR to the date of the first documented intracranial 
progression per RANO-BM criteria as assessed by BIRC review or the date of death due to any 
cause. Participants with a confirmed intracranial CR or PR will be censored if they have disease 
progression in organs other than brain and have no scans in brain after that. Participants will 
also be censored if they did not have an event. The censoring date will be the date of the last 
adequate tumor assessment in brain. DOIR will be summarized using the KM method. Median 
DOIR, 
with 
corresponding 
95% 
CI, 
and 
25th 
and 
75th 
percentiles 
(Brookmeyer and Crowley 1982, Klein and Moeschberger 1997) will be presented. KM 
estimates for DOIR proportions at specific time points, along with 95% CI (Greenwood’s 
formula, Kalbfleisch and Prentice 2002) will also be provided. 


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Time to intracranial response (TTIR) 
TTIR is defined as the time from the date of randomization to the date of the first documented 
intracranial response of either CR or PR per RANO-BM criteria as assessed by the BIRC review, 
which must be subsequently confirmed (date of initial response is used, not date of 
confirmation). All participants in the FAS-BM will be included in TTIR calculations. 
Participants without a confirmed intracranial CR or PR will be censored at the study-maximum 
follow-up time (i.e., LPLV−FPFV) for participants with a PFS event (intracranial progression 
or death due to any cause), or at the date of the last adequate tumor assessment in brain for 
participants without a PFS event. 
TTIR will be summarized using the KM method, based on data from the FAS-BM. Median 
TTIR, 
with 
corresponding 
95% 
CI, 
and 
25th 
and 
75th 
percentiles 
(Brookmeyer and Crowley 1982, Klein and Moeschberger 1997) will be presented. KM 
estimates for TTIR proportions at specific time points, along with 95% CI (Greenwood’s 
formula, Kalbfleisch and Prentice 2002) will also be provided. 
Intracranial disease control rate (IDCR) 
IDCR is calculated based on response assessment in the brain for participants having 
measurable and/or non-measurable brain metastases at baseline. IDCR is the proportion of 
participants with a confirmed BOIR of CR or PR or SD (or non-CR/non-PD) per RANO-BM 
criteria as assessed by BIRC review. 
IDCR calculated based on the data from the FAS-BM and the corresponding 95% CI based on 
the exact binomial distribution (Clopper and Pearson 1934) will be presented. 
12.5.2 
Safety endpoints 
For the safety run-in part, summary tables and listings will be presented by dose regimen using 
the safety set. For the randomized part, all listings and tables will be presented by treatment 
group. For all safety analyses, the safety set will be used. 
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). Further details will be included in the SAP. 
The overall observation period will be divided into three mutually exclusive segments: 
1. Pre-treatment period: from day of participant’s informed consent to the day before first dose 
of study medication, 
2. On-treatment period: from date of first administration of study treatment to the earlier of  
• 30 days after date of last administration of study treatment (including start and stop 
date), 
• the date prior to start of extension treatment with capmatinib + osimertinib following 
crossover from control arm, 


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3. Post-treatment period: starting at day 30+1 after last dose of study medication or first day of 
extension treatment with capmatinib + osimertinib. 
Further details of the analysis and data reporting from participants who crossover from 
platinum-pemetrexed based doublet chemotherapy arm to capmatinib in combination with 
osimertinib therapy will be provided in the SAP. 
Adverse events 
All information obtained on adverse events will be displayed by treatment group and participant. 
The number (and percentage) of participants with treatment emergent adverse events (events 
started after the first dose of study medication or events present prior to start of double-blind 
treatment but increased in severity based on preferred term) will be summarized in the following 
ways: 
by treatment, primary system organ class and preferred term. 
by treatment, primary system organ class, preferred term and maximum severity. 
by treatment, Standardized MedDRA Query (SMQ) and preferred term. 
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation, and adverse events 
leading to dose adjustment. 
The number (and proportion) of participants with adverse events of special interest will be 
summarized by treatment. 
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class. 
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs. 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment. 
Serious adverse events, non-serious adverse events and adverse events of special interest 
(AESI) during the on-treatment period will be tabulated. 
All deaths (on-treatment and post-treatment) will be summarized. 
All AEs, deaths, and serious adverse events (including those from the pre- and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged. 


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Vital signs 
All vital signs data will be summarized by treatment and visit/time. 
12-lead ECG 
1. PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each 
participant during the study. ECG data will be read and interpreted centrally. 
2. Categorical Analysis of QT/QTc interval data based on the number of participants meeting 
or exceeding predefined limits in terms of absolute QT/QTc intervals or changes from baseline 
will be presented. 
All ECG data will be summarized by treatment and visit/time. 
Clinical laboratory evaluations 
All laboratory data will be summarized by treatment group and visit/time. Shift tables using the 
low/normal/high/ (low and high) classification will be used to compare baseline to the worst 
on-treatment value. 
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used. 
For laboratory tests where grades are not defined by CTCAE version 5.0, results will be 
categorized as low/normal/high (based on laboratory normal ranges). 
The following listings/summaries will be generated separately for hematology, and 
biochemistry tests: 
• Listing of all laboratory data with values flagged to show the corresponding CTCAE 
version 5.0 grades if applicable and the classifications relative to the laboratory normal 
ranges. 
For laboratory tests where grades are defined by CTCAE version 5.0: 
• Worst post-baseline CTCAE grade (regardless of the baseline status). Each participant will 
be counted only once for the worst grade observed post-baseline. 
• Shift tables using CTCAE version 5.0 grades to compare baseline to the worst on-treatment 
value. 
For laboratory tests where grades are not defined by CTCAE version 5.0: 
• Shift tables using the low/normal/high/ (low and high) (or other project-specific) 
classification to compare baseline to the worst on-treatment value. 
 
 


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12.5.3 
Pharmacokinetics 
The PAS will be used in all pharmacokinetic data analysis and PK summary statistics. 
Capmatinib, osimertinib, AZ5104 and AZ7550 plasma concentration data will be listed by 
treatment, subject, and visit/sampling time point. Descriptive summary statistics will be 
provided pre-dose (trough) concentrations by visit/sampling time point. Summary statistics will 
include mean (arithmetic and geometric), SD, CV (coefficient of variation) (arithmetic and 
geometric), median, minimum, and maximum. Concentrations below LLOQ (< 1.0 ng/mL) will 
be treated as zero in summary statistics and for PK parameter calculations.  
For C1D1 and C2D1 in run-in part (intensive PK), pharmacokinetic parameters (i.e., AUC, Cmin, 
Cmax, Tmax, T1/2) will be calculated by noncompartmental methods and listed by subject. 
Descriptive summary statistics will include mean (arithmetic and geometric), SD, and CV 
(arithmetic and geometric), median, minimum, and maximum. An exception to this is Tmax 
where median, minimum, and maximum will be presented. 
PK-QTc Analysis will be performed to evaluate the relationship between osimeritinib 
concentration and change from baseline in QT corrected for heart rate and the details will be 
provided in the SAP. 
12.5.4 
Patient reported outcomes 
Four patient-reported outcomes questionnaires will be assessed: EORTC QLQ-C30, QLQ-
LC13, EQ-5D-5L and NCCN Fact Brain Symptom index. Scoring of PRO data and methods 
for handling of missing items or missing assessments will be handled according to the scoring 
manual and user guide for each respective patient questionnaire (Fayers 2001, 
Van Reenen and van Nistelrooij 2019). Details will be provided in the SAP. 
Descriptive statistics will be used to summarize the scored scales and subscales of the EORTC 
QLQ-C30, QLQ-LC13 and EQ-5D-5L and NCCN Fact Brain Symptom index at each scheduled 
assessment time point for each treatment group. Additionally, change from baseline in the scale 
and subscale values at the time of each assessment will be summarized. Participants with an 
evaluable baseline score and at least one evaluable post-baseline score during the treatment 
period will be included in the change from baseline analyses. 
The distribution of time to symptom deterioration will be analyzed by treatment group for 
patient scores from the EORTC QLQ-C30, QLQ-LC13 and NCCN FBrSI questionnaires. It 
will be estimated using the Kaplan-Meier method and the median time along with two-sided 
95% CIs will be presented. The hazard ratio will be estimated, along with its 95% confidence 
interval, using a stratified Cox proportional hazard model using the randomization stratification 
factor. Further details will be specified in the SAP. 
The number of participants completing each questionnaire and the number of missing or 
incomplete assessments will be summarized by treatment group for each scheduled assessment 
time point. No formal statistical tests will be performed for PRO data and hence no multiplicity 
adjustment will be applied. The FAS will be used for analyzing PRO data. Additional analyses 
may be performed if deemed necessary. Such analyses will be defined in the SAP. 


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12.7 
Interim analyses 
Run-in part 
No formal interim analysis is planned. The decision on the recommended dose of capmatinib 
in combination with osimertinib in the run-in part will be based on analyses performed after at 
least 6 evaluable participants completed the first cycle. Dose recommendation decisions will be 
made by Investigators and Novartis study personnel 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. Details of this procedure and the process for communication with investigators are 
provided in Section 6.5.1.2. 
Randomized part 
One interim analysis is planned after approximately 65 of the 162 targeted PFS events (i.e., at 
approximately 40% information fraction) have been documented (expected around 18.5 months 
from the date of first participant randomized in the study). The primary intent of the interim 
analysis is to stop early for futility. Approximately 130 (57.8%) participants are expected to be 
randomized at the time of the interim analysis, i.e., when approximately 65 PFS events have 
occurred. To be conservative, it is assumed that both futility and efficacy analyses are performed 
at the interim analysis. However, there is no plan to stop the study for efficacy at the interim 
analysis. An α-spending according to Haybittle-Peto stopping boundary with fixed p-
value=0.0001 will be used for the IA for efficacy. 
A gamma spending function (γ = 1) will be used as a beta-spending function to determine the 
non-binding futility boundary. 
Based on the choice of alpha-spending function described above and if the interim analysis is 
performed exactly at 65 PFS events, the futility boundary in terms of the Z statistic scale at the 
interim is calculated as Z=-0.472. The observed z-statistic has to be greater than Z = -0.472 to 
conclude futility. 
Since the observed number of events at the interim analysis may not be exactly equal to the 
planned 65 PFS events, the futility boundaries will need to be re-calculated using the pre-
specified α-spending and β-spending functions and based on the actual number of observed 
events at interim and the total number of targeted events to calculate the exact information 


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fraction. The observed hazard ratio at the interim analysis will then be compared against the re-
calculated or futility boundary. 
If the study continues to the final PFS analysis, the final PFS analysis will be performed when 
approximately 162 PFS events have been documented. If exactly 65 events are observed at the 
interim analysis, the study continues and exactly 162 events are obtained at the final analysis, 
the observed p-value will have to be less than 0.025 to declare statistical significance. In practice, 
the final analysis will be based on the actual number of PFS events documented at the cut-off 
date for the final PFS analysis and the alpha already spent at the interim analysis. The boundary 
for the final analysis will be derived accordingly from the pre-specified α-spending such that 
the overall significance level across all analyses is maintained at 0.025. 
The statistical properties of the group sequential design are summarized in Table 12-1 below. 
Table 12-1 
Simulated probabilities to stop for futility at the interim or final PFS 
analysis 
Scenario 
Look 
# PFS events 
Simulated cumulative probabilities (%) 
Stop for efficacy 
Stop for futility 
Under H0 (HR=1) 
Interim 
65 
0.02 
67.61 
  
Final 
162 
2.79 
97.21 
Under Ha 
(HR=0.529) 
Interim 
65 
13.60 
2.23 
  
Final 
162 
95.63 
4.37 
Under other Ha 
(HR=0.7) 
Interim 
65 
1.38 
18.42 
  
Final 
162 
54.84 
45.16 
NOTE: Simulation is performed in East (6.4) with number of simulations = 10,000 and 
randomization seed =100 
To be conservative, a small alpha-will be spent based on Haybittle-Peto boundary with fixed p-
value=0.0001 (as implemented in East 6.4) for the key secondary endpoints of ORR and OIRR. 
However, there is no intention to stop the study for efficacy at interim analysis. 
Approximately 57.8% participants are expected to be randomized at the time of the interim 
analysis. If the primary endpoint of PFS meets the futility stopping criteria, the study will be 
discontinued and no further tests on the key secondary endpoints will be performed. In addition, 
OS will be summarized for hazard ratio at the time of the final PFS analysis. 
The interim analyses will be performed by an independent statistician (not involved with the 
conduct of the study). Further details will be described in the DMC charter. The results of the 
interim analyses will be provided to the DMC by the independent statistician. 
12.8 
Sample size calculation 
12.8.1 
Primary endpoint(s) 
Run-in part 
No formal statistical power calculations to determine sample size were performed for this part 
of the study. Approximately 10 participants will be enrolled with the starting dose of capmatinib 
(400 mg b.i.d.) and osimertinib (80 mg q.d.) to have at least 6 evaluable participants. If the 


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initial dose is not considered safe and tolerable, additional 10 more participants could be 
enrolled at a lower dose level (DL-1) of capmatinib (400 mg b.i.d.) and osimertinib (40 mg q.d.) 
to achieve additional 6 evaluable participants.  
Randomized part 
The sample size calculation is based on the primary variable PFS. The hypotheses to be tested 
and details of the testing strategy are described in Section 12.4.2 
Based on available data Mok et al (2017) and the negative prognostic impact of the MET 
dysregulation and T790M negative population, the median PFS in the control arm (platinum - 
pemetrexed based doublet chemotherapy) is expected to be around 4.5 months. It is expected 
that treatment with capmatinib in combination with osimertinib (experimental treatment arm) 
will result in 47.1% reduction in the risk of progression and/or death, i.e., an expected overall 
hazard ratio of 0.529 (which corresponds to an increase in median PFS to 8.5 months under the 
exponential model assumption). 
Then in order to ensure at least 95% power to test the null hypothesis: PFS hazard ratio = 1, 
versus the specific alternative hypothesis: PFS hazard ratio = 0.529, it is calculated that a total 
of 162 PFS events need to be observed. This calculation assumes analysis by a one-sided log-
rank test at the overall 2.5% level of significance, participants randomized to the two treatment 
arms in a 2:1 ratio, and a 2-look group sequential design with a gamma spending function (γ=1) 
using information fractions of 40% to define a non-binding futility rule at the interim analysis. 
Assuming that enrollment will continue for 32 months at a uniform rate of 7 participants per 
month, a total of 225 participants will need to be randomized to observe the targeted 162 PFS 
events at about 5 months after the randomization date of the last participant, i.e., 37 months 
after the randomization date of the first participant. Then assuming losses to follow-up for PFS 
of 20%, the required sample size of the study is 225 randomized participants, which requires an 
accrual rate of 7 participants per month during the 32-month recruitment period. The sample 
size of 225 participants will be randomly assigned to each treatment arm in a 2:1 ratio (150 
participants in the experimental treatment arm, 75 participants in the control arm). These 
calculations were made using the software package East (6.4). 
12.8.2 
Secondary endpoint(s) 
Overall Response Rate (ORR) 
ORR, as the key secondary variable, will be formally statistically tested, provided that the 
primary variable PFS is statistically significant. The hypotheses to be tested and details of the 
testing strategy are provided in Section 12.5.1. Based on available data (Soria et al 2015, 
Mok et al 2017), the ORR in the control arm is expected to be around 35%. It is hypothesized 
that treatment with capmatinib and osimertinib will result in a 20% increase in the ORR for 
treatment, i.e., an expected ORR of 55%. The ORR will be tested at the time of the final PFS 
analysis. Based on the number of participants that are planned to be enrolled in this study to 
provide sufficient power for the primary endpoint (225 participants), and randomization ratio 
of 2:1; the test for ORR (H01: θ1 - θ2 ≤ 20 % vs. HA1: θ1 - θ2 > 20 % ) based on difference in 
ORR without the stratification factors with pooled estimate of variance will have 72.8% power 


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with a one-sided alpha of 0.0125 if OIRR is not significant or 81.6% power at 2.5% level of 
significance if OIRR is significant. 
The approximate treatment difference required to reach the bound (Δ ORR) is 15.8% when 
OIRR is not significant and 13.9% when OIRR is significant. 
Overall Intracranial Response Rate (OIRR) 
OIRR, as the key secondary variable, will be formally statistically tested, provided that the 
primary variable PFS is statistically significant. The hypotheses to be tested and details of the 
testing strategy are provided in Section 12.5.1. Based on available data (Schuler et al 2016), the 
OIRR in the control arm is expected to be around 25%. It is hypothesized that treatment with 
capmatinib and osimertinib will result in a 30% increase in the OIRR for treatment, i.e., an 
expected OIRR of 55%. The OIRR will be tested at the time of the final PFS analysis. Based 
on the number of participants that are planned to be enrolled in this study (225 participants) and 
approximately 30% of participants will have brain metastasis at randomization, it is expected 
that there will be approximately 68 participants available in the brain metastasis analysis set. 
The test for OIRR (H01: θ1 - θ2 ≤ 30 % vs. HA1: θ1 - θ2 > 30 %) based on difference in OIRR 
without the stratification factor with pooled estimate of variance will have 54.5% power with a 
one-sided alpha of 0.0125 if ORR is not significant or 66.3% power at 2.5% level of significance 
if ORR is significant. 
The approximate treatment difference required to reach the bound (Δ OIRR) is 28.7% when 
ORR is not significant and 25.1% when ORR is significant. 
Overall Survival (OS) 
At the time of the final analysis of PFS, the hazard ratio of OS will be estimated. A positive 
trend of OS hazard ratio in favor of the treatment arm (hazard ratio <1) is expected to support 
the efficacy conclusion from PFS. Since OS is not powered given the limitation of sample size 
and enrollment, no test will be conducted for OS. 
The number of OS events expected to observe an OS hazard ratio less than 1 are summaried in 
the Table 12-2: 
Table 12-2 
Number of OS events expected at the time of the final PFS analysis 
under different assumptions and scenarios 
Scenario 
Median OS (months) in 
Control Arm 
Median OS (months) in 
Treatment Arm 
# OS events 
HR = 0.70 
14 
20 
112 
HR = 0.75 
14 
18.67 
114 
HR = 0.85 
14 
16.47 
117 
These calculations were made using the software package East (6.4). 


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13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) international ethical guidelines 
• Applicable ICH Good Clinical Practice (GCP) guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, ICF, IB, and other relevant documents must be submitted 
to Health Authorities and IRB/IEC by the investigator and reviewed and approved by the HA 
and the IRB/IEC before the study is initiated. 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g., [Clinicaltrials.gov], EudraCT 
etc.). For details on the Novartis publication policy including authorship criteria, please refer to 
the Novartis publication policy training materials that were provided to you at the trial 
investigator meetings. 


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13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
13.5 
Participant Engagement 
Participant engagement initiatives are included in this study and will be provided, as available, 
for distribution to study participants at the timepoints indicated. If compliance is impacted by 
cultural norms or local laws and regulations, sites may discuss modifications to these 
requirements with Novartis. Examples of Patient Engagement initiatives that might be included 
in this study are: 
• Thank You letter 
• Plain language trial summary – after CSR publication 
• Individual study results – after CSR publication 
• Trial Feedback Questionnaires (TFQ) – end of trial 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented. 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 


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Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
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16 
Appendices 
16.1 
Appendix 1: Guidelines for Response, Duration of Overall 
Response, TTF, TTP, Progression-Free Survival, and Overall 
Survival (based on RECIST 1.1) 
Document type: 
TA Specific Guidelines 
Document Status: 
Version 3.2: February 11, 2016 Version 3.1: 
November 29, 2011 Version 3: October 19, 2009 
Version 2: January 18, 2007 Version 1: December 13, 
2002 
Release date: 
11-Feb-2016 
Authors (Version 3.2): 
Kalyanee Appanna, Bharani Dharan, Steven Green, 
Randi Isaacs, Susan Schnakenberg, Jessica Wang, 
Cristian Massacesi 
Authors (Version 3.1): 
Kalyanee Appanna, Bee Chen, Bharani Dharan, 
Steven Green, Diana Porshneva, Kannan 
Subramanian, Michel Gauthier, Nilima Patel, Sandra 
Chica, Aruna Vattikola, Emmanuel Zuber 
Authors (Version 3): 
Kalyanee Appanna, Steven Green, Samit Hirawat, 
David Lebwohl, Cristian Massacesi, Liza Morgan, 
Haren Rupani, Jeffrey Stuart, Aruna Vattikola, Gabriel 
von Ingersleben 
Authors (Version 2): 
Renaud Capdeville, Bee Chen, Insa Gathmann, 
Steven Green, David Lebwohl, Michael Murawsky, 
Lixia Wang, Emmanuel Zuber 
Authors (Version 1): 
Insa Gathmann, William Mietlowski, Beate Kiese, 
Kathy Mellars, Renaud Capdeville, Margaret Dugan 
16.1.1 
Introduction 
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This document 
is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the revised 
RECIST 1.1 guidelines (Eisenhauer et al 2009). 
The efficacy assessments described in Section 16.1.2 and the definition of best response in 
Section 16.1.3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 16.1.3.2 is summarizing the “time to event” 
variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 16.1.4 of 
this guideline describes data handling and programming rules. This section is to be referred to 
in the SAP (Statistical Analysis Plan) to provide further details needed for programming. 
16.1.2 
Efficacy assessments 
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), and revised 
RECIST guidelines (version 1.1) (Eisenhauer et al 2009). 


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16.1.2.1 Definitions 
16.1.2.1.1 
Disease measurability 
In order to evaluate tumors throughout a study, definitions of measurability are required in order 
to classify lesions appropriately at baseline. In defining measurability, a distinction also needs 
to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions. 
Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. If the 
measurable disease is restricted to a solitary lesion, its neoplastic nature should be confirmed 
by cytology/histology. 
For patients without measurable disease see Section 16.1.3.2.8. 
Measurable lesions (both nodal and non-nodal) 
• Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10 mm 
whichever is greater - e.g., the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm. 
• Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft tissue 
component meets the definition of measurability. 
• Measurable nodal lesions (i.e., lymph nodes) - Lymph nodes ≥ 15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring ≥ 10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at baseline, 
regardless of the slice thickness, are normal and not considered indicative of disease. 
• Cystic lesions: - Lesions that meet the criteria for radiographically defined simple cysts (i.e., 
spherical structure with a thin, non-irregular, non-nodular and non-enhancing wall, no 
septations, and low CT density [water-like] content) should not be considered as malignant 
lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts; 
- ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if noncystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
• Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with ≥ 10 
to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly identified by 
physical exam that is not measurable by reproducible imaging techniques. 
16.1.2.1.2 
Eligibility based on measurable disease 
If no measurable lesions are identified at baseline, the patient may be allowed to enter the study 
in some situations (e.g., in Phase III studies where PFS is the primary endpoint). However, it is 
recommended that patients are excluded from trials where the main focus is on the Overall 
Response Rate (ORR). Guidance on how patients with just non-measurable disease at baseline 
will be evaluated for response and also handled in the statistical analyses is given in 
Section 16.1.3.2.8. 


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16.1.2.2 Methods of tumor measurements - general guidelines 
In this document, the term “contrast” refers to intravenous (i.v.) contrast. 
The following considerations are to be made when evaluating the tumor: 
• All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the treatment. 
• Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment. 
• For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-up. 
Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed using 
a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan slice 
thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. If, at 
baseline, a patient is known to have a medical contraindication to CT contrast or develops 
a contraindication during the trial, the following change in imaging modality will be 
accepted for follow-up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis. 
• A change in methodology can be defined as either a change in contrast use (e.g., keeping 
the same technique, like CT, but switching from with to without contrast use or vice-versa, 
regardless of the justification for the change) or a major change in technique (e.g. from CT 
to MRI, or vice-versa), or a change in any other imaging modality. A change from 
conventional to spiral CT or vice versa will not constitute a major “change in method” for 
the purposes of response assessment. A change in methodology will result by default in a 
UNK overall lesion response assessment as per Novartis calculated response. However, 
another response assessment than the Novartis calculated UNK response may be accepted 
from the investigator or the central blinded reviewer if a definitive response assessment can 
be justified, based on the available information. 
• FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:  
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 
• No FDG-PET at baseline with a positive FDG-PET at follow-up 
• 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. 


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• Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
• Physical exams: Evaluation of lesions by physical examination is accepted when lesions are 
superficial, with at least 10mm size, and can be assessed using calipers. 
• Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions, unless pre-specified by the 
protocol. It is, however, a possible alternative to clinical measurements of superficial 
palpable lymph nodes, subcutaneous lesions and thyroid nodules. US might also be useful 
to confirm the complete disappearance of superficial lesions usually assessed by clinical 
examination. 
• Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for objective 
tumor evaluation has not yet been fully and widely validated. Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may only be 
available in some centers. Therefore, the utilization of such techniques for objective tumor 
response should be restricted to validation purposes in specialized centers. However, such 
techniques can be useful in confirming complete pathological response when biopsies are 
obtained. 
• Tumor markers: Tumor markers alone cannot be used to assess response. However, some 
disease specific and more validated tumor markers (e.g., CA-125 for ovarian cancer, PSA 
for prostate cancer, alpha-FP, LDH and Beta-hCG for testicular cancer) can be integrated 
as non-target disease. If markers are initially above the upper normal limit they must 
normalize for a patient to be considered in complete clinical response when all lesions have 
disappeared. 
• Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 
and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed). 
• Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
16.1.2.3 Baseline documentation of target and non-target lesions 
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions: 
• Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 


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clinically). Each target lesion must be uniquely and sequentially numbered on the eCRF 
(even if it resides in the same organ). 
Minimum target lesion size at baseline 
• Non-nodal target: Non-nodal target lesions identified by methods for which slice thickness 
is not applicable (e.g., clinical examination, photography) should be at least 10 mm in 
longest diameter. See Section 16.1.2.1.1. 
• Nodal target: See Section 16.1.2.1.1. 
A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target lesions 
will be calculated and reported as the baseline sum of diameters (SOD). The baseline sum of 
diameters will be used as reference by which to characterize the objective tumor response. Each 
target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF. 
• Non-target lesions: All other lesions are considered non-target lesions, i.e., lesions not 
fulfilling the criteria for target lesions at baseline. Presence or absence or worsening of non-
target lesions should be assessed throughout the study; measurements of these lesions are 
not required. Multiple non-target lesions involved in the same organ can be assessed as a 
group and recorded as a single item (i.e., multiple liver metastases). Each non-target lesion 
identified at baseline must be followed at each subsequent evaluation and documented on 
eCRF. 
16.1.2.4 Follow-up evaluation of target and non-target lesions 
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 16-1) and non-target lesions (Table 16-2) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 16-3) as well as the presence or absence of new lesions. 
16.1.2.4.1 
Follow-up and recording of lesions 
At each visit and for each lesion the actual date of the scan or procedure which was used for the 
evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate lesion 
evaluation data are examined by the investigator in order to derive the overall visit response. 
Therefore, all such data applicable to a particular visit should be associated with the same 
assessment number. 
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. 


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Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement. This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval. 
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated. 
Nodal lesions 
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are not 
expected to disappear completely, so a “non-zero size” will always persist. 
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness). Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval. 
However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
lesions, which may be required subsequently for response determination. 
16.1.2.4.2 
Determination of target lesion response 
Table 16-1 
Response criteria for target lesions 
Response Criteria 
Evaluation of target lesions 
Complete Response (CR) 
Disappearance of all non-nodal target lesions. In addition, any pathological 
lymph nodes assigned as target lesions must have a reduction in short axis 
to < 10 mm 1 
Partial Response (PR) 
At least 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 emasured 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 and increase in 
lesions which would qualify for PD 
Unknown (UNK) 
Progression has not been documented and one or more target lesions have 
not been assessed or have been assessed using a different method than 
baseline 3 
1. SOD for CR may not be zero when nodal lesions are part of target lesions 
2. Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present and all 
nodal lesions are <10 mm in size. In this case, the target lesion response is CR 
3. In exceptional circumstances an UNK response due to change in method could be over-ruled by the 
investigator or central reviewer using expert judgement based on the available information (see Notes on target 
lesion response and methodology change in Section 16.1.2.2) 


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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 eCRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in Table 16-1 above (i.e., a PD will be 
determined if there is at least 20% increase in the sum of diameters of 
• For those patients who have only one target lesion at baseline, the reappearance of the target 
lesion which disappeared previously, even if still small, is considered a PD. 
• Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
is 140 mm (with data for 2 other lesions missing) then a PD should be assigned. However, 
in other cases where a PD cannot definitely be attributed, the target lesion response would 
be UNK. 
• Nodal lesions 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. 


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• 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 response categories have well defined 
criteria. 
16.1.2.4.3 
Determination of non-target lesion response 
Table 16-2 
Response criteria for non-target lesions 
Response Criteria 
Evaluation of non-target lesions 
Complete Response (CR): 
Disappearance of all non-target lesions. In addition, all lymph nodes 
assigned a non-target lesions must be non pathological in size (< 10 mm 
short axis) 
Progressive Disease (PD): 
Unequivocal progression of existing non-target lesions 1 
Non-CR/Non-PD 
Neither CR nor PD 
Unknown (UNK) 
Progression has not been documented and one or more non-target lesions 
have not been assessed or have been assessed using 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 reviewer does 
prevail 
2. It is recommended that the investigator and/or central reviewer should use expert judgement to assign a Non-
UNK response whenever 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 


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any abnormal nodal lesions (i.e., ≥ 10 mm) the response can only be ‘Non-CR/Non-PD’ 
unless there is unequivocal progression of the non-target lesions (in which case response is 
PD) or it is not possible to determine whether there is unequivocal progression (in which 
case response is UNK) 
• Unequivocal progression: To achieve “unequivocal progression” on the basis of non-target 
disease there must be an overall level of substantial worsening in non-target disease such 
that, even in presence of CR, PR or SD in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. A modest “increase” in the size 
of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
non-target disease in the face of CR, PR or SD of target disease is therefore expected to be 
rare. In order for a PD to be assigned on the basis of non-target lesions, the increase in the 
extent of the disease must be substantial even in cases where there is no measurable disease 
at baseline. If there is unequivocal progression of non-target lesion(s), then at least one of 
the non-target lesions must be assigned a status of “Worsened”. Where possible, similar 
rules to those described in Section 16.1.2.4.2 for assigning PD following a CR for the non-
target lesion response in the presence of non-target lesions nodal lesions should be applied. 
16.1.2.4.4 
New lesions 
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion eCRF page. 
• If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion. 
• If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 16.1.2.5).  
• A lymph node is considered as a "new lesion" and, therefore, indicative of progressive 
disease if the short exis increases in size to ≥ 10 mm for the first time in the study plus 5 
mm absolute increase. FDG-PET: can complement CT scans in assessing progression 
(particularly possible for "new" disease). See Section 16.1.2.2. 
16.1.2.5 Evaluation of overall lesion response 
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response and presence of new lesions as shown below in Table 16-3. 
Table 16-3 
Overall lesion response at each assessment 
Target lesions 
Non-target lesions 
New lesions 
Overall lesion response 
CR 
CR 
No 
CR1 
CR 
Non-CR/Non-PD3 
No 
PR 
CR, PR, SD 
UNK 
No 
UNK 


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Target lesions 
Non-target lesions 
New lesions 
Overall lesion response 
PR 
Non-PD and not UNK 
No 
PR1 
SD 
Non-PD and not UNK 
No 
SD 1,2 
UNK 
Non-PD or UNK 
No 
UNK1 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1. This overall lesion response also applies when there are no non-target lesions identified at baseline 
2. Once confirmed PR was achieved, all these assessments are considered PR 
3. As defined in Section 16.1.2.4 
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR. 
16.1.3 
Efficacy definitions 
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 16.1.3.2.8 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts. 
16.1.3.1 Best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria. 
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the protocol 
should specifically describe if these will be included in the determination of best overall 
response and/or whether these additional assessments will be required for sensitivity or 
supportive analyses. As a default, any assessments taken more than 30 days after the last dose 
of study treatment will not be included in the best overall response derivation. If any alternative 
cancer therapy is taken while on study any subsequent assessments would ordinarily be 
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. 


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• For non-randomized trials where response is the primary endpoint, confirmation is needed 
• For trials intended to support accelerated approval, confirmation is needed 
• For all other trials, confirmation of response may be considered optional 
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules: 
• CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required 
• PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR prior 
to progression where confirmation not required 
• SD = at least one SD assessment (or better) > 6 weeks after randomization/start of treatment 
(and not qualifying for CR or PR 
• PD = progression ≤ 12 weeks after randomization/ start of treatment (and not qualifying for 
CR, PR or SD) 
• UNK = all other cases (i.e., not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 12 weeks) 
The time durations specified in the SD/PD/UNK definitions above are defaults based on a 6 
weeks 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 


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PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the PR for this patient. 
All subsequent assessments are considered PR even if tumor measurements decrease only by 
20% compared to baseline (200 mm to 160 mm) at the following assessments. 
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response. 
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates. 
The best overall response for a patient is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided 
from different sources: 
• Investigator overall lesion response 
• Central Blinded Review overall lesion response 
• Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review) 
The primary analysis of the best overall response will be based on the sequence of 
investigator/central blinded review/calculated (investigator)/calculated (central) overall lesion 
responses. 
Based on the patients’ best overall response during the study, the following rates are then 
calculated: 
Overall response rate (ORR) is the proportion of patients with a best overall response of CR 
or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications. 
Disease control rate (DCR) is the proportion of patients with a best overall response of CR or 
PR or SD. The objective of this endpoint is to summarize patients with signs of “activity” 
defined as either shrinkage of tumor (regardless of duration) or slowing down of tumor growth. 
Clinical benefit rate (CBR) is the proportion of patients with a best overall response of CR or 
PR , or an overall lesion response of SD or Non-CR/Non-PD which lasts for a minimum time 
duration (with a default of at least 24 weeks in breast cancer studies). This endpoint measures 
signs of activity taking into account duration of disease stabilization. 
Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used: 
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 
(Dent et al 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 


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and DCR calculation depending on the analysis population (e.g., populations based on an ITT 
approach). 
16.1.3.2 Time to event variables 
16.1.3.2.1 
Progression-free survival 
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g., in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint. 
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment. 
PFS rate at x weeks is an additional measure used to quantify PFS endpoint. It is recommended 
that a Kaplan Meier estimate is used to assess this endpoint. 
16.1.3.2.2 
Overall survival 
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date the 
patient was last seen alive / last known date patient alive, the date of death and the reason of 
death (“Study indication” or “Other”). 
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be censored 
at the date of last known date patient alive. 
16.1.3.2.3 
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. 


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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. 
16.1.3.2.4 
Time to treatment failure 
This endpoint is often appropriate in studies of advanced disease where early discontinuation is 
typically related to intolerance of the study drug. In some protocols, time to treatment failure 
may be considered as a sensitivity analysis for time to progression. The list of discontinuation 
reasons to be considered or not as treatment failure may be adapted according to the specificities 
of the study or the disease. 
Time to treatment failure (TTF) is the time from date of randomization/start of treatment to 
the earliest of date of progression, date of death due to any cause, or date of discontinuation due 
to reasons other than ‘Protocol violation’ or ‘Administrative problems’. The time to treatment 
failure for patients who did not experience treatment failure will be censored at last adequate 
tumor assessment. 
16.1.3.2.5 
Duration of response 
The analysis of the following variables should be performed with much caution when restricted 
to responders since treatment bias could have been introduced. There have been reports where 
a treatment with a significantly higher response rate had a significantly shorter duration of 
response but where this probably primarily reflected selection bias which is explained as 
follows. It is postulated that there are two groups of patients: a good risk group and a poor risk 
group. Good risk patients tend to get into response readily (and relatively quickly) and tend to 
remain in response after they have a response. Poor risk patients tend to be difficult to achieve 
a response, may have a longer time to respond, and tend to relapse quickly when they do respond. 
Potent agents induce a response in both good risk and poor risk patients. Less potent agents 
induce a response mainly in good risk patients only. This is described in more detail by 
Morgan 1988. 
It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then interpreted 
with caution by evaluating the results in the context of the observed response rates. If an 
inferential comparison between treatments is required this should only be performed on all 
patients (i.e. not restricting to “responders” only) using appropriate statistical methods such as 
the techniques described in Ellis et al 2008. It should also be stated in the protocol if duration 
of response is to be calculated in addition for unconfirmed response. 
For summary statistics on “responders” only the following definitions are appropriate (specific 
definitions for an all-patient analysis of these endpoints are not appropriate since the status of 
patients throughout the study is usually taken into account in the analysis). 
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed the start date is the date of first documented response (CR or PR) and the end date 
and censoring is defined the same as that for time to progression. 


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The following two durations might be calculated in addition for a large Phase III study in which 
a reasonable number of responders is seen. 
Duration of overall complete response (CR): For patients with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression. 
Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to be 
confirmed) or SD the start and end date as well as censoring is defined the same as that for time 
to progression. 
16.1.3.2.6 
Time to response 
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be confirmed 
depending on the type of study and its importance. Where the response needs to be confirmed 
then time to response is the time to the first CR or PR observed. 
Although an analysis on the full population is preferred a descriptive analysis may be performed 
on the “responders” subset only, in which case the results should be interpreted with caution 
and in the context of the overall response rates, since the same kind of selection bias may be 
introduced as described for duration of response in Section 16.1.3.2.5. It is recommended that 
an analysis of all patients (both responders and non-responders) be performed whether or not a 
“responders only” descriptive analysis is presented. Where an inferential statistical comparison 
is required, then all patients should definitely be included in the analysis to ensure the statistical 
test is valid. For analysis including all patients, patients who did not achieve a response (which 
may have to be a confirmed response) will be censored using one of the following options: 
• at maximum follow-up (i.e., First Patient First Visit (FPFV) to Last Patient Last Visit 
(LPLV) used for the analysis) for patients who had a PFS event (i.e., progressed or died due 
to any cause). In this case the PFS event is the worst possible outcome as it means the patient 
cannot subsequently respond. Since the statistical analysis usually makes use of the ranking 
of times to response it is sufficient to assign the worst possible censoring time which could 
be observed in the study which is equal to the maximum follow-up time (i.e., time from 
FPFV to LPLV) 
• at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding 
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint. 
16.1.3.2.7 
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. 


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In the calculation of the assessment date for time to event variables, any unscheduled 
assessment should be treated similarly to other evaluations. 
Start Dates 
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date. 
For the calculation of duration of response the following start date should be used: 
• Date of first documented response is the assessment date of the first overall lesion response 
of CR (for duration of overall complete response) or CR / PR (for duration of overall 
response) respectively, when this status is later confirmed. 
End dates 
The end dates which are used to calculate ‘time to event’ variables are defined as follows: 
• Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page). 
• Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease. 
• Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) the date 
of randomization/start of treatment is used. 
• Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 16.1.3.2.7). 
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months. 
• Date of discontinuation is the date of the end of treatment visit. 
• Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date patient alive from the survival follow-up page is used. 
If no survival follow-up is available, the date of discontinuation is used as last contact date. 
• Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery. 
16.1.3.2.8 
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 


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consideration with respect to inclusion in any analysis of endpoints based on the overall 
response evaluations. 
It is recommended that any patients with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints. 
Although the text of the definitions described in the previous sections primarily relates to 
patients with measurable disease at baseline, patients without measurable disease should also 
be incorporated in an appropriate manner. The overall response for patients with non-
measurable disease is derived slightly differently according to Table 16-4. 
Table 16-4 
Overall lesion response at each assessment: patients with non-target 
disease only 
Non-target lesions 
New lesions 
Overall lesion response 
CR 
No 
CR 
Non-CR/Non-PD1 
No 
Non-CR/Non-PD 
UNK 
No 
UNK 
PD 
Yes or No 
PD 
Any 
Yes 
PD 
1. As defined in Section 16.1.2.4 
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g., in particular by 
displaying the specific numbers with the non-CR/non-PD category. 
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account. 
For ORR it is recommended that the main (ITT) analysis includes data from patients with only 
non-measurable disease at baseline, handling patients with a best response of CR as “responders” 
with respect to ORR and all other patients as “non-responders”. 
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses which 
exclude these particular patients. Endpoints such as PFS which are reliant on the determination 
and/or timing of progression can incorporate data from patients with only non-measurable 
disease. 
16.1.3.2.9 
Sensitivity analyses 
This section outlines the possible event and censoring dates for progression, as well as addresses 
the issues of missing tumor assessments during the study. For instance, if one or more 
assessment visits are missed prior to the progression event, to what date should the progression 
event be assigned? And should progression event be ignored if it occurred after a long period 
of a patient being lost to follow-up? It is important that the protocol and RAP specify the 
primary analysis in detail with respect to the definition of event and censoring dates and also 
include a description of one or more sensitivity analyses to be performed. 


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Based on definitions outlined in Section 16.1.3.2.7, and using the draft FDA guideline on 
endpoints (FDA 2018) as a reference, the following analyses can be considered: 
Table 16-5 
Options for event dates used in PFS, TTP, duration of response 
Situation 
Options for end-date 
(progression or 
censoring)1 (1) = 
default unless specified 
differently in the 
protocol or RAP 
Outcome 
A 
No baseline assessment 
(1) Date of 
randomization/start of 
treatment3 
Censored 
B 
Progression at or before 
next scheduled 
assessment 
(1) Date of progression 
(2) Date of next 
scheduled assessment2 
Progressed 
Progressed 
C1 
Progression or death 
after exactly one missing 
assessment 
(1) Date of progression 
(or death) 
(2) Date of next 
scheduled assessment2 
Progressed 
Progressed 
C2 
Progression or death 
after two or more 
missing assessments 
(1) Date of last adequate 
assessment2 
(2) Date of next 
scheduled assessment2 
(3) Date of progression 
(or death) 
Censored 
Progressed 
Progressed 
D 
No progression 
(1) Date of last adequate 
assessment 
Cendored 
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 the situations 
above (ITT approach) 
(2) Date of last adequate 
assessment prior to new 
anticancer therapy 
(3) Date of secondary 
anticancer therapy 
(4) Date of secondary 
anticancer 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) 


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Situation 
Options for end-date 
(progression or 
censoring)1 (1) = 
default unless specified 
differently in the 
protocol or RAP 
Outcome 
1. Definitions can be found in Section 16.1.3.2.7 
2. After the last adequate tumor assessment. "Date of next scheduled assessment" is defined in 
Section 16.1.3.2.7 
3. The rare exception to this is if the patient dies no later than the time of the second scheduled assessment as 
defined in the protocol in which case this is a PFS event at the date of death 
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F. 
Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e.: 
• (C1) taking the actual progression or death date, in the case of only one missing assessment 
• (C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments 
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2. 
Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as patients without documented PD 
should be followed for progression after discontinuation of treatment. However, option (2) may 
be used as sensitivity analysis. If progression is claimed based on clinical deterioration instead 
of tumor assessment by e.g., CT-scan, option (2) may be used for indications with high early 
progression rate or difficulties to assess the tumor due to clinical deterioration. 
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1) (ITT) is the recommended approach; events 
documented after the initiation of new cancer therapy will be considered for the primary 
analysis i.e., progressions and deaths documented after the initiation of new cancer therapy 
would be included as events. This will require continued follow-up for progression after the 
start of the new cancer therapy. In such cases, it is recommended that an additional sensitivity 
analysis be performed by censoring at last adequate assessment prior to initiation of new cancer 
therapy. 
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. 


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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 5 the “Date 
of last adequate assessment” by the “Date of previous scheduled assessment (from baseline)”, 
with the following definition: 
• Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly followed 
from baseline, immediately before or on the date of the last adequate tumor assessment. 
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on the 
individual requirements for the specific study and disease area and have to be specified in the 
protocol or RAP documentation. 
16.1.4 
Data handling and programming rules 
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g., on incomplete dates). 
16.1.4.1 Study/project specific decisions 
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation. 
The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock). 
16.1.4.2 End of treatment phase completion 
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow-
up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc. 
The end of treatment visit and its associated assessments should occur within 7 days of the last 
study treatment.  


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Patients may discontinue study treatment for any of the following reasons: 
• Adverse event(s) 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 
• Participant/guardian decision 
• Progressive disease 
• Study terminated by the sponsor 
• Non-compliant with study treatment 
• No longer requires treatment 
• Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given) 
Death is a reason which “must” lead to discontinuation of patient from trial. 
16.1.4.3 End of post-treatment follow-up (study phase completion) 
End of post-treatment follow-up visit will be completed after discontinuation of study treatment 
and post-treatment evaluations but prior to collecting survival follow-up. 
Patients may provide study phase completion information for one of the following reasons: 
• Adverse event 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 
• Participant/guardian decision 
• Death 
• Progressive disease 
• Study terminated by the sponsor 
16.1.4.4 Medical validation of programmed overall lesion response 
In order to be as objective as possible the RECIST programmed calculated response assessment 
is very strict regarding measurement methods (i.e., any assessment with more or less sensitive 
method than the one used to assess the lesion at baseline is considered UNK) and not available 
evaluations (i.e., if any target or non-target lesion was not evaluated the whole overall lesion 
response is UNK unless remaining lesions qualified for PD). This contrasts with the slightly 
more flexible guidance given to local investigators (and to the central reviewers) to use expert 
judgment in determining response in these type of situations, and therefore as a consequence 
discrepancies between the different sources of response assessment often arise. To ensure the 


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quality of response assessments from the local site and/or the central reviewer, the responses 
may be re-evaluated by clinicians (based on local investigator data recorded in eCRF or based 
on central reviewer data entered in the database) at Novartis or external experts. In addition, 
data review reports will be available to identify assessments for which the investigators’ or 
central reader’s opinion does not match the programmed calculated response based on RECIST 
criteria. This may be queried for clarification. However, the investigator or central reader’s 
response assessment will never be overruled. 
If Novartis elect to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall lesion response 
at that specific assessment is to be kept in a dataset. This must be clearly documented in the 
RAP documentation and agreed before database lock. This dataset should be created and stored 
as part of the ‘raw’ data. 
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation. 
16.1.4.5 Programming rules 
The following should be used for programming of efficacy results: 
16.1.4.5.1 
Calculation of time to event variables 
Time to event = end date - start date + 1 (in days) 
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative. 
16.1.4.5.2 
Incomplete assessment dates 
All investigation dates (e.g., X-ray, CT scan) must be completed with day, month and year. 
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 16.1.3.2.7). If all measurement dates have 
no day recorded, the 1st of the month is used. 
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation. 
16.1.4.5.3 
Incomplete dates for last known date patient alive or death 
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact. 


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16.1.4.5.4 
Non-target lesion response 
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’. 
16.1.4.5.5 
Study/project specific programming 
The standard analysis programs need to be adapted for each study/project. 
16.1.4.5.6 
Censoring reason 
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page. 
For survival the following censoring reasons are possible: 
• Alive 
• Lost to follow-up 
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible: 
• Ongoing without event 
• Lost to follow-up 
• Withdrew consent 
• Adequate assessment no longer available* 
• Event documented after two or more missing tumor assessments (optional, see Table 16-5) 
• Death due to reason other than underlying cancer (only used for TTP and duration of 
response) 
• Initiation of new anti-cancer therapy 
*Adequate assessment is defined in Section 16.1.3.2.7. This reason is applicable when adequate 
evaluations are missing for a specified period prior to data cut-off (or prior to any other 
censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason 
should also be noted: 
• This may be when there has been a definite decision to stop evaluation (e.g., reason = 
“Sponsor decision” on study evaluation completion page), when patients are not followed 
for progression after treatment completion or when only UNK assessments are available 
just prior to data cut-off) 
• The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g., withdrawal of consent, loss to follow-up or alternative anti-
cancer therapy) has occurred more than the specified period following the last adequate 
assessment 
• This reason will also be used to censor in case of no baseline assessment. 


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16.2 
Appendix 2: Response assessment in neuro-oncology (RANO) 
criteria for Brain Metastases 
Document type 
TA specific guidelines 
Document status 
Version 1: 04-Jun-2020 
Release Date 
04-Jun-2020 
Authors (Version 1) 
Maeve Waldron-Lynch, Sylvie Le Mouhaer, Pavan 
Jayavaram, Jagannath Ghosh 
16.2.1 
Introduction 
This guideline provides the general principles and application of the Response Assessment in 
Neuro-Oncology for Brain Metastases (RANO-BM) criteria to assess tumor response and to 
derive efficacy endpoints in Novartis oncology brain metastases trials. This guideline is based 
on the publication: “Response assessment criteria for brain metastases: proposal from the 
RANO group” (Lin et al 2015).  
In studies with an endpoint of overall intracranial response rate (OIRR), tumor response will be 
primarily evaluated by the Response Assessment in Neuro-Oncology (RANO) working group 
Brain Metastases criteria, the RANO-BM Criteria (Lin et al 2015).  
The standard response and progression criteria from RANO-BM are relevant for the assessment 
of parenchymal brain metastases only. Leptomeningeal metastases, which are generally not 
radiographically measurable in a reliable and reproducible manner, will be treated as for non-
target lesions.  
Similar to RECIST 1.1 (Eisenhauer et al 2009), definitions for radiographical response in 
RANO-BM are based on unidimensional measurements. Participants will undergo gadolinium-
enhanced MRI* assessments for response evaluation as defined in the protocol. 
The efficacy assessments described in Section 16.2.2 and the definition of best overall 
intracranial response in Section 16.2.3.1 are based on the RANO-BM criteria but also give more 
detailed instructions and rules for determination of best response. Section 16.2.3.2 is 
summarizing the endpoints and related variables.  
The following components will be taken into account when assessing a participant’s overall 
intracranial response at an individual evaluation: 
• Tumor evaluation for gadolinium-enhanced MRI assessments  
• Overall lesion response category (CR/PR/PD/SD (or non-CR/non-PD)/NE) 
• Corticosteroid usage 
• ECOG performance scale and other clinical evaluation findings 
*In this document, the term “MRI” refers to gadolinium-enhanced MRI.  
16.2.2 
Efficacy assessments 
Tumor evaluations are made based on RANO-BM (Lin et al 2015).  


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16.2.2.1 Definitions 
16.2.2.1.1 
Disease measurability 
In order to evaluate CNS tumors throughout a study, definitions of measurability are required 
in order to classify lesions appropriately at baseline. 
Measurable disease  
Measurable disease is defined as a contrast-enhancing lesion that can be accurately measured 
in at least one dimension, with a minimum size of 10 mm, and is visible on two or more axial 
slices that are preferably 5 mm or less apart with 0 mm skip (and ideally ≥1.5 mm apart with 
0 mm skip). Additionally, although the longest diameter in the plane of measurement is to be 
recorded, the diameter perpendicular to the longest diameter in the plane of measurement should 
be at least 5 mm for the lesion to be considered measurable. If the MRI is performed with thicker 
slices, the size of the measurable lesion at baseline should be at least double the slice thickness. 
Interslice gaps, if present, should also be considered in the determination of the minimum size 
of measurable lesions at baseline. 
Non-measurable disease  
Non-measurable disease includes all other lesions, including: 
• Other measurable lesions that cannot be considered as target lesions 
• Lesions with longest dimension less than 10 mm,  
• Lesions with borders that cannot be reproducibly measured,  
• Dural, bony skull metastases,  
• Cystic-only lesions, and  
• Leptomeningeal disease.  
Lesions composed of a tumor around a cyst or a surgical cavity are considered non-measurable 
unless there is a nodular component that measures 10 mm or more in longest diameter and 5 mm 
or more in perpendicular plane. The cystic or surgical cavity should not be measured for the 
determination of a response. Non-measurable lesions should all be followed as non-target 
lesions. 
16.2.2.1.2 
Eligibility based on measurable disease 
If no measurable lesions are identified at baseline, the participant may be allowed to enter the 
study in some situations (e.g., studies including participants with leptomeningeal disease). 
Guidance on how participants with just non-measurable disease at baseline will be evaluated 
for response is given in Section 16.2.3.4. 
16.2.2.2 Methods of tumor measurement general guidelines 
Participants will undergo gadolinium-enhanced MRI assessments for response evaluation as 
defined per protocol.  
The following considerations are to be made when evaluating the tumor:  


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• All measurements should be taken and recorded in metric notation (mm) using a digital 
measurement tool.  
• All baseline evaluations should be performed as closely as possible to randomization/start 
of treatment and never more than 28 days before the randomization/start of treatment. 
• The same method of assessment and technique (gadolinium- enhanced MRI) should be used 
to characterize each identified and reported lesion at baseline and during follow-up. 
16.2.2.2.1 
Special circumstances 
In the case of participants who have been treated with stereotactic radiosurgery or 
immunotherapy-based approaches, for whom there has been radiographical evidence of 
enlargement of target and non-target lesions, which do not necessarily represent tumor 
progression, if radiographical evidence of progression exists, but clinical evidence indicates that 
the radiological changes are due to treatment effect (and not due to progression of cancer), 
additional evidence is needed to distinguish between true progression and treatment effect. In 
this case, standard MRI alone is insufficient. Participants can continue on protocol therapy 
pending further investigation with one or more of the following options: 
• The MRI can be repeated at the next protocol-scheduled assessment or sooner, and generally 
within 6-8 weeks. The investigator can choose a shorter time interval if progressive 
symptoms or other clinical concerns arise.  
• Continued tumor growth might be consistent with radiographical progression, in which case 
the participant should discontinue the study. 
• Stabilisation and shrinkage of a lesion can be consistent with treatment effect, in such case 
the participant can stay on study. 
• For participants with equivocal results even on the next scheduled restaging scan, the scan 
can be repeated again at a subsequent protocol scheduled assessment or sooner, although 
surgery or use of an advanced imaging modality are encouraged. Surgical pathology can be 
obtained via biopsy or resection. 
• For lesions treated by stereotactic radiosurgery, additional evidence of tumor progression 
or treatment effect (radionecrosis) can be acquired with an advanced imaging modality, such 
as perfusion MRU; magnetic resonance spectroscopy, or 18FLT PET. In addition, clinical 
judgment and involvement of a multidisciplinary team may be required to adjudicate and 
distinguish between radiation necrosis and true progression. Note, that these advanced 
imaging modalities have not been extensively studied with regards to immunotherapy-based 
approaches and therefore cannot be recommended to distinguish between tumor progression 
and immune-related changes at present.  
• Irrespective of the additional testing obtained, if subsequent testing shows that progression 
has occurred, the date of progression should be recorded as the date of the scan at which 
this issue was first raised. 
• Participants can also have an equivocal finding on a scan (e.g., as small lesion that is not 
clearly new).  
• Continued treatment is permissible until the next protocol-scheduled assessment. 


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


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corticosteroid usage relative to baseline, ECOG performance scale and other clinical evaluation 
findings relative to baseline. 
16.2.2.4.1 
Follow-up and recording lesions 
At each visit and for each lesion the actual date of the MRI which was used for the evaluation 
of each specific lesion should be recorded. This applies to target and non-target lesions as well 
as new lesions that are detected. At the assessment visit, all of the separate lesion evaluation 
data are examined by the investigator/local reader in order to derive the overall visit response.  
16.2.2.4.2 
Determination of response/progression 
The evaluation of overall intracranial lesion response at each assessment is a composite of the 
target lesion response, non-target lesion response, the presence of new lesions, corticosteroid 
usage relative to baseline, and clinical status as assessed by investigator and supported by the 
ECOG Performance Scale relative to baseline. 
Participants (except participants with leptomeningeal disease, see Section 16.2.3.4) who have 
measurable and/or non-measurable disease in the brain at baseline and have received at least 
one dose of therapy will be considered evaluable for response. 
All target lesion or non-target lesions must be assessed using the same methods and techniques 
as baseline for CR/PR/SD. 
Determination of target lesion response 
Target lesions should be assessed quantitatively at each of the time points specified in the 
protocol. 
Table 16-6 
Response assessment of target lesions 
Response Criteria 
Evaluation of target lesions 
Complete response (CR) 
Disappearance of all CNS target lesions sustained for at least 4 weeks; with 
no new lesions, no use of corticosteroids, and participant is stable or 
improved clinically 
Partial response (PR) 
At least a 30% decrease in the sum of longest diameters of CNS target 
lesions, taking as reference the baseline sum of longest diameters 
sustained for at least 4 weeks; no new lesions; stable to decreased 
corticosteroid dose; stable or improved clinically 
Progressive disease (PD) 
At least a 20% increase in the sum of longest diameters of CNS target 
lesions, taking as a reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the relative 
increase of 20%, at least one lesion must increase by an absolute value of 5 
mm or more to be considered progression 
Stable disease (SD) 
Neither sufficient shrinkage to qualify for partial response nor sufficient 
increase to qualify for progressive disease 
Not evaluable (NE) 
Progression has not been documented and one or more target lesions have 
not been assessed or have been assessed using a different method than 
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Determination of non-target lesion response 
Non-target lesions should be assessed qualitatively at each of the time points specified in the 
protocol. 
Table 16-7 
Response assessment of non-target lesions 
Response Criteria 
Evaluation of non-target lesions 
Complete response (CR) 
Requires all of the following: disappearance of all enhancing 
CNS non-target lesions, no new CNS lesions 
Non-complete response or non-progressive 
disease (Non-CR/Non-PD) 
Persistence of one or more non-target CNS lesion or lesions 
Progressive disease (PD) 
Any of the following: unequivocal progression of existing 
enhancing non-target CNS lesions, new lesion(s) (except 
while on immunotherapy-based treatment), CNS lesions. In 
the case of immunotherapy-based treatment, new lesions 
alone may not constitute progressive disease 
Not evaluable 
Progression has not been documented and one or more 
target lesions have not been assessed or have been 
assessed using a different technique than baseline 
New lesions 
New lesions can appear during treatment. The finding of a new CNS lesion should be 
unequivocal and not due to technical or slice variation. A lesion not present at baseline and 
appearing at any follow-up evaluation timepoint is considered a new lesion. 
If the MRI is obtained with slide thickness of 1.5 mm or less, the new lesion should also be 
visible in axial, coronal and sagittal reconstructions of 1.5 mm or thinner projections. If a new 
lesion is equivocal, for example because of its small size (i.e., ≤ 5 mm), continued therapy can 
be considered, and a follow-up assessment will clarify if it really is new disease. If repeated 
scans confirm a new lesion, progression should be declared using the date of the initial scan 
showing the new lesion. In the case of immunotherapy-based treatment, however, new lesions 
alone may not constitute progressive disease. 
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion eCRF page. 
Corticosteroids 
The corticosteroids (including medication name, dose and unit, frequency, route, start and end 
date, indication, ongoing, status compared to baseline) used for response determination have to 
be recorded in the eCRF. 
The corticosteroids dose at the time of the tumor assessment will be compared with the dose 
taken at the time of the baseline tumor assessment. If the participant is not taking corticosteroids 
at baseline, a zero dose will be considered as the baseline value. If corticosteroids dose is not 
available at baseline, then the baseline dose will be considered unknown. Every effort should 
be made to document the baseline and subsequent corticosteroid doses. 
If corticosteroids information is not collected at the intracranial assessment, the most recently 
recorded corticosteroid dose will be considered. 


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In the absence of clinical deterioration related to the tumor, an increase in corticosteroid dose 
alone should not be used as a sole determinant of progression. Participants with stable imaging 
results and whose corticosteroid dose has increased for reasons other than clinical deterioration 
related to the tumor do not qualify as having stable disease or progression. These participants 
should be observed closely, and if their corticosteroid dose can be reduced back to baseline, 
they will be considered as having stable disease, but if further clinical deterioration related to 
the tumor becomes apparent they will be considered as having progression. The date of 
progression should be the first time point at which corticosteroid dose increase was necessary. 
Clinical Status 
Clinical performance status will be evaluated based on the investigators’ opinion and 
complemented by the ECOG performance status scale. At each protocol-specified time point, 
ECOG assessment should occur and intracranial tumor assessment should be coincident with 
ECOG assessment. 
Clinical status based on the investigators’ opinion used for response determination has to be 
recorded in the eCRF page. 
If ECOG is unknown or not done at the intracranial tumor assessment, the previous ECOG 
assessment could be used for determination of the response. 
16.2.2.4.3 
Evaluation of overall lesion response 
The evaluation of overall intracranial lesion response at each assessment is a composite of the 
target lesion response, non-target lesion response, the presence of new lesions, corticosteroid 
use relative to baseline, and clinical status as assessed by investigator and supported by the 
ECOG Performance Scale as shown below in Table 16-8. 
Table 16-8 
Overall Lesion Response at each assessment 
Criterion 
Complete 
Response 
Partial Response 
Stable Disease 
Progressive 
Disease 
Target Lesions 
None 
≥ 30% decrease in 
sum LD relative to 
baseline 
< 30% decrease 
relative to baseline 
but < 20% increase 
in sum LD relative 
to nadir 1 
≥ 20% increase in 
sum LD relative to 
nadir 1 
Non-target Lesions 
2 
None 
Stable or improved 
Stable or improved 
Unequivocal PD 3 
New Lesion(s)4 
None 
None 
None 
Present 3 
Corticosteroids 
compared to 
baseline 
None 
Stable or 
decreased 
Stable or 
decreased 
Not applicable 5 
Clinical Status 
compared to 
baseline 
Stable or improved 
Stable or improved 
Stable or improved 
Worse 3 


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


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


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


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• PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR prior 
to progression where confirmation not required 
• SD = at least one SD assessment (or better) > 6 weeks after randomization/start of treatment 
(and not qualifying for CR or PR). 
• PD = progression ≤ 12 weeks after randomization/start of treatment (and not qualifying for 
CR, PR or SD). 
• Not evaluable (NE) = all other cases (i.e., not qualifying for confirmed CR or PR and 
without SD after more than 6 weeks or early progression within the first 12 weeks) 
The time durations specified in the SD/PD/NE definitions above are defaults based on a 6-8 
weeks tumor assessment frequency. However, these may be modified for specific indications 
(to be more or less aggressive). In addition, it is envisaged that the time duration may also take 
into account assessment windows. E.g., if the assessment occurs every 6 weeks with a time 
window of +/- 7 days, a BOR of SD would require a SD or better response longer than 5 weeks 
after randomization/start of treatment. 
16.2.3.2 Endpoints 
Based on the participants’ best overall intracranial response during the study, the following 
endpoints are then calculated: 
Overall intracranial response rate (OIRR) is the proportion of participants with a confirmed 
best overall intracranial response (BOIR) of CR or PR.  
Intracranial Disease control rate (IDCR) is the proportion of participants with a confirmed 
BOIR of CR or PR or SD (or non-CR/Non-PD).  
Duration of intracranial response (DOIR): DOIR only applies to participants whose 
confirmed BOIR is CR or PR. DOIR is defined as time from first documented intracranial 
response of either CR or PR to the date of the first documented intracranial progression or date 
of death due to any cause. Participants will be censored if they have disease progression in 
organs other than brain and have no scans in brain after that. The censoring date will be the date 
of the last adequate tumor assessment in brain. 
Time to intracranial response (TTIR): TTIR is defined as the time from the date of 
randomization/start of the treatment to the date of the first documented intracranial response of 
either CR or PR, which must be subsequently confirmed (date of initial response is used, not 
date of confirmation).  
All participants will be included in TTIR calculations. Participants without a confirmed 
intracranial CR or PR will be censored at the study-maximum follow-up time (i.e., 
LPLV−FPFV) for participants with event (intracranial progression or death due to any cause), 
or at the date of the last adequate intracranial tumor assessment for participants without an event.  


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


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


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4. Stable or improved clinical status per investigator supported ECOG performance status 
scale compared to baseline.  
Progressive disease (PD) 
Any of the following criteria must be met: 
1. Unequivocal progression of non-target lesions. To achieve unequivocal progression on the 
basis of non-target disease there must be an overall level of substantial worsening on the 
NT disease  
2. Any new lesion 
3. Clear clinical deterioration not attributable to other causes apart from the tumor (e.g., 
seizures, medication side effects, complications of therapy, cerebrovascular events, 
infection etc.). The definition of clinical deterioration is at the discretion of the investigator, 
however, it is recommended that a decline in the ECOG performance status, for at least 7 
days, be considered a clinical deterioration unless attributable to co-morbid events or 
changes in corticosteroid dose (increase in corticosteroids alone will not be taken into 
account in determining progression in the absence of persistent clinical deterioration) 
4. Failure to return for evaluation due to death or deteriorating condition unless caused by 
documented non-related disorders.  
16.2.3.4.2 
Best overall intracranial response 
The best overall intracranial response for each participant is determined from the sequence of 
overall (lesion) responses according to the following rules: 
• CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required 
• Non-CR/Non-PD = at least one Non-CR/Non-PD assessment (or better) > 6 weeks after 
randomization/start of treatment (and not qualifying for CR)  
• PD = progression ≤ 12 weeks after randomization/start of treatment (and not qualifying for 
CR or Non-CR/Non-PD). 
• Not evaluable (NE) = all other cases (i.e., not qualifying for confirmed CR and without 
Non-CR/Non-PD after more than 6 weeks or early progression within the first 12 weeks). 


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16.3 
Appendix 3: Permitted concomitant therapy requiring caution 
and/or action 
Table 16-11 
Drugs to be used with caution during co-administration with 
capmatinib and osimertinib 
Mechanism of Interaction 
Drug Name 
Strong CYP3A inhibitor 
ombitasvir/paritaprevir/dasabuvir/ritonavir (Viekira Pak), indinavir/ritonavir, 
tipranavir/ritonavir, 
ritonavir, 
cobicistat, 
indinavir, 
ketoconazole, 
troleandomycin, 
telaprevir, 
danoprevir/ritonavir, 
eltegravir/ritonavir, 
saquinavir/ritonavir, lopinavir/ritonavir, itraconazole, voriconazole, mibefradil, 
posaconazole, telithromycin, grapefruit juice, conivaptan, nefazodone, 
nelfinavir, idelalisib, boceprevir, atazanavir/ritonavir, darunavir/ritonavir 
Moderate CYP3A inducer 
bosentan, dabrafenib, efavirenz, etravirine, genistein, modafinil, nafcillin, 
tipranavir/ritonavir, lopinavir, telotristat 
CYP1A2 substrate with NTI 
theophylline, tizanidine 
P-gp substrates 1 
afatinib, alfuzosin, aliskiren, alogliptin, ambrisentan, apixaban, apremilast, 
aprepitant, atorvastatin, boceprevir, bosentan, carvedilol, caspofungin, ceritinib, 
colchicine, cyclosporine, dabigatran, digoxin, docetaxel, doxepin, doxorubicin, 
eribulin, 
everolimus, 
fentanyl, 
fexofenadine, 
fidaxomicin, 
fluvastatin, 
fosamprenavir, idelalisib, iloperidone, indacaterol, irbesartan, lacosamide, 
lapatinib, levetiracetam, linagliptin, linezolid, loperamide, losartan, maraviroc, 
mirabegron, nadolol, naloxegol, nateglinide, nevirapine, nintedanib, olodaterol, 
paclitaxel, pantoprazole, paroxetine, pazopanib, posaconazole, pravastatin, 
proguanil, ranolazine, riociguat, risperidone, ritonavir, rivaroxaban, saquinavir, 
silodosin, simeprevir, simvastatin, sirolimus, sitagliptin, sofosbuvir, sorafenib, 
tacrolimus, telaprevir, tenofovir, ticagrelor, tipranavir, tolvaptan, topotecan, 
umeclidinium, valsartan, vardenafil, vincristine, voriconazole 
BCRP substrates 1 
atorvastatin 
daunorubicin, 
dolutegravir, 
doxorubicin, 
ethinyl 
estradiol, 
hematoporphyrin, imatinib, irinotecan, methotrexate, mitoxantrone, paritaprevir, 
pitavastatin, rosuvastatin, simvastatin, sofosbuvir, sulfasalazine, tenofovir, 
topotecan, venetoclax 
Proton pump inhibitor 
Dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, 
rabeprazole 
H2-receptor antagonists 
cimetidine, famotidine, nizatidine, ranitidine 
Antacids 
aluminum carbonate, aluminum hydroxide, calcium carbonate, calcium 
hydroxide, bismuth subsalicylate 
Source: The list is adapted from the Novartis Institutes for Biomedical PK Sciences internal memorandum (v01, 
2018): drug-drug interactions (DDI) database, which is compiled primarily from the Indiana University School of 
Medicine’s “Clinically Relevant” Table (drug-interactions.medicine.iu.edu/Main-Table.aspx), the University of 
Washington’s Drug Interaction Database (druginteractioninfo.org), and the FDA’s “Guidance for Industry, Drug 
Interaction Studies”. 
This list may not be exhaustive and could be updated periodically. Please refer to the above mentioned source 
of 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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The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g., Clinicaltrials.gov, EudraCT 
etc.). 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 


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16.4 
Appendix 4: Prohibited QT prolongation concomitant medication 
for capmatinib and osimertinib 
Drugs with a known risk of Torsades de Pointes (TdP) are prohibited. For identification of drugs 
with known risk of TdP please refer to qtdrugs.org (refer to Table 16-12). 
Table 16-12 
Drugs with a known risk of Torsades de Pointes 
Torsades de Pointes Risk 
Generic Name 
Known 
Aclarubicine, 
amiodarone, 
anagrelide, 
arsenic 
trioxide, 
astemizole, 
azithromycin, bepridil, cesium chloride, chloroquine, chlorpromazine, 
chlorprothixene, 
cilostazol, 
ciprofloxacin, 
cisapride, 
citalopram, 
clarithromycin, cocaine, disopyramide, dofetilide, domperidone, donepezil, 
dronedarone, droperidol, erythromycin, escitalopram, flecainide, fluconazole, 
gatifloxacin, 
grepafloxacin, 
halofantrine, 
haloperidol, 
hydroquinidine, 
hydroxychloroquine, ibogaine, ibutilide, levofloxacin, levomepromazine, 
levomethadyl acetate, levosulpiride, mesoridazine, methadone, moxifloxacin, 
nifekalant, ondansetron, oxaliplatin, papaverine HCl (intra-coronary), 
pentamidine, pimozide, procainamide, propofol, quinidine, roxithromycin, 
sevoflurane, sotalol, sulpiride, sultopride, terfenadine, terlipressin, terodiline, 
thioridazine, vandetanib 
Check crediblemeds.org/healthcare-providers/drug-list for the most updated list. 
This may not be an exhaustive list, will be updated periodically. 
Note: if a medication is listed in more than one table, the more stringent practice is to be applied 


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16.5 
Appendix 5: Prohibited drugs 
Table 16-13 
Capmatinib and osimertinib: prohibited drugs 
Mechanism of Interaction 
Drug Name 
Strong CYP3A inducer 
carbamazepine, enzalutamide, lumacaftor, mitotane, 
phenobarbital, phenytoin, rifabutin, rifampicin, St. 
John's wort (Hypericum perforatum) 
Source: The list is adapted from the Novartis Institutes for Biomedical PK Sciences internal memorandum (v01, 
2018): drug-drug interactions (DDI) database, which is compiled primarily from the Indiana University School of 
Medicine’s “Clinically Relevant” Table (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 source 
of information. 
 

SAP_001.pdf: 
Clinical Development 
INC280/Capmatinib/Tabrecta® 
CINC280L12301 / NCT04816214
A phase III randomized, controlled, open-label, multicenter, global 
study of capmatinib in combination with osimertinib versus 
platinum - pemetrexed based doublet chemotherapy in patients with 
locally advanced or metastatic NSCLC harboring EGFR activating 
mutations who have progressed on prior 1st / 2nd generation 
EGFR‑TKI or osimertinib therapy and whose tumors are T790M 
mutation negative and harbor MET amplification (GEOMETRY-E)  
Statistical Analysis Plan (SAP) 
Author: 
Document type: 
SAP Amendment 
Document status: 
Final 1.0 
Release date: 
26-Sep-2022
Number of pages: 
45 
Property of Novartis 
 Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Template Version 4.0, Effective from 23-Apr-2021 


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SAP – Amendment 1 
 
CINC280L12301 
 
 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and 
title impacted 
(Current) 
10-
Aug-
2021 
Prior to 
DB lock 
Creation of 
final version 
N/A - First version 
NA 
26-
Sep-
2022 
Prior to 
DB lock 
for 
close-
out 
CSR 
Decision to 
terminate the  
study early 
and not open 
the 
randomized 
part  
Only a final synoptic CSR will be 
prepared as an abbreviated report 
based on the data from run-in part with 
reduced analyses. 
Abbreviate 
sections 1.1 
Study Design, 
2.1 Data 
analysis general 
information, 2.2 
Analysis sets, 
2.3.2 
Demographics, 
2.4 Treatments, 
2.5 Analysis 
supporting 
primary 
objective(s), 2.6 
Analysis 
supporting 
secondary 
objective(s), 
2.7.4 Other 
safety data, 2.8 
Pharmacokinetic 
endpoints, 5.5 
Appendix for 
Statistical 
models, 6 
Reference; 
Remove 
contents for 
sections 2.10 
Patient-reported 
outcomes, 
 
 
2.13 Interim 
analysis, 3 
Sample size 
calculation, 4 
Change to 
protocol 
specified 
analyses.  


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Table of contents 
Table of contents ................................................................................................................. 3 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
1 
Introduction ......................................................................................................................... 8 
1.1 
Study design............................................................................................................. 8 
1.2 
Study objectives, endpoints and estimands ........................................................... 11 
2 
Statistical methods ............................................................................................................. 13 
2.1 
Data analysis general information ......................................................................... 13 
2.1.1 
General definitions ................................................................................ 14 
2.2 
Analysis sets .......................................................................................................... 17 
2.2.1 
Subgroup of interest .............................................................................. 18 
2.3 
Participant disposition, demographics and other baseline characteristics ............. 18 
2.3.1 
Participant disposition ........................................................................... 18 
2.3.2 
Demographics and other baseline characteristics ................................. 18 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 19 
2.4.1 
Study treatment / compliance ................................................................ 19 
2.4.2 
Prior, concomitant and post therapies ................................................... 21 
2.5 
Analysis supporting primary objective(s) .............................................................. 22 
2.5.1 
Primary endpoint(s) ............................................................................... 22 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 22 
2.5.3 
Handling of missing values ................................................................... 23 
2.6 
Analysis supporting secondary objectives ............................................................. 23 
2.6.1 
Secondary endpoint(s) ........................................................................... 23 
2.6.2 
Sensitivity analyses ............................................................................... 26 
2.7 
Safety analyses ....................................................................................................... 27 
2.7.1 
Adverse events (AEs) ............................................................................ 27 
2.7.2 
Deaths .................................................................................................... 29 
2.7.3 
Laboratory data ..................................................................................... 29 
2.7.4 
Other safety data ................................................................................... 31 
2.8 
Pharmacokinetic endpoints .................................................................................... 32 
2.9 
PD and PK/PD analyses......................................................................................... 33 
2.10 
Patient-reported outcomes ..................................................................................... 33 
 
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 33 
2.13 
Interim analysis ...................................................................................................... 33 
3 
Sample size calculation ..................................................................................................... 33 
3.1.1 
Primary endpoint(s) ............................................................................... 33 
3.1.2 
Secondary endpoint(s) ........................................................................... 33 
4 
Change to protocol specified analyses .............................................................................. 33 
5 
Appendix ........................................................................................................................... 33 
5.1 
Dose interruptions and dose changes ..................................................................... 33 
5.1.1 
Definitions for capmatinib and osimertinib .......................................... 34 
5.1.2 
Definitions for cisplatin, carboplatin and pemetrexed .......................... 36 
5.2 
Imputation rules ..................................................................................................... 36 
5.2.1 
Study treatment ..................................................................................... 36 
5.2.2 
AE, concomitant medication (CM) , and safety assessment date 
imputation ............................................................................................. 37 
5.3 
AEs coding/grading ............................................................................................... 40 
5.4 
Laboratory parameters derivations ........................................................................ 40 
5.5 
Statistical models ................................................................................................... 40 
5.5.1 
Analysis supporting primary objective(s) ............................................. 40 
5.5.2 
Analysis supporting secondary objective(s).......................................... 40 
5.6 
Determination of missing adequate tumor assessments ........................................ 41 
5.7 
Novartis internal criteria for CTC grading of laboratory parameters (based on 
CTCAE v5 – Nov 2017) ........................................................................................ 43 
6 
Reference ........................................................................................................................... 45 
 
 


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List of tables 
Table 1-1 
Objectives and related endpoints .......................................................... 11 
Table 2-1 
Outcome and event/censor dates for PFS analysis ................................ 26 
Table 5-1 
Imputation of start dates (AE, CM) and assessments (LB, EG, VS) .... 37 
Table 5-2 
Imputation of end dates (AE, CM) ........................................................ 38 
 
List of figures 
Figure 1-1 
Part 1: Run-in Part ................................................................................. 10 
 


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List of abbreviations 
AE 
Adverse Event 
AESI 
Adverse Event of Special interest  
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AST 
Aspartate transaminase 
AUC 
Area under curve 
b.i.d. 
bis in die/twice a day 
BILI 
Total Bilirubin 
BIRC 
Blinded Independent Review Committee 
BOR 
Best Overall Response  
CI 
Confidence Interval  
CNS 
Central Nervous System 
CR 
Complete Response 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria Adverse Event 
 
 
CV 
coefficient of variation 
DCR 
Disease Control Rate  
DDS 
Dose-Determination Set  
DI 
Dose Intensity 
DL 
Dose Level  
DLT 
Dose Limiting Toxicity 
DOIR 
Duration Of Intracranial Response 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eCRS 
Electronic Case Retrieval Strategy 
EGFR 
Epidermal Growth Factor Receptor  
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
End Of Treatment 
EQ-5D-5L 
EuroQoL-5 Dimension-5 Level 
FAS 
Full Analysis Set 
FBrSI 
Fact Brain Symptom index 
FPFV 
First Patient First Visit 
HGRAC 
Human Genetic Resource Administration of China  
HRQoL 
Health-Related Quality of Life 
ICF 
Informed Consent Form 


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IDCR 
Intracranial disease control rate 
KM 
Kaplan-Meier 
LLOQ 
lower limit of quantification 
LPLV 
Last Patient Last Visit 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
MET 
Mesenchymal-to-Epithelial Transition factor 
mg 
milligram(s) 
mL 
milliliter(s) 
MRI 
Magnetic Resonance Imaging 
NCCN 
National Comprehensive Cancer Network 
NSCLC 
Non-small-cell lung cancer 
OIRR 
Overall Intracranial Response Rate  
ORR 
Overall Response Rate  
OS 
Overall survival  
PAS 
Pharmacokinetic Analysis Set 
PD  
Progressive disease  
PDI 
Planned Dose Intensity 
PFS 
Progression free survival  
PFS2 
Progression-Free Survival after next line of treatment 
PK 
Pharmacokinetics 
PR 
Partial Response 
PT 
Preferred term 
 
 
QTcF 
Fridericia QT correction formula 
RANO 
Response assessment in neuro-oncology  
RANO-BM 
Response Assessment in Neuro-Oncology Brain Metastases 
RDI 
Relative Dose Intensity 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SD 
Stable Disease 
SOCs 
System Organ Classes 
TKI 
Tyrosine Kinase Inhibitors  
TTIR 
Time To Intracranial Response 
TTR 
Time To Response 
ULN 
upper limit of normal 
WHO 
World Health Organization 


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1 
Introduction 
This statistical analysis plan (SAP) describes all planned analyses for the clinical study report(s) 
(CSR) of study CINC280L12301, a phase III randomized, controlled, open-label, multicenter, 
global study of capmatinib in combination with osimertinib versus platinum - pemetrexed based 
doublet chemotherapy in participants with locally advanced or metastatic NSCLC harboring 
EGFR activating mutations who have progressed on prior 1st/2nd generation EGFR-TKI, 
osimertinib or other 3rd generation EGFR-TKI therapy used per local standard of care and whose 
tumors are T790M mutation negative and harbor MET amplification (GEOMETRY-E).  
The content of this SAP is based on the protocol version 01. All decisions regarding final 
analysis, as defined in the SAP document, have been made prior to database lock. 
Due to the changes of the treatment landscape which have heavily impacted the enrollment of 
new subjects in the study, the study was closed prematurely after thorough and careful 
assessment of the study enrollment status and projected timelines for completing enrollment in 
a timely manner. Consequently, the enrollment for the run-in part was halted on May 18th  2022, 
and the randomized part of the study will not be opened. 
In consideration of the early termination and given that the randomized part of the study will 
not be opened, the final analysis will not be performed as originally planned for all endpoints. 
This abbreviated SAP describes the analyses to be performed. 
1.1 
Study design 
This is a multicenter, open-label, randomized, active-controlled, global phase III study that will 
enroll adult participants with locally advanced or metastatic NSCLC with EGFR activating 
mutation, T790M negative, MET amplified who have progressed following EGFR TKIs (EGFR 
TKIs can be 1st/2nd generation EGFR TKIs, osimertinib or other 3rd generation EGFR TKIs 
used per local standard care). Randomization of participants who have progressed on prior line 
with osimertinib will be approximately 50% to 60 % of the planned total number of participants, 
while for the other third generation EGFR TKI will be maximum of 10% of the planned total 
number of participants.  
The study will consist of an initial safety run-in part to evaluate the safety and tolerability of 
capmatinib in combination with osimertinib and to confirm the recommended dose for the 
randomized part, and a randomized part that will evaluate the efficacy and safety of capmatinib 
in combination with osimertinib compared to platinum (cisplatin or carboplatin) - pemetrexed 
doublet based chemotherapy as second line treatment. 
The study will enroll approximately 10 to 20 participants in the run-in part and 225 participants 
in the randomized part. Participant's respective treatment (either with capmatinib in 
combination with osimertinib, or with platinum (cisplatin or carboplatin) - pemetrexed based 
doublet chemotherapy) will be continued until participant experiences any of the following: 
documented disease progression by RECIST 1.1 (as assessed by the investigator in the run-in 
part, and as assessed by the investigator confirmed by BIRC in the randomization part), 
withdrawal of consent, pregnancy, lost to follow-up,  death etc. (futher details in study protocol 
section 9.1.1).  


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For all participants, the respective treatment may be continued beyond initial disease 
progression as per RECIST 1.1, if, in the judgement of the investigator, there is evidence of 
clinical benefit, and the participant wishes to continue on the study treatment.   
After treatment discontinuation, all participants will be followed for safety evaluations during 
the safety follow-up period. 
Run-in part: 
Approximately 10 participants will be enrolled and treated with dose level 1 (DL1) of 400 mg 
b.i.d. of capmatinib in combination with 80 mg q.d. of osimertinib, in order to have at least 6 
evaluable participants during the dose limiting toxicity (DLT) period (DLT period defined as 
the first cycle - 1 cycle = 21 days).   
A dose level review meeting to evaluate the safety and tolerability of the DL1 will take place 
after the sixth evaluable participant has been treated for at least 21 days. If DL1 is tolerated, 
capmatinib 400 mg b.i.d. in combination with osimertinib 80 mg q.d will be the recommended 
dose for the randomized part. 
If DL1 is not tolerated, a second cohort of approximately 10 participants may be added to have 
at least 6 evaluable participants. This second cohort will be treated at a lower dose level (DL-
1) of 400 mg b.i.d. capmatinib in combination with 40 mg q.d. osimertinib. The same rule 
utilized for the evaluation of DL1 will be utilized to evaluate DL-1. A dose level review team 
meeting will take place after the sixth evaluable participant of that second cohort has been 
treated for at least 21 days. If DL-1 is tolerated, capmatinib 400 mg b.i.d. in combination with 
osimertinib 40 mg q.d will be the recommended dose for the randomized part. If DL-1 is not 
tolerated, the randomized part will not open.  


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Figure 1-1 
Part 1: Run-in Part 
  
Participants participating in the run-in part are not eligible to participate in the randomized part. 
Randomized Part:  
The randomized part of the study will not be opened. 
 
 


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1.2 
Study objectives, endpoints and estimands  
The following Table 1-1 summarizes the original objectives and related enpoints of the study 
that align with the protocol version 01. To reflect the decision on early termination of the study 
and given that the randomized part will not be opened, all objectives and endpoints for the 
randomized part are no longer applicable, only the analyses corresponding to the primary and 
the secondary endpoints for the run-in part in Table 1-1 will be performed. 
Table 1-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
Run-in part 
• 
Run-in part 
- To confirm the recommended dose of 
capmatinib in combination with osimertinib 
- Incidence of Dose Limiting Toxicities (DLT) 
during the first 21 days (3 weeks) of treatment 
for each dose level associated with 
administration of capmatinib in combination with 
osimertinib 
• 
Randomized part 
• 
Randomized part 
- To compare the progression free survival 
(PFS) of capmatinib in combination with 
osimertinib as compared to platinum-
pemetrexed 
- Progression free survival (PFS) per Blinded 
Independent Review Committee (BIRC) 
according to RECIST 1.1.  
Key secondary objective(s) 
Endpoint(s) for key secondary objective(s) 
• 
Randomized part 
• 
Randomized part 
- To compare the overall response rate (ORR) of 
capmatinib in combination with osimertinib as 
compared to platinum-pemetrexed 
- ORR calculated per RECIST 1.1 by BIRC.  
- To compare the overall intracranial response 
rate (OIRR) of capmatinib in combination with 
osimertinib as compared to platinum-
pemetrexed in participants with Central Nervous 
System (CNS) lesions 
- OIRR by BIRC as per RANO-BM criteria.  
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
Run-in part 
• 
Run-in part 
- To characterize the safety and tolerability of 
capmatinib in combination with osimertinib 
- Safety: Incidence, type, and severity of 
adverse events per Common Terminology 
Criteria for Adverse Events (CTCAE) version 
5.00 including changes in laboratory values, vital 
signs, liver assessments and cardiac 
assessments; Tolerability: dose interruptions, 
reductions, dose intensity, and duration of 
exposure for all drug components 
- To characterize the pharmacokinetics of 
capmatinib, osimertinib, and  osimertinib's active 
metabolites (AZ5104 and AZ7550) in 
combination setting 
- Plasma PK concentrations and derived PK 
parameters 


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Objective(s) 
Endpoint(s) 
- To assess the tumor response of capmatinib in 
combination with osimertinib 
- All calculated per RECIST 1.1 by investigator: 
Overall response rate (ORR), Duration of 
response (DOR), Time to response (TTR), 
Disease control rate (DCR), Progression free 
survival (PFS) 
• 
Randomized part 
• 
Randomized part 
- To assess the anti-tumor activities of 
capmatinib in combination with osimertinib as 
compared to platinum-pemetrexed  
- All calculated by BIRC per RECIST 1.1: 
Duration of response (DOR), Time to response 
(TTR), Disease control rate (DCR) 
- To assess PFS2 (PFS after next-line of 
treatment) 
- PFS2 based on local investigator assessment.  
- To evaluate the association between MET 
amplification status as measured in ctDNA at 
baseline with PFS and ORR upon treatment with 
capmatinib in combination with osimertinib  
- PFS and ORR by BIRC using RECIST 1.1 
criteria for participant with MET amplification as 
measured in ctDNA at baseline 
- To characterize the pharmacokinetics of 
capmatinib, osimertinib, and  osimertinib's active 
metabolites (AZ5104 and AZ7550) in 
combination setting 
- Plasma PK concentrations 
- To evaluate overall survival (OS) in participants 
treated with capmatinib in combination with 
osimertinib as compared to platinum-
pemetrexed  
- Overall Survival 
- To evaluate the safety profile of capmatinib in 
combination with osimertinib as compared to 
platinum-pemetrexed  
- Incidence of adverse events and serious 
adverse events, change in vital signs, laboratory 
results and ECG 
- To assess the effect of capmatinib in 
combination with osimertinib as compared to 
platinum-pemetrexed on patient-reported 
disease-related symptoms, functioning, and 
health-related quality of life (HRQoL) 
- Change from baseline in European 
Organization for Research and Treatment of 
Cancer (EORTC) QLQ-LC13, QLQ-C30, 
EuroQoL-5 Dimension-5 Level/EQ-5D-5L and 
NCCN Fact Brain Symptom index 
questionnaires and time to symptom 
deterioration for EORTC QLQ-C30, QLQ-LC13 
and NCCN FBrSI 
- To assess intracranial anti-tumor activity of 
capmatinib in combination with osimertinib as 
compared to platinum-pemetrexed in 
participants with Central Nervous System (CNS) 
lesions at baseline by BIRC 
- Duration of intracranial response (DOIR), time 
to intracranial response (TTIR), intracranial 
disease control rate (IDCR) by BIRC as per 
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Objective(s) 
Endpoint(s) 
 
 
2 
Statistical methods 
The final close-out CSR analysis will be performed by Novartis. SAS version 9.4 or later will 
be used to perform all data analyses and to generate tables, figures and listings. 
2.1 
Data analysis general information 
Data from all participants who signed the main informed consent for this study will be used in 
the analysis. Data collected after participants’ withdrawal of informed consent for further 
participation in the study will not be reported (except for death date, if it is obtained from public 
records). 
Part 1 - Run-in part 
The analysis cut-off date for the final analysis of study data will be established at the end of 
the study. All statistical analyses will be performed using all data collected in the database up 
to the data cut-off date. All data with an assessment date or event start date (e.g., vital sign 
assessment date or start date of an adverse event) prior to or on the cut-off date will be included 
in the analysis. Any data collected beyond the cut-off date will not be included in the analysis 
and will not be used for any derivations. 
All events with start date before or on the cut-off date and end date after the cut-off date will be 
reported as ‘ongoing’. The same rule will be applied to events starting before or on the cut-off 
date and not having documented end date. This approach applies, in particular, to adverse event 
and concomitant medication reports. For these cases, the end date will not be imputed and 
therefore will not appear in the listings. 
The end of study is defined as the earliest occurrence of one of the following: 
• All participants have discontinued study treatment and completed the safety 
follow-up and approximately 80% of the participants have died, withdrawn 
consent or are lost to follow-up. 
• Another clinical study becomes available that can continue to provide capmatinib 
and osimertinib combination in this subject population, and all subjects ongoing 
are eligible to be transferred to that clinical study.  
Part 2 - Randomized part 


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The randomized part of the study will not be opened. 
General analysis conventions 
Pooling of centers: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small number of participants enrolled at centers, no center effect 
will be assessed.  
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables 
by treatment arm; a missing category will be included as applicable. Percentages will be 
calculated using the number of participants in the relevant population or subgroup as the 
denominator. 
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate descriptive 
statistics (i.e., mean, standard deviation, median, minimum, and maximum) by treatment arm.   
2.1.1 
General definitions  
Unless otherwise specified, definitions below apply for each study part. A participant included 
in the safety run-in will not enter in the randomized part. Platinum – pemetrexed based doublet 
chemotherapy is only applicable to the randomized part of the study.  
2.1.1.1 
Study drug and study treatment 
Study drug will refer to capmatinib (INC280) and osimertinib and the control drugs 
(pemetrexed and cisplatin/carboplatin). Whereas study treatment will refer to capmatinib in 
combination with osimertinib or the control treatment (platinum – pemetrexed based doublet 
chemotherapy). 
2.1.1.2 
Date of first administration of study drug 
The date of first administration of study drug is defined as the first date when a non-zero dose 
of study drug is administered and recorded on the Study Treatment eCRF.  
2.1.1.3 
Date of last administration of study drug 
The date of last administration of study drug is defined as the last date when a non-zero dose of 
study drug is administered and recorded on the Study Treatment eCRF. The date of last 
administration of study drug will also be referred as end of study drug. 
2.1.1.4 
Date of first administration of study treatment  
The date of first administration of study treatment is derived as the first date when a non-zero 
dose of any component of study treatment (capmatinib/osimertinib or pemetrexed/cisplatin or 
carboplatin) was administered as per the Study Treatment eCRF.  
For example: if 1st dose of capmatinib is administered on 05-Jan-2015, and 1st dose of 
osimertinib is administered on 03-Jan-2015, then the date of first administration of study 
treatment is on 03-Jan-2015.  


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2.1.1.5 
Date of last administration of study treatment  
The date of last administration of study treatment is derived as the last date when a non-zero 
dose of any component of study treatment (capmatinib/osimertinib or pemetrexed/cisplatin or 
carboplatin) was administered as per the Study Treatment eCRF.  
For example: if the last capmatinib dose is administered on 15-Apr-2014, and the last dose of a 
osimertinib is administered on 17-Apr-2014, then the date of last administration of study 
treatment is on 17-Apr-2014.  
2.1.1.6 
Last exposure to study treatment 
The date of last exposure to study treatment is derived as the latest date of the last date of 
exposure to study drug. The last date of exposure to study drug is defined as follows: 
- 
For Capmatinib/Osimertinib: The date of last exposure will be the same as the date of 
last administration of study drug because of the continuous daily dosing. 
‘Date of last administration of study drug’ is defined in Section 2.1.1.3. 
If the derived last date of exposure to study drug/study treatment goes beyond the data cutoff 
date, it should be truncated to the date of data cutoff.  
2.1.1.7 
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 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 event precedes the reference start date. 
In the Safety run-in part, the reference date for all assessments (safety, efficacy, PK, etc) is the 
start of study treatment.  
‘Death’ (date of death) will contribute to both efficacy (PFS) and safety analyses. For efficacy 
and safety, the study will be calculated relative to 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. 
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. 


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2.1.1.8 
Baseline 
In the Safety run-in part, for safety and efficacy evaluations, the last available assessment on or 
before the date of start of study treatment is defined as “baseline” assessment for both efficacy 
and safety.  
In rare cases where multiple measurements meet the baseline definition, with no further flag or 
label that can identify the chronological order, then the following rule should be applied: If 
values are from central and local laboratories, the value from central assessment should be 
considered as baseline. If multiple values are from the same laboratory (local or central) or 
collected for ECGs or vital signs, then the last value should be considered as baseline. 
If participants have no value as defined above, the baseline result will be missing. 
2.1.1.9 
On-treatment assessment/event and observation periods  
For safety reporting (including adverse events), the overall observation period will be divided 
into three mutually exclusive segments:  
1. pre-treatment period: from day of participant’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 31 after last administration of study treatment. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided.  In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).   
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. 
2.1.1.10 Windows for multiple assessments  
In order to summarize 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 one 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 there are 
multiple assessments on the same date then the worst case will be used.  Data from all 
assessments (scheduled and unscheduled), including multiple assessments, will be listed. 


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2.2 
Analysis sets  
Full analysis set 
For the safety run-in part, the Full Analysis Set (FAS) comprises all participants that received 
any component of the study drug. 
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 actually received, i.e. either capmatinib in combination with 
osimertinib.  FAS and safety set are the same in the run-in part of this study. 
Pharmacokinetic analysis set 
The Pharmacokinetic analysis set (PAS) includes all participants who provided at least one 
evaluable PK concentration. For a concentration to be evaluable, participants are required to: 
• Have received at least one dose of capmatinib + osimertinib 
• For steady state trough samples (pre-dose samples) on or after Cycle 2 Day 1 (C2D1), 
have taken the consistent dose of capmatinib + osimertinib for at least 5 consecutive days 
prior to sampling except for Cycle 1 Day 1 (C1D1) 
• A PK sample is considered as non-evaluable if it is collected after a participant has 
vomited within 4 hours post-dose. 
Dose-Determining Set (DDS) 
The Dose-Determining Set (DDS) includes all participants from the FAS (safety run in parts) 
who met the minimum exposure criterion and had sufficient safety evaluations, or experienced 
a dose limiting toxicity (DLT) during cycle 1 (the first 21 days of dosing). 
A participant has met the minimum exposure criterion if the participant takes during the first 
21 days of dosing at least 75% of the planned doses for each of the combination drugs (i.e. ≥ 
16 out of 21 daily doses for capmatinib and ≥ 16 out of 21 daily doses for osimertinib) and at 
least 50% of the planned combination doses of the two drugs administered together (i.e. ≥ 11 
out 21 daily doses). 
Participants who do not experience a DLT during cycle 1 (the first 21 days of dosing) are 
considered to have sufficient safety evaluations if they have been observed for ≥ 21 days 
following the first dose, and are considered by both the sponsor and investigators to have 
enough safety data to conclude that a DLT did not occur. 


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2.2.1 
Subgroup of interest 
In Safety run-in part, no subgroup analysis will be performed. 
2.3 
Participant disposition, demographics and other baseline 
characteristics 
The Full Analysis Set (FAS) will be used for all participant disposition and baseline and 
demographic summaries and listings.  
No inferential statistics will be provided. 
2.3.1 
Participant disposition 
The FAS will be used for the participant disposition summary tables and listings.  
The number (%) of treated participants will be presented for the Safety Run-in part. The number 
(%) of participants who are still on treatment, who discontinued treatment, and the primary 
reason for study treatment discontinuation will be presented.  
Screening phase disposition 
Screen failures recorded in the screening phase disposition will comprise participants who have 
been enrolled, i.e. signed the molecular pre-screening ICF, and were (pre-)screened but were 
not randomized. These participants are not treated with study treatment. Frequency counts and 
percentages will be tabulated for all enrolled participants as follows: 
• Number (%) of participants who completed the screening phase; 
• Number (%) of participants who discontinued during the screening phase (participants did 
not continue into the next phase of the trial); 
• Reasons for screening phase discontinuation. 
All screen failure participants with reasons for screen failure will be listed. The study allows 
re-screening of screen failure participants and both the original participant number entered on 
the re-screen eCRF and the new participant number assigned at re-screening will be used to 
displayed in the listing. 
2.3.2 
Demographics and other baseline characteristics 
Basic demographic and background data 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively (see Section 2.1).  
Diagnosis and extent of cancer 
Summary statistics will be tabulated for diagnosis and extent of cancer. This analysis will be 
based on data collected on the eCRF including: primary site of cancer, tumor histology/cytology 
(predominanat and additional), histological grade, time (in months) since initial diagnosis of 


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primary site, stage at initial diagnosis and stage at study entry, time (in months) from initial 
diagnosis to first recurrence/progression, time (in months) since most recent relapse/progression, 
number and type of metastatic sites, types of lesions (target and non-target lesions) at baseline, 
number of target lesions at baseline, and disease burden at baseline for target lesion. Metastatic 
sites will be based on diagnosis eCRF, lesion information will be based on the RECIST eCRF. 
Medical history 
Relevant medical histories and current medical conditions at baseline will be summarized and 
listed. The summaries will be presented by primary system organ class (SOC) and preferred 
term (PT). Medical history and current medical conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) terminology. The MedDRA version used for 
reporting will be specified in the CSR and as a footnote in the applicable tables/listings. 
Protocol Deviations 
Frequency counts and percentages of participants in the FAS with any important protocol 
deviations (eligibility, withdrawal, concomitant medication, study treatment, other) will be 
tabulated by the deviation category. All protocol deviations will be listed. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
The safety set will be used for all medication data summaries and listings unless otherwise 
specified. 
2.4.1 
Study treatment / compliance 
The exposure related analyses will be presented by dose regimen for the safety run-in part. 
Duration of exposure to study treatment, actual cumulative dose, dose intensity (DI) and relative 
dose intensity (RDI) will be summarized for the study drug. In addition, a categorical summary 
of RDI will be presented in the respective summaries. The duration of exposure will be 
categorized into time intervals (<6, ≥ 6–<12, ≥ 12–<18, ≥ 18– <24, ≥ 24–<48, ≥ 48–<72 etc); 
frequency counts and percentages will be presented for the number (%) of participants in each 
interval. The number (%) of participants who have dose reductions or interruptions, and the 
reasons, will be summarized.  
Participant level listings of all doses administered on treatment along with dose change reasons 
will be produced. 
Duration of exposure to study drug 
Duration of exposure is considered by taking into account the dosing regimen. 
• Duration of exposure to study drug (days) = [(last date of exposure to study drug) – (date of 
first administration of study drug) + 1]. 


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Duration of exposure to study treatment 
The duration of exposure to study treatment is defined considering the duration of exposure of 
each study treatment as: 
• Duration of exposure (days) = (last date of exposure to study treatment – date of first 
administration of study treatment + 1) 
The duration of exposure includes the periods of temporary interruption except for the last one, 
a dose interruption occurring after the last date of exposure to study treatment won’t be 
considered. 
Duration of exposure to study drug/treatment will be categorized into time intervals in weeks. 
In addition summary statistics will be displayed in weeks. 
Cumulative dose 
Cumulative dose is defined as the total dose given during the study drug exposure. The 
cumulative dose is calculated using the information from the study treatment eCRF page and is 
expressed in mg for all study drugs.  
For the combination arm, the actual cummulative dose is the sum of “dose administered” during 
exposure to capmatinib and osmertinib respectively and is expressed in mg.  
For participants who did not take any drug the cumulative dose is by definition equal to zero. 
Dose intensity 
Dose intensity (DI) for participants with non-zero duration of exposure is defined as follows: 
• For Capmatinib and Osimertinib: 
DI (mg/week) = Actual Cumulative dose (mg) / Duration of exposure to study drug (week). 
For participants who did not take any drug the DI is by definition equal to zero. 
Planned dose intensity 
Planned dose intensity (PDI) is the assigned dose by unit of time planned to be given to 
participants as per protocol in the same dose unit and unit of time as that of the dose intensity 
and is defined as follows: 
• For Capmatinib and Osimertinib:  
PDI (mg/week) = planned dose as per protocol  
Relative dose intensity 
Relative dose intensity (RDI) is defined as follows: 
• For Capmatinib and Osimertinib: 
RDI (%) = 100 × [DI (mg/week) / PDI (mg/week)].  


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Dose reductions, interruptions or permanent discontinuations 
The number of participants who have dose reductions, permanent discontinuations or 
interruptions, and the reasons, will be summarized. 
Section 5.1 provides further details on the definition of dose changes and interruptions. 
2.4.2 
Prior, concomitant and post therapies 
Prior anti-cancer therapy 
The number and percentage of participants who received any prior anti-neoplastic medications, 
prior anti-neoplastic radiotherapy or prior anti-neoplastic surgery will be summarized. 
Prior anti-neoplastic medications will be summarized by therapy type (e.g. chemotherapy, 
hormonal therapy etc.), setting (e.g. adjuvant, palliative etc.), number of prior regimens of 
anticancer medications, setting at last medication (based on the last end date of all prior regimen 
components). Prior antineoplastic medications will also be summarized by ATC class, and 
preferred term. The medication therapy type of any combination therapy will be classified based 
on the following order: immunotherapy, chemotherapy, biologic therapy (other than 
immunotherapy), targeted therapy, hormonal therapy. For example, a combination therapy of 
chemotherapy and immunotherapy will be classified as immunotherapy. 
For radiotherapy, time since last radiotherapy, locations and setting of last therapy will be 
summarized. For prior surgery, time since last surgery, procedure and residual disease of last 
therapy will be summarized. 
Separate listings will be produced for prior anti-neoplastic medications, radiotherapy, and 
surgery. 
The above analyses will be performed using the FAS. 
Concomitant antineoplastic radiotherapies 
For concomitant radiotherapy, the location, setting, method and lesion subcategory will be 
summarized based on the FAS. The concomitant radiotherapies will also be listed. 
Concomitant therapy 
Concomitant therapies are defined as any medications (excluding study treatment, prior 
antineoplastic treatments and blood transfusions), surgeries or procedures (including physical 
therapy) administered in the study and are recorded on the eCRFs for Concomitant Medications 
and Prior or Concomitant non-drug therapies/procedures, respectively. 
Concomitant medications will be coded using the WHO Drug Reference Listing (WHO DRL) 
dictionary that employs the WHO Anatomical Therapeutic Chemical (WHO ATC) 
classification system. Surgeries or procedures will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) terminology. All summaries will be tabulated using 
frequency counts and percentages. 


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Concomitant therapies will be summarized by lowest ATC class and preferred term. Surgical 
and medical procedures will be coded using MedDRA and summarized by SOC and preferred 
term. These summaries will include: 1) medications starting on or after the start of study 
treatment but starting no later than 30 days after last dose of study treatment (in the on-treatment 
period as defined in Section 2.1.1.9) and 2) medications starting prior to the start of study 
treatment but continuing after the start of study treatment. 
All concomitant therapies will be listed. Any concomitant therapies starting more than 30 days 
after the last date of study treatment will be flagged in the listings. The safety set will be used 
for all concomitant medication tables and listings. 
Antineoplastic therapy after discontinuation of study treatment 
The FAS will be used for all listings and summaries of antineoplastic therapies initiated after 
discontinuation of study treatment. All summaries will be tabulated using frequency counts and 
percentages by cohort. 
Antineoplastic medications initiated after discontinuation of study treatment will be 
summarized and listed by lowest Anatomical Therapeutic Chemical (ATC) class and preferred 
term. 
Antineoplastic radiotherapy since discontinuation of study treatment will be summarized and 
listed. 
Antineoplastic surgery since discontinuation of study treatment will be summarized and listed 
by SOC and preferred term. 
2.5 
Analysis supporting primary objective(s) 
The primary objective is to confirm the recommended dose of capmatinib in combination with 
osimertinib. The analysis will be performed on the FAS. 
2.5.1 
Primary endpoint(s) 
The primary endpoint for the safety run-in part is incidence of Dose Limiting Toxicities (DLT) 
during Cycle 1 of treatment for each dose level associated with administration of capmatinib in 
combination with osimertinib. 
2.5.2 
Statistical hypothesis, model, and method of analysis  
The primary endpoint for the safety run-in phase is the incidence of DLT during cycle 1. The 
dose recommendation decision will be based on the following criteria:  
• At least six evaluable participants treated at this dose and regimen. 
• No more than two DLT have been observed out of six evaluable participants. 
• It is the dose recommended for participants after review of all clinical data by Novartis 
and Investigators in a dose level review team meeting. 
If one of the conditions specified above is not satisfied, dose confirmation cannot be declared 
and a second cohort may be treated at the lower dose level with capmatinib (400 mg b.i.d.) and 


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osimertinib (40 mg q.d.). The same criteria are applied for this new dose and regimen. If dose 
confirmation cannot be declared on this lower dose, the randomized part cannot start and the 
study will end.  
DLTs will be listed, and their incidence summarized by primary system organ class, preferred 
term and worst grade (CTCAE v5.0). Listings and summaries will be based on the DDS.  
2.5.3 
Handling of missing values not related to intercurrent event 
Participants who are ineligible for the DDS will be excluded from the primary analysis of DLT 
although their data will be used for all remaining analyses. Other missing data will simply be 
noted as missing on appropriate tables/listings. 
2.6 
Analysis supporting secondary objectives  
The secondary efficacy objective for the safety run-in part is to assess the tumor response of 
capmatinib in combination with osimertinib 
2.6.1 
Secondary endpoint(s) 
For the run-in part, the secondary efficacy endpoints: ORR, DOR, TTR, DCR and PFS by 
investigator assessment per RECIST 1.1 will be analyzed. 
2.6.1.1 
Key secondary endpoints  
Not applicable 
2.6.1.2 
Other secondary efficacy endpoints 
2.6.1.2.1 Overall response rate (ORR) 
ORR will be assessed in the safety run-in part based on investigator assessment. 
ORR is defined as the proportion of participants with confirmed best overall response (BOR) 
of complete response (CR) or partial response (PR) according to RECIST 1.1. 
The BOR will be determined from response assessments undertaken while on treatment. In 
addition, only tumor assessments performed before the start of any further anti-neoplastic 
therapies will be considered in the assessment of BOR. Localized palliative radiotherapy for 
pre-existing, painful bone and/or liver metastases is permitted when not delivered to a target 
lesion. 
BOR for each participant is determined from the sequence of overall (lesion) responses 
according to the following rules: 
• CR = at least two determinations of CR at least 4 weeks apart before progression. 
• PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR). 
• SD = at least one SD assessment (or better) >5 weeks after the start of study treatment 
(and not qualifying for CR or PR). 


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• PD = progression ≤ 13 weeks after the start of study treatment (and not qualifying for CR, 
PR or SD) 
• NE = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 5 weeks or early progression within the first 13 weeks) 
Complete and partial responses must be confirmed by repeat assessments that should be 
performed not less than 4 weeks after the criteria for response are first met.  
Participants with ‘NE’ BOR will be summarized by reason for having NE status. The following 
reasons will be used: 
• No valid post-baseline assessment 
• All post-baseline assessments have overall lesion response NE 
• New anti-neoplastic therapy started before first post-baseline assessment 
• SD too early 
• PD too late  
Note 1: A SD is considered as “SD too early”’ if the SD is documented within the first 5 weeks 
after the start of study treatment.  
Note 2: A PD is considered as “PD too late” if the first documentation of PD is recorded more 
than 13 weeks after the start of study treatment with no qualifying CR, PR or SD in between. 
Note 3: Special (and rare) cases where BOR is “NE” due to both too early SD and too late PD 
will be classified as “SD too early”. 
ORR will be calculated based on the data from the FAS and the corresponding 95% confidence 
intervals based on the exact binomial distribution (Clopper and Pearson 1934) will be presented. 
2.6.1.2.2 Duration of response (DOR) 
DOR will be assessed in the safety run-in part based on investigator assessment.  
DOR only applies to participants whose BOR is CR or PR according to RECIST 1.1 based on 
tumor response data. DOR is defined as the time from the date of first documented response 
(CR or PR) to the first documented progression per RECIST 1.1 or death due to any cause. If a 
participant has not had an event, DOR is censored at the date of last adequate tumor assessment 
using the censoring rules described in Table 2-1. Participants who never achieved a BOR of CR 
or PR will be excluded from the analysis. The distribution function of DOR will be estimated 
using the Kaplan-Meier method. DOR will be analyzed based on the data from the FAS. Median 
DOR, with corresponding 95% CI, and 25th and 75th percentiles (Brookmeyer and Crowley 
1982, Klein and Moeschberger 1997) will be presented.  
2.6.1.2.3 Time to response (TTR) 
TTR will be assessed in the safety run-in part based on investigator assessment.  
TTR is defined as the time from the start of study treatment to the first documented response of 
either CR or PR, which must be subsequently confirmed (date of initial response is used, not 


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date of confirmation), according to RECIST 1.1. Participants without a confirmed PR or CR 
will be censored at 
• the maximum follow-up time (i.e. FPFV − LPLV) for participants with a PFS event (i.e. 
disease progression or death due to any cause), or 
• at the date of the last adequate tumor assessment date for participants without a PFS event 
The distribution function of TTR will be estimated using the Kaplan-Meier method based on 
data from the FAS. Median TTR, with corresponding 95% CI, and 25th and 75th percentiles 
(Brookmeyer and Crowley 1982, Klein and Moeschberger 1997) will be presented. KM 
estimates for TTR proportions at specific time points, along with 95% CI (Greenwood’s formula, 
Kalbfleisch and Prentice 2002) will also be provided.  
2.6.1.2.4 Disease control rate (DCR) 
DCR will be assessed in the safety run-in part based on investigator.  
DCR is defined as the proportion of participants with a BOR of confirmed CR, PR and stable 
disease (SD) according to RECIST 1.1. 
DCR will be calculated based on the data from the FAS and the corresponding 95% confidence 
intervals based on the exact binomial distribution (Clopper and Pearson 1934) will be presented. 
2.6.1.2.5 Progression-free survival (PFS) 
PFS will be assessed in the safety run-in part based on investigator. 
PFS is defined as the time from the start of study treatment to the first documented progression 
or death due to any cause per RECIST 1.1. PFS will be censored at the date of the last adequate 
tumor assessment performed on or before the cut-off date, if no PFS event (progression or death) 
is observed prior to the analysis cut-off date. Clinical deterioration will not be considered as 
documented disease progression. PFS events will be included in the analysis if they occur after 
one missing assessment. 
Radiological progression or death observed after 2 or more missing tumor assessments will not 
be included in the derivation of the time to event for PFS, and the observation will be censored 
at the time of the last adequate tumor assessment prior to the first missing assessment. 
Participants without a post-baseline tumor assessment (and without death) will be censored at 
the time of the start of study treatment. 
The date of last adequate tumor assessment is the date of the last tumor assessment with overall 
lesion response of CR, PR or SD or non-CR/non-PD before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment will be used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) then the 
date of the start of study treatment will be used. 
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 anticancer therapy is administered; the 
event occurred after two or more missing tumor assessments. The term “missing adequate tumor 
assessment” is defined as a tumor assessment (TA) not performed or tumor assessment with 


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overall lesion response of “NE”. The rule to determine number of missing TAs is based on the 
time interval between the date of last adequate tumor assessment and the date of an event. If the 
interval is greater than twice the protocol-specified interval between the TAs and 2 times the 
protocol-allowed time window around assessments, then the number of missing assessments 
will be 2 or more.  
Refer to Table 2-1 for censoring and event date options and outcomes for PFS and Section 5.6 
for details regarding missing adequate tumor assessments. 
The distribution function of PFS will be estimated using the Kaplan-Meier method based on 
data from the FAS. Median PFS, with corresponding 95% CI, and 25th and 75th percentiles 
(Brookmeyer and Crowley 1982, Klein and Moeschberger 1997) will be presented. KM 
estimates for TTR proportions at specific time points, along with 95% CI (Greenwood’s formula, 
Kalbfleisch and Prentice 2002) will also be provided. 
Table 2-1 
Outcome and event/censor dates for PFS analysis 
Situation 
Date 
Outcome 
No baseline assessment 
Date of start of study 
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 anticancer 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 
 
2.6.2 
Sensitivity analyses 
No sensitivity analyses are planned for the secondary endpoints. 


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2.7 
Safety analyses 
For the safety run-in part, summary tables and listings will be presented by dose regimen using 
the safety set.  
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for deaths including on treatment and 
post treatment deaths will be provided. In particular, summary tables for adverse events (AEs) 
will summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs). The definition of the pre-treatment, on-treatment, and post-
treatment period are given in Section 2.1.1.9.  
All data, regardless of observation period, will be listed and assessments collected in the post-
treatment period will be flagged in all the listings.  
2.7.1 
Adverse events (AEs) 
AEs will be coded using MedDRA using the latest version available prior to clinical database 
lock and will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0. 
AE summaries will include all AEs occurring during the on-treatment period. All AEs collected 
in the AE eCRF page will be listed along with the information collected on those AEs e.g. 
relationship to study treatment, outcome etc.  
Treatment-emergent adverse events (events that started after the first administration of study 
treatment or events present prior to start of study treatment but increased in severity after the 
first administration of study treatment, based on preferred term) will be summarized by number 
and percentage of participants having at least one AE, having at least one AE in each primary 
system organ class (SOC) and for each preferred term (PT) and maximum grade. A participant 
with multiple occurrences of an AE will be counted only once in the respective AE category. A 
participant with multiple CTCAE grades for the same preferred term will be summarized under 
the maximum CTCAE grade recorded for the event. AE with missing CTCAE grade will be 
included in the “All grades” column of the summary tables.  
In AE summaries, the primary system organ class will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order for 
the preferred term will be based on their frequency in the investigational drug arm. 
The following AE summaries will be produced: 
• AEs regardless of study treatment relationship 
• AEs suspected to be study treatment related 
• On-treatment deaths, by primary system organ class and preferred term 
• All deaths, by primary system organ class and preferred term 
• SAEs regardless of study treatment relationship 


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• SAEs suspected to be study treatment related 
• AEs leading to permanent discontinuation of study treatment regardless of study 
treatment relationship 
• AEs leading to permanent discontinuation of study treatment suspected to be study 
treatment related 
Clinical trial safety disclosure 
For the legal requirements of ClinicalTrials.gov and EudraCT, two tables will be provided by 
SOC and PT based on the safety set: 
• On-treatment AEs which are not SAEs with an incidence greater than 5% 
• On-treatment SAEs and SAEs suspected to be related to study treatment 
If for the same participant, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT, 
• a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• more than one occurrence will be counted if there is >1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE/SAE suspected to be related to study 
treatment/non SAE has to be checked in a block, e.g., among AEs in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.  
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
2.7.1.1 
Adverse events of special interest / grouping of AEs 
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to capmatinib. These groupings are defined using MedDRA terms, 
SMQs (standardized MedDRA queries), HLGTs (high level group terms), HLT (high level 
terms) and PTs (preferred terms). Customized SMQs (Novartis MedDRA queries, NMQ) may 
also be used. A NMQ is a customized group of search terms which defines a medical concept 
for which there is no official SMQ available or the available SMQ does not completely fit the 
need. It may include a combination of single terms and/or an existing SMQ, narrow or broad. 
All AESI definitions or AE groupings are specified in the electronic Case Retrieval Strategy 
(eCRS). The latest version of the eCRS available at the time of the analysis will be used. For 
each specified AESI, the number and percentage of participants with at least one event of the 
AESI occurring during the on-treatment period will be summarized. A listing of all grouping 
levels down to the MedDRA preferred terms used to define each AESI will be generated. 


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2.7.2 
Deaths 
Separate summaries for on-treatment deaths and all deaths will be produced by treatment arm, 
system organ class and preferred term. All deaths will be listed, and post-treatment deaths will 
be flagged. A separate listing of deaths prior to start of treatment will be provided for all 
screened participants. 
2.7.3 
Laboratory data 
For laboratory data assessments, data from all sources (central and local laboratories) will be 
combined. The summaries will include all laboratory assessments collected in the pre-treatment 
(for baseline, if applicable) and on-treatment period. All laboratory assessments will be listed 
and those collected in the post-treatment period will be flagged in the listings.  
Grading of laboratory values will be assigned programmatically as per NCI CTCAE version 
5.0. The calculation of CTCAE grades will be based on the observed laboratory values (in SI 
units) only, clinical assessments will not be taken into account. CTCAE Grade 0 will be 
assigned for all non-missing values not graded as 1 or higher. Grade 5 will not be used. For 
laboratory tests where grades are not defined by CTCAE version 5.0, results will be categorized 
as low, normal, or high based on laboratory normal ranges. 
• The following summaries will be produced for hematology and biochemistry laboratory 
data (by laboratory parameter and treatment arm):Worst post-baseline CTC grade 
(regardless of the baseline status). Each participant will be counted only for the worst 
grade observed post-baseline. 
• Shift tables using CTC grades to compare baseline to the worst on-treatment value (hypo 
and hyper worst grade will be summarized separately, if applicable) 
• For laboratory tests where CTC grades are not defined, shift tables using low, normal, 
high (as well as low and high combined) classification to compare baseline to the worst 
on-treatment value. 
• Listing of all laboratory data with values flagged to show the corresponding CTCAE 
version 5.0 grades, if applicable, and the classifications relative to the laboratory normal 
ranges. 
All laboratory data will be listed by participant and visit/time, and if normal ranges are available, 
abnormalities will be flagged. 
Liver function parameters 
Liver function parameters of interest are total bilirubin (BILI), ALT, AST and alkaline 
phosphatase (ALP). The number and percentage of participants with worst post-baseline values 
as per Novartis Liver Toxicity guideline will be summarized. Because the study protocol 
inclusion criteria allowed participants 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 


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o ALT >3×ULN 
o ALT >5×ULN 
o ALT >10×ULN 
o ALT >20×ULN 
o AST >3×ULN 
o AST >5×ULN 
o AST >10×ULN 
o AST >20×ULN 
o ALT or AST >3×ULN 
o ALT or AST >5×ULN 
o ALT or AST >8×ULN 
o ALT or AST >10×ULN 
o ALT or AST >20×ULN 
o BILI >2×ULN 
o BILI >3×ULN 
• Combined elevations post-baseline 
o AST and ALT ≤ ULN at baseline 
o (ALT or AST >3×ULN) and BILI >2×ULN 
o (ALT or AST >3×ULN) and BILI >2×ULN and ALP ≥ 2×ULN 
o (ALT or AST >3× ULN) and BILI >2× ULN and ALP <2×ULN 
• ALT or AST >ULN at baseline 
o (Elevated ALT or AST) and BILI >2×BL and BILI >2×ULN 
o (Elevated ALT or AST) and BILI >2×BL and BILI >2×ULN and ALP ≥ 2×ULN 
o (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 
participant. 
(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 participants who, depending on their baseline 
status, fulfill one of the criteria as defined in the Novartis Hepatotoxoicity Guidelines 2019. 


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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). 
2.7.4 
Other safety data 
2.7.4.1 
ECG and cardiac imaging data 
12-lead ECGs including PR, QRS, QT and QTcF intervals and heart rate will be obtained for 
each participant during the study. ECG data will be read and interpreted centrally. The average 
of the ECG parameters at each assessment should be used in the analyses. ECGs collected 
during the on-treatment period will be summarized. 
The number and percentage of participants with notable ECG values will be presented by 
treatment arm based on the categories below. 
• QT, QTcF 
o New value of >450 and ≤ 480 ms 
o New value of >480 and ≤ 500 ms  
o New value of >500 ms 
o Increase from Baseline of >30 ms to ≤ 60 ms 
o Increase from Baseline of >60 ms 
• Heart rate 
o Increase from baseline >25% and to a value >100 bpm 
o Decrease from baseline >25% and to a value <50 bpm 
• PR 
o Increase from baseline >25% and to a value >200 ms 
o New value of >200 ms 
• QRS 
o Increase from baseline >25% and to a value >120 ms 
o New values of QRS >120 ms 
A listing of all ECG assessments will be produced by treatment arm and notable values will be 
flagged. In the listing, the assessments collected during the post-treatment period will be flagged. 


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2.7.4.2 
Vital signs 
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: systolic and diastolic blood pressure (mmHg), pulse 
(beats per minute), body temperature (°C), weight (kg), and height (cm). 
Vital signs collected during the on-treatment period will be summarized. Values measured 
outside the on-treatment period will be flagged in the listings. 
The number and percentage of participants with notable vital signs values will be presented by 
treatment arm based on the categories below. 
Clinically notable elevated values: 
• Systolic BP: ≥ 180 mmHg and an increase ≥ 20 mmHg from baseline 
• Diastolic BP: ≥ 105 mmHg and an increase ≥ 15 mmHg from baseline 
• Body temperature: ≥ 39.1°C 
• Weight: increase from baseline of ≥ 10% 
• Pulse rate: ≥ 100 bpm with increase from baseline of ≥ 25% 
Clinically notable values below the normal values: 
• Systolic BP: ≤ 90 mmHg and a decrease ≥ 20 mmHg from baseline 
• Diastolic BP: ≤ 50 mmHg and a decrease ≥ 15 mmHg from baseline 
• Weight: decrease from baseline of ≥ 10% 
• Pulse rate: ≤ 50 bpm with decrease from baseline of ≥ 25% 
A listing of all vital sign assessments will be produced and notable values will be flagged. In 
the listing, the assessments collected during the post-treatment period will be flagged. 
2.8 
Pharmacokinetic endpoints   
The PAS will be used in all pharmacokinetic data analysis and PK summary statistics. 
Capmatinib, osimertinib, AZ5104 and AZ7550 plasma concentration data will be listed by 
treatment, subject, and visit/sampling time point. Descriptive summary statistics will be 
provided pre-dose (trough) concentrations by visit/sampling time point. Summary statistics will 
include mean (arithmetic and geometric), SD, CV (coefficient of variation) (arithmetic and 
geometric), median, minimum, and maximum. Concentrations below lower limit of 
quantification (LLOQ) will be treated as zero in summary statistics. LLOQ is defined as 1.0 
ng/mL for capmatinib and 0.4 ng/mL for osimertinib, AZ5104 and AZ7550. 
For C1D1 and C2D1 in run-in part (intensive PK), pharmacokinetic parameters (e.g. AUC, 
Cmin, Cmax, Tmax, T1/2) will be calculated by noncompartmental methods and listed by 
participant. Descriptive summary statistics will include mean (arithmetic and geometric), SD, 
and CV (arithmetic and geometric), median, minimum, and maximum. An exception to this is 
Tmax where median, minimum, and maximum will be presented. 


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2.9 
PD and PK/PD analyses 
Not applicable 
2.10 
Patient-reported outcomes 
Not applicable 
2.11 
Biomarkers 
Not applicable 
2.12 
Other Exploratory analyses 
Not applicable 
2.13 
Interim analysis 
Not applicable 
  
3 
Sample size calculation 
3.1.1 
Primary endpoint(s) 
Run-in part 
No formal statistical power calculations to determine sample size were performed for this part 
of the study.  
3.1.2 
Secondary endpoint(s) 
Not applicable. 
4 
Change to protocol specified analyses 
Not applicable 
5 
Appendix 
5.1 
Dose interruptions and dose changes 
This section provides additional details to those included in Section 2.4.1. 
All calculations of dose interruptions and dose changes are based on the dose actually taken by 
the participant. 


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5.1.1 
Definitions for capmatinib and osimertinib 
A dose interruption is defined as a 0 mg dose taken on one or more days between two non-
zero dosing periods. The last zero dose of study drug followed by permanent discontinuation 
are not considered as dose interruption. 
In the case of multiple dose interruptions, these will be handled as follows. 
• If an interruption occurs consecutively for at least two days due to the same reason, then it 
will be counted only once (example: If the actual dose on days 1–3 is 800 mg and actual 
dose on days 4–5 is 0 mg and dose interruption on days 4–5 is due to AE, then the total 
number of dose interruptions is 1). 
• If an interruption occurs consecutively for at least two days due to different reasons, then 
it will be counted for each reason (example: If the actual dose on days 1–3 is 800 mg and 
actual dose on days 4–5 is 0 mg and dose interruption on day 4 is due to AE and dose 
interruption on day 5 is due to dosing error, then the total number of dose interruptions is 
2). 
• If an interruption occurs for more than one day due to the same reason, but the days are 
not consecutive, i.e. there is at least one dosing day in between, then each dose 
interruption will be counted as a different occurrence (example: if the actual dose on days 
1, 3 and 5, is 800 mg and actual dose on days 2 and 4 is 0 mg, and dose interruptions on 
day 2 and 4 are both due to dosing error, the total number of dose interruptions is 2). 
A dose change is defined as a change in dosing from one record to the next, however a dose 
interruption will not be counted as a dose change. 
Dose reductions are a subset of dose changes where the total daily dose is lower than the 
previous non-zero dose or differs from the prescribed dose. Some special scenarios are listed 
below. 
Case 1: If a participant did not receive the protocol planned dose for any reason, then this is a 
dose reduction (400 mg total daily dose, 800 mg total daily dose). 
Participant 
ID 
Start date 
End date 
Prescribed 
dose 
(mg b.i.d.) 
Total daily 
dose 
(mg) 
Reason 
Reduction 
(derived) 
Comments 
0001 
22/03/2017 
25/03/2017 
400 
400 
DOSING 
ERROR 
Y 
1st administration 
different from protocol 
planned dose 
(800 mg) 
 
26/03/2017 
26/05/2017 
400 
800 
 
 
 
Case 2: If, due to a dosing error, a participant receives a higher than the protocol planned dose 
and moves down to the planned dose then this is not a dose reduction (total daily dose 800 mg, 
1000 mg, 800 mg); However if the change is directly from a higher than planned dose down to 
a lower than protocol planned dose, then this is a dose reduction (e.g. in the sequence, total 
daily dose 800 mg, 1000 mg, 400 mg, it is a dose reduction). 
Participant ID Start date 
End date 
Prescribed 
dose 
(mg b.i.d.) 
Total 
daily dose 
(mg) 
Reason 
Reduction 
(derived) 
Comments 
0002 
22/03/2017 
21/05/2017 
400 
800 
 
 
 
 
22/05/2017 
23/05/2017 
0 
0 
ADVERSE EVENT 
 
 


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Participant ID Start date 
End date 
Prescribed 
dose 
(mg b.i.d.) 
Total 
daily dose 
(mg) 
Reason 
Reduction 
(derived) 
Comments 
 
24/05/2017 
01/08/2017 
300 
600 
ADVERSE EVENT 
Y 
 
 
02/08/2017 
05/08/2017 
400 
800 
 
 
 
 
06/08/2017 
06/08/2017 
400 
1000 
DOSING ERROR 
 
 
 
07/08/2017 
12/09/2017 
400 
800 
 
N 
moves down to the 
dose administered 
just before dosing 
error 
0003 
22/03/2017 
21/05/2017 
400 
800 
 
 
 
22/05/2017 
23/05/2017 
0 
0 
ADVERSE EVENT 
 
 
24/05/2017 
01/08/2017 
300 
600 
ADVERSE EVENT 
Y 
 
02/08/2017 
05/08/2017 
400 
800 
 
 
 
06/08/2017 
06/08/2017 
400 
1000 
DOSING ERROR 
 
 
07/08/2017 
12/09/2017 
400 
600 
 
Y 
moves down to a 
lower dose than 
administered just 
before dosing error 
Case 3: If due to an interruption, a participant receives half of the dose during 1 day, followed 
by an interruption (due to the same reason) then this is not a dose reduction (e.g. 800 mg total 
daily dose from 27-Dec-2016 to 14-Jan-2018, and 400 mg total daily dose on 15-Jan-2018, 
followed by an interruption 16-Jan-2018 to 22-Jan-2018). After the interruption, the dose 
reduction will be determined using the dose received on a day without interruption (e.g. total 
daily dose 600 mg vs 800 mg ignoring 400 mg on 15-Jan, given it is related to the interruption). 
Participant ID Start date 
End date 
Prescribed 
dose 
(mg b.i.d.) 
Total 
daily dose 
(mg) 
Reason 
Reduction 
(derived) 
Comments 
0004 
27/12/2017 
14/01/2018 
400 
800 
 
 
 
 
15/01/2018 
15/01/2018 
400 
400 
ADVERSE EVENT 
N 
½ dose for 1 day  
same reason than 
interruption 
Interruption started 
on 15-Jan 
 
16/01/2018 
22/01/2018 
0 
0 
ADVERSE EVENT 
 
 
23/01/2018 
07/02/2018 
400 
600 
ADVERSE EVENT 
Y 
Dose reduction from 
800 mg to 600 mg 
[400 mg on 15Jan 
ignored for reduction 
determination as part 
of the interruption] 
 
08/02/2018 
19/02/2018 
0 
0 
ADVERSE EVENT 
 


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Participant ID Start date 
End date 
Prescribed 
dose 
(mg b.i.d.) 
Total 
daily dose 
(mg) 
Reason 
Reduction 
(derived) 
Comments 
0005 
25/04/2016 
22/05/2016 
400 
800 
 
 
 
23/05/2016 
23/05/2016 
400 
400 
ADVERSE EVENT 
N 
½ dose for 1 day  
same reason than 
interruption 
Interruption started 
on 23-May 
 
24/05/2016 
25/05/2016 
0 
0 
ADVERSE EVENT 
 
 
26/05/2016 
26/05/2016 
400 
400 
ADVERSE EVENT 
Y 
Dose reduction from 
800 mg to 400 mg 
[400 mg on 23May 
ignored for reduction 
determination as part 
of the interruption] 
 
27/05/2016 
05/06/2016 
400 
800 
 
 
 
06/06/2016 
06/06/2016 
400 
400 
DOSING ERROR 
Y 
 
 
07/06/2016 
01/08/2016 
400 
800 
 
 
 
02/08/2016 
02/08/2016 
400 
400 
DOSING ERROR 
Y 
½ dose for 1 day  
different reason than 
interruption 
 
03/08/2016 
07/08/2016 
0 
0 
ADVERSE EVENT 
 
 
Case 4: If due to a permanent discontinuation, a participant receives half of the dose the last day 
of treatment then this is not a dose reduction (e.g. 800 mg total daily dose from 30-May-2016 
to 03-Oct-2016, and 400 mg total daily dose on 04-Oct-2016). This rule is applied for any dose 
levels (e.g. 600 mg total daily dose from 15-Dec-2017 to 20-Dec-2017, and 300 mg total daily 
dose on 04-Oct-2016). 
Participant ID Start date 
End date 
Prescribed 
dose 
(mg b.i.d.) 
Total 
daily dose 
(mg) 
Reason 
Permanently 
discontinuat
ion 
Reduction 
(derived) 
0006 
30/05/2016 
03/10/2016 
400 
800 
 
 
 
 
04/10/2016 
04/10/2016 
200 
400 
ADVERSE EVENT 
Y 
N 
5.1.2 
Definitions for cisplatin, carboplatin and pemetrexed  
The options ‘dose change’, ‘dose interrupted’, and ‘dose permanently discontinued’ from the 
study treatment eCRF page for cisplatin, carboplatin and pemetrexed infusion will be used to 
determine the dose changes, dose interruptions, and permanent discontinuations, respectively. 
5.2 
Imputation rules 
5.2.1 
Study treatment 
For Capmatinib and Osimertnib 
The following rules should be used for the imputation of the dose end date for the study drug: 
Scenario 1 


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If the dose end date is completely missing and there is no end of treatment (EOT) and no death 
date, the participant is considered as ongoing. 
The participant should be treated as ongoing and the cut-off date should be used as the last 
dosing date. 
Scenario 2 
If the dose end date is completely or partially missing and the EOT page is available: 
Case 1: The dose end date is completely missing and the EOT completion date is complete, 
then this latter date should be used. 
Case 2: Only year (YYYY) of the dose end date is available and YYYY < the year of EOT 
date, then use 31DECYYYY. 
Case 3: Only year (YYYY) of the dose end date is available and YYYY = the year of EOT 
date, then use EOT date. 
Case 4: Both year (YYYY) and month (MMM) are available for dose end date and 
YYYY = the year of EOT date and MMM < the month of EOT date, then use last day of 
the Month (MMM). 
Case 5: Both year (YYYY) and month (MMM) are available for dose end date and 
YYYY = the year of EOT date and MMM = the month of EOT date, then use EOT date. 
All other cases should be considered as a data issue and the data manager of the study should 
be contacted. 
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 
Participants with missing start dates are to be considered missing for all study treatment related 
calculations and no imputation will be made. If the start date is missing then the end-date should 
not be imputed. 
5.2.2 
AE, concomitant medication (CM) , and safety assessment 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 


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Missing 
element 
Rule 
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 or 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 or end date of the on-treatment period* 
*=last treatment date plus 30 days not > (death date, cut-off date, withdrawal of consent 
date) 
Any AEs and medications with partial/missing dates will be displayed as such in the data 
listings. 
Any AEs and 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. 
5.2.2.1 
Prior therapies date imputation 
Start date 
The same rule which is applied to the imputation of AE/concomitant medication start date will 
be used with the exception that study treatment start date will be replaced with (study treatment 
start date − 1). 
End date 
• Imputed date = min (reference end date , last day of the month), if day is missing 
• Imputed date = min (reference end date , 31Dec), if month and day are missing 
Reference end date will be the start date of study 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. 


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Incomplete date of progression – Prior antineoplastic therapy-medication 
A missing day is defaulted to the 1st of the month. However, date of progression should be 
expected to be after start date of prior antineoplastic therapy. 
• Imputed date = max (start date of prior antineoplastic therapy, 1st day of the month), if day 
is missing 
5.2.2.2 
Post therapies date imputation 
Start date 
• Imputed date = max (reference start date, first day of the month), if day is missing 
• Imputed date = max (reference start date , 01JAN), if day and month are missing 
Reference start date will be the last date of study treatment administration + 1. 
End date 
No imputation. 
5.2.2.3 
Other imputations 
Incomplete date of initial diagnosis of cancer and date of most recent 
recurrence 
A missing day is defaulted to the 15th of the month and a missing month and day is defaulted to 
01Jan. 
If because of this imputation the chronology of the events is altered then the imputation should 
be made to the minimum value up to where the chronology remains unchanged. E.g. if due to 
imputation the date of most recent recurrence becomes prior to the initial diagnosis date then it 
should be set to initial diagnosis date. 
Incomplete assessment dates for tumor assessment 
All investigation dates (e.g. MRI scan, CT scan) must be completed with day, month and year. 
If one or more assessment dates are incomplete but other investigation dates are available, the 
incomplete date(s) are not considered for calculation of the assessment date and assessment date 
is calculated as the latest of all investigation dates (e.g. MRI scan, CT-scan) if the overall lesion 
response at that assessment is CR/PR/SD/UNK. Otherwise – if overall response is progression 
– the assessment date is calculated as the earliest date of all investigation dates at that evaluation 
number. If all measurement dates have no day recorded, the 1st of the month is used. If the 
month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between the previous and the following assessment. 
If a previous and following assessment is not available, this assessment will not be used for any 
calculation. 


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Incomplete or missing death date 
For cases when either day is missing or both month and day are missing for the date of death, 
the following imputation rules will be implemented: 
• If only day is missing, then impute 15th day of the month and year of death. 
If both day and month are missing, then impute 01JUL of the year of death. 
5.3 
AEs coding/grading 
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. 
AEs will be assessed according to the CTCAE version 5.0. 
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). 
5.4 
Laboratory parameters derivations 
Grade categorization of lab values will be assigned programmatically as per CTCAE version 
5.0. The calculation of CTCAE grades will be based on the observed laboratory values only, 
clinical assessments will not be taken into account. 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 5.0 at the time of 
analysis will be used (see Appendix 5.7 for the current version). For laboratory tests where 
grades are not defined by CTCAE version 5.0, results will be graded by the low/normal/high 
(or other project-specific ranges, if more suitable) 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. 
5.5 
Statistical models 
5.5.1 
Analysis supporting primary objective(s)  
Not applicable 
5.5.2 
Analysis supporting secondary objective(s) 
Kaplan-Meier estimates 
An estimate of the survival function in each treatment arm will be constructed using the 
Kaplan-Meier (product-limit) method as implemented in PROC LIFETEST with the 


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METHOD=KM option. The PROC LIFETEST statement will use the option CONFTYPE = 
LOGLOG. 
Median survival for each treatment arm will be obtained along with 95% confidence intervals 
calculated from PROC LIFETEST output using the method of Brookmeyer and Crowley 1982. 
Kaplan-Meier estimates of the survival function with 95% confidence intervals at specific 
time points will be summarized. The standard error of the Kaplan-Meier estimate will be 
calculated using Greenwood’s formula (Collett 1994). 
Confidence interval for response rate 
Responses will be summarized in terms of percentage rates with 100(1 − α)% confidence 
interval using an exact binomial confidence interval (implemented using SAS procedure FREQ 
with EXACT statement for one-way table (Clopper and Pearson 1934). 
5.6 
Determination of missing adequate tumor assessments  
As detailed in the Study Protocol Appendix 16.1, the PFS censoring and event date options 
depend on the presence and the number of missing tumor assessments. For example, an event 
occurring after two or more missing assessments is censored in the analysis of PFS at the last 
adequate tumor assessment (LATA) before the event date. 
An exact rule to determine whether there is none, one or two missing assessments is therefore 
needed. This rule will be based on the distance between the last adequate tumor assessment date 
and the event date. If the distance is larger than threshold D1 or D2 then the analysis will assume 
one or two missing assessments, respectively. The threshold D1 will be defined as the protocol 
specified interval between the tumor assessments plus the protocol allowed window around the 
assessments. Similarly, the threshold D2 is defined as two times the protocol specified interval 
between the tumor assessments plus the protocol allowed window around the assessments.  
• In this study, the protocol defined schedule of assessments is:  
• every 6 weeks during the first 18 months (i.e. at weeks 6, 12, 18, ... upto week 72),  
• every 12 weeks thereafter (i.e. at weeks 84, 96, 108, 120, etc…) up to the primary PFS 
analysis 
Since there is a change of schedule for tumor assessments after first 18 months, D1 and D2 are 
defined differently depending on when last available tumor assessment occurs: 
- 
In the first 18 months: each assessment is expected to be performed every 6 weeks at 
the scheduled time point plus or minus 1 week, i.e. the window is 2 weeks, then any 
distance larger than D1 = 6 + 2 = 8 weeks means one missing assessment and any 
distance larger than D2 = (2×6) + 2 = 14 weeks means two missing assessments. 
- 
After the first 18 months: each assessment is expected to be performed every 12 weeks 
at the scheduled time point plus or minus 1 week, i.e. the window is 2 weeks, then any 
distance larger than D1 = 12 + 2 = 14 weeks means one missing assessment and any 
distance larger than D2 = (2×12) + 2 = 26 weeks means two missing assessments. 


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The above definition of D2 will be used to determine the PFS censoring reason. Possible 
censoring reasons for PFS are: 
1: Ongoing without event 
2: Lost to follow-up 
3: Withdrew consent 
4: Adequate assessment no longer available 
6: Event after ≥ 2 missing tumor assessments 
7: New anticancer therapy given prior to protocol defined progression 
The PFS censoring reason is then derived by the following sequence of rules. 
• If the participant is considered to have a PFS event then PFS censoring reason is set to 
missing. 
• Else, if the participant has had no baseline assessment then PFS censoring reason = 4. 
• Else, if the participant has a PFS event after two or more missing assessments [if (PFS 
event date ≤ censoring date and (PFS event date − date of last adequate tumor 
assessment (LATA) ≥ D2)] then PFS censoring reason = 6. 
• Else, if the participant has no PFS event, and the participant is censored at a date after 
two or more missing assessments ((censoring date − date of LATA) ≥ D2) then PFS 
censoring reason = 4. 
• Else, if the censoring date equals the date of discontinuation due to consent 
withdrawal then PFS censoring reason = 3. 
• Else, if the censoring date equals the date of discontinuation due to loss to follow-up 
then PFS censoring reason = 2. 
• Else, if the censoring date equals the analysis cut-off date and the time between 
LATA and the cut-off date is greater than D2 days then PFS censoring reason = 4. 
• Else, if the censoring date equals the analysis cut-off date and the time between 
LATA and the cut-off date is less than or equal to D2 days then PFS censoring 
reason = 1 
• Else, if the censoring date equals the date of  start of new anticancer therapy then PFS 
censoring reason = 7 
Where censoring date = min (analysis cut-off date, date of discontinuation due to consent 
withdrawal, date of discontinuation due to loss to follow-up).


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5.7 
Novartis internal criteria for CTC grading of laboratory parameters (based on CTCAE v5 – Nov 2017) 
 


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6 
Reference 
Brookmeyer R and Crowley J (1982) A Confidence Interval for the Median Survival Time, 
Biometrics 38:29-41. 
Clopper CJ, Pearson ES (1934) The use of confidence or fiducial limits illustrated in the case 
of the binomial. Biometrika; 26(4):404–13. 
Collet D (1994) Modelling survival data in medical research. London, Chapman & Hall. 
Kalbfleisch JD, Prentice RL (2002) The Statistical Analysis of Failure Time Data. 2nd ed; 
New York: John Wiley & Sons Inc. (available upon request). 
Klein JP, Moeschberger ML (1997) Survival Analysis, Nonparametric Estimation of Basic 
Quantities for Right-Censored and Left-Truncated Data. New York: John Wiley & Sons Inc. 
(available upon request).