A Randomized, Double-blind, Placebo-controlled, Phase III Study Evaluating the Efficacy and Safety of Pembrolizumab Plus Platinum-based Doublet Chemotherapy With or Without Canakinumab as First Line Therapy for Locally Advanced or Metastatic Non-squamous and Squamous Non-small Cell Lung Cancer Subjects (CANOPY-1)
Phase: PHASE3
Conditions: Non-small Cell Lung Cancer
Sponsor: Novartis Pharmaceuticals

 
 
 
Novartis Research and Development 
ACZ885 
Clinical Trial Protocol CACZ885U2301 
A randomized, double-blind, placebo-controlled, phase III study 
evaluating the efficacy and safety of pembrolizumab plus platinum-
based doublet chemotherapy with or without canakinumab as first 
line therapy for locally advanced or metastatic non-squamous and 
squamous non-small cell lung cancer subjects (CANOPY-1) 
Document type: 
Amended Protocol Version  
EUDRACT number: 
2018-001547-32 
Version number: 
06 (Clean) 
Clinical Trial Phase: 
III 
Release date: 
25-Aug-2023 
 
 
 
 
 
 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
 
Clinical Trial Protocol Template version 1.0 dated 01-Dec-2017 

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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 8 
List of abbreviations ............................................................................................................ 9 
Glossary of terms ............................................................................................................... 14 
Amendment 6 (25-Aug-2023) ........................................................................................... 16 
Amendment 5 (01-Dec-2022) ............................................................................................ 18 
Amendment 4 (21-Aug-2020) ........................................................................................... 22 
Amendment 3 (08-Jan-2020) ............................................................................................. 25 
Amendment 2 (12-Jul-2019) ............................................................................................. 27 
Amendment 1 (12-Dec-2018) ............................................................................................ 30 
Protocol summary .............................................................................................................. 35 
1 
Introduction ....................................................................................................................... 40 
1.1 
Background ............................................................................................................ 40 
1.1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment ................................................................................................ 40 
1.1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) ........................................................................................... 43 
1.1.3 
Potential for drug-drug interactions ...................................................... 45 
1.2 
Purpose .................................................................................................................. 46 
2 
Objectives and endpoints ................................................................................................... 47 
3 
Study design ...................................................................................................................... 48 
4 
Rationale ............................................................................................................................ 52 
4.1 
Rationale for study design ..................................................................................... 52 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 54 
4.2.1 
Pharmacokinetics (PK) consideration ................................................... 54 
4.2.2 
Efficacy and pharmacodynamics (PD) considerations ......................... 55 
4.2.3 
Safety considerations ............................................................................ 56 
4.2.4 
Consideration for combination with pembrolizumab and 
chemotherapy ........................................................................................ 57 
4.2.5 
Conclusion for dose regimen selection ................................................. 58 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 59 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 60 
4.5 
Risks and benefits .................................................................................................. 60 
4.6 
Rationale for public health emergency mitigation procedures .............................. 61 
4.7 
End of study definition .......................................................................................... 61 

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5 
Population .......................................................................................................................... 62 
5.1 
Inclusion criteria .................................................................................................... 62 
5.2 
Exclusion criteria ................................................................................................... 64 
6 
Treatment ........................................................................................................................... 67 
6.1 
Study treatment ...................................................................................................... 67 
6.1.1 
Investigational and control drugs .......................................................... 67 
6.1.2 
Additional study treatments .................................................................. 75 
6.1.3 
Guidelines for continuation of treatment .............................................. 75 
6.1.4 
Treatment duration ................................................................................ 76 
6.2 
Other treatment(s) .................................................................................................. 77 
6.2.1 
Concomitant therapy ............................................................................. 77 
6.2.2 
Prohibited medication ........................................................................... 78 
6.3 
Subject numbering, treatment assignment, randomization .................................... 79 
6.3.1 
Subject numbering ................................................................................ 79 
6.3.2 
Treatment assignment, randomization .................................................. 80 
6.4 
Treatment blinding ................................................................................................. 80 
6.5 
Dose escalation and dose modification .................................................................. 81 
6.5.1 
Dose confirmation guidelines ............................................................... 81 
6.5.2 
Definitions of dose limiting toxicities (DLTs) ...................................... 83 
6.5.3 
Dose modifications ................................................................................ 85 
6.5.4 
Follow-up for toxicities ......................................................................... 89 
6.6 
Additional treatment guidance ............................................................................... 91 
6.6.1 
Treatment compliance ........................................................................... 91 
6.6.2 
Emergency breaking of assigned treatment code .................................. 91 
6.7 
Preparation and dispensation ................................................................................. 92 
6.7.1 
Handling of study treatment and additional treatment .......................... 93 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 93 
7 
Informed consent procedures ............................................................................................ 93 
8 
Visit schedule and assessments ......................................................................................... 95 
8.1 
Screening ............................................................................................................. 114 
8.1.1 
Eligibility screening ............................................................................ 114 
8.1.2 
Information to be collected on screening failures ............................... 114 
8.2 
Subject demographics/other baseline characteristics ........................................... 115 
8.3 
Efficacy assessments ........................................................................................... 115 
8.3.1 
Tumor assessments.............................................................................. 115 
8.3.2 
Appropriateness of efficacy assessments ............................................ 118 
8.3.3 
Survival assessments ........................................................................... 118 

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8.4 
Safety ................................................................................................................... 119 
8.4.1 
Laboratory evaluations ........................................................................ 119 
8.4.2 
Determination of tuberculosis status ................................................... 122 
8.4.3 
Performance status .............................................................................. 122 
8.4.4 
Electrocardiogram (ECG) ................................................................... 122 
8.4.5 
Pregnancy and assessments of fertility ............................................... 123 
8.5 
Additional assessments ........................................................................................ 124 
8.5.1 
Clinical Outcome Assessments (COAs) ............................................. 124 
8.5.2 
Pharmacokinetics (PK), immunogenicity (IG) and 
pharmacodynamics (PD) assessments ................................................. 125 
8.5.3 
Biomarkers .......................................................................................... 128 
9 
Discontinuation of study treatment and participant discontinuation/withdrawal ............ 129 
9.1 
Discontinuation .................................................................................................... 129 
9.1.1 
Discontinuation of study treatment ..................................................... 129 
9.2 
Participant discontinuation from the study .......................................................... 130 
9.2.2 
Withdrawal of informed consent and exercise of participants’ data 
privacy rights ....................................................................................... 131 
9.2.3 
Lost to follow-up ................................................................................. 132 
9.2.4 
Early study termination by the sponsor ............................................... 132 
9.3 
Study completion and post-study treatment ........................................................ 132 
10 Safety monitoring and reporting ...................................................................................... 133 
10.1 
Definition of adverse events and reporting requirements .................................... 133 
10.1.1 
Adverse events .................................................................................... 133 
10.1.2 
Serious adverse events ........................................................................ 135 
10.1.3 
SAE reporting...................................................................................... 136 
10.1.4 
Pregnancy reporting ............................................................................ 137 
10.1.5 
Reporting of study treatment errors including misuse/abuse .............. 138 
10.2 
Additional Safety Monitoring .............................................................................. 138 
10.2.1 
Data Monitoring Committee ............................................................... 138 
10.2.2 
Steering Committee ............................................................................. 139 
11 Data Collection and Database management .................................................................... 139 
11.1 
Data collection ..................................................................................................... 139 
11.2 
Data protection ..................................................................................................... 139 
11.3 
Database management and quality control .......................................................... 140 
11.4 
Site monitoring .................................................................................................... 140 
12 Data analysis and statistical methods .............................................................................. 141 
12.1 
Analysis sets ........................................................................................................ 141 

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12.1.1 
Full Analysis Set ................................................................................. 141 
12.1.2 
Safety set ............................................................................................. 142 
12.1.3 
Dose-determining set .......................................................................... 142 
12.1.4 
Pharmacokinetic set ............................................................................ 143 
12.2 
Subject demographics and other baseline characteristics .................................... 143 
12.3 
Treatments ........................................................................................................... 143 
12.4 
Analysis of the primary endpoint(s) .................................................................... 144 
12.4.1 
Definition of primary endpoint(s) ....................................................... 144 
12.4.2 
Statistical model, hypothesis, and method of analysis ........................ 144 
12.4.3 
Handling of missing values/censoring/discontinuations ..................... 147 
12.4.4 
Sensitivity and Supportive analyses .................................................... 147 
12.5 
Analysis of secondary endpoints ......................................................................... 149 
12.5.1 
Efficacy endpoints ............................................................................... 149 
12.5.2 
Safety endpoints .................................................................................. 150 
12.5.3 
Pharmacokinetics ................................................................................ 152 
12.5.4 
Patient reported outcomes ................................................................... 152 
12.6 
Analysis of exploratory endpoints ....................................................................... 153 
12.6.1 
Exploratory efficacy endpoints ........................................................... 153 
12.6.2 
Pharmacokinetics and pharmacodynamics (PK/PD) relationships ..... 154 
12.6.3 
Biomarkers .......................................................................................... 154 
12.7 
Interim analyses ................................................................................................... 155 
12.8 
Sample size calculation ........................................................................................ 157 
12.8.1 
Primary endpoint(s) ............................................................................. 157 
13 Ethical considerations and administrative procedures .................................................... 159 
13.1 
Regulatory and ethical compliance ...................................................................... 159 
13.2 
Responsibilities of the investigator and IRB/IEC ................................................ 159 
13.3 
Publication of study protocol and results............................................................. 159 
13.4 
Quality Control and Quality Assurance ............................................................... 159 
14 Protocol adherence .......................................................................................................... 160 
14.1 
Protocol Amendments ......................................................................................... 160 
15 References ....................................................................................................................... 161 
16 Appendices ...................................................................................................................... 168 
16.1 
Appendix 1: Guidelines for Response, Duration of Overall Response, TTF, 
TTP, Progression-Free Survival, and Overall Survival (based on RECIST 1.1) 168 
16.1.1 
Introduction ......................................................................................... 169 
16.1.2 
Efficacy assessments ........................................................................... 169 
16.1.3 
Efficacy definitions ............................................................................. 178 

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16.1.4 
Data handling and programming rules ................................................ 187 
16.1.5 
References (available upon request) ................................................... 191 
16.2 
Appendix 2: Guidelines for iRECIST.................................................................. 192 
16.2.1 
Introduction ......................................................................................... 192 
16.2.2 
Efficacy assessments ........................................................................... 193 
16.2.2.4.3.1 New lesion-target (NLT) response .............................................................. 197 
16.2.2.4.3.2 New lesion-non-target response .................................................................. 197 
16.2.3 
Efficacy definitions ............................................................................. 201 
16.2.4 
References ........................................................................................... 204 
16.2.5 
Supplement 1: Example Scenarios ...................................................... 204 
16.3 
Appendix 3: Statistical Details for Safety Run-in Part: Bayesian logistic 
regression model (BLRM): prior and design properties for hypothetical data 
scenarios .............................................................................................................. 211 
16.3.1 
Statistical Models ................................................................................ 211 
16.3.2 
Summary of prior distributions ........................................................... 215 
16.3.3 
Hypothetical on-study scenarios ......................................................... 217 
16.3.4 
References (available upon request) ................................................... 219 
16.4 
Appendix 4: Medications to be used with caution with paclitaxel/nab-
paclitaxel while on study ..................................................................................... 219 
16.5 
Appendix 5: Medications to be used with caution with canakinumab while on 
study ..................................................................................................................... 221 
16.6 
Appendix 6: Safety follow-up flow chart (post implementation of protocol 
amendment 05) .................................................................................................... 221 
16.7 
Appendix 7: Pembrolizumab Dose Modification Guidelines .............................. 222 
 
List of tables 
Table 1-1 
Canakinumab characteristics ................................................................. 44 
Table 2-1 
Objectives and related endpoints .......................................................... 47 
Table 4-1 
Rationale for study design ..................................................................... 53 
Table 4-2 
Summary of key hematological and infection adverse events for 
different treatment combinations for NSCLC ....................................... 60 
Table 6-1 
Part 1 (safety run-in part) - Cohort A: Dose and treatment schedule 
(non-squamous subjects only) ............................................................... 67 
Table 6-2 
Part 1 (safety run-in part) - Cohort B: Dose and treatment schedule 
(non-squamous subjects only) ............................................................... 68 
Table 6-3 
Part 1 (safety run-in part) - Cohort C: Dose and treatment schedule 
(squamous or non-squamous subjects) .................................................. 68 

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Table 6-4 
Part 2 (double-blind, randomized, placebo-controlled part): Dose 
and treatment schedule .......................................................................... 69 
Table 6-5 
Dose and treatment schedule post implementation of protocol 
amendment 05 ....................................................................................... 70 
Table 6-6 
Investigational and study drug post implementation of protocol 
amendment 06 ....................................................................................... 71 
Table 6-7 
Provisional dose levels .......................................................................... 83 
Table 6-8 
Criteria for defining dose-limiting toxicities......................................... 84 
Table 6-9 
Criteria for mandatory dose interruption and re-initiation for 
canakinumab/matching-placebo for adverse drug reactions ................. 86 
Table 6-10 
Guidance on specific clinical and diagnostic assessments .................... 90 
Table 8-1 
Allowable visit windows are specified as follows: ............................... 95 
Table 8-2 
Assessment Schedule, Safety run-in part .............................................. 97 
Table 8-3 
Assessment Schedule, Double-blind, randomized, placebo-
controlled part ..................................................................................... 102 
Table 8-4 
Assessment Schedule, Open Label Extension Phase .......................... 108 
Table 8-5 
Assessment Schedule, Post implementation of protocol amendment 
05 ......................................................................................................... 112 
Table 8-6 
Imaging Assessment Collection Plan .................................................. 116 
Table 8-7 
Clinical laboratory parameters collection plan prior to 
implementation of protocol amendment 05 ........................................ 121 
Table 8-8 
Clinical laboratory parameters collection plan post implementation 
of protocol amendment 05 .................................................................. 121 
Table 8-9 
ECOG performance status ................................................................... 122 
Table 8-10 
Blood collection schedule for canakinumab (PK, IG and PD), 
pembrolizumab (PK and IG) and chemotherapy agents (PK) ............ 126 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ....................................................................................... 138 
Table 12-1 
Simulated probabilities to stop for overall survival efficacy at final 
PFS analysis, interim or final OS analyses ......................................... 156 
Table 16-1 
Response criteria for target lesions ..................................................... 174 
Table 16-2 
Response criteria for non-target lesions .............................................. 176 
Table 16-3 
Overall lesion response at each assessment ........................................ 177 
Table 16-4 
Overall lesion response at each assessment: subjects with non-
target disease only ............................................................................... 185 
Table 16-5 
Options for event dates used in PFS, TTP, duration of response ........ 185 
Table 16-6 
Determination of target lesion response by iRECIST ......................... 195 
Table 16-7 
Determination of non-target lesion response by iRECIST ................. 196 
Table 16-8 
Determination of new lesion-target response by iRECIST ................. 197 

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Table 16-9 
Determination of new lesion-non-target response by iRECIST ......... 197 
Table 16-10 
Overall lesion response for a time-point based on consideration of 
target lesions, non-target lesions and new lesions .............................. 199 
Table 16-11 
Prior distributions for the parameters of the MAP model used to 
derive the prior for the single-agent canakinumab model 
parameters ........................................................................................... 214 
Table 16-12 
Historical data from [CACZ885I2202] for canakinumab single 
agent .................................................................................................... 214 
Table 16-13 
Prior distribution for the 3 models parameters .................................... 215 
Table 16-14 
Summary of prior distribution of DLT rates ....................................... 216 
Table 16-15 
Dose decisions recommended by BLRM for pemetrexed plus 
carboplatin chemotherapy regimen under EWOC .............................. 217 
Table 16-16 
Dose decisions recommended by BLRM for pemetrexed plus 
cisplatin chemotherapy regimen under EWOC ................................... 217 
Table 16-17 
Dose decisions recommended by BLRM for carboplatin plus 
paclitaxel chemotherapy regimen under EWOC ................................. 218 
Table 16-18 
Drugs to be used with caution with paclitaxel/nab-paclitaxel while 
on study ............................................................................................... 219 
Table 16-19 
CYP3A substrates with narrow therapeutic index, or sensitive 
CYP2C9 substrates with narrow therapeutic index** ........................ 221 
Table 16-20 
Dose Modification and Toxicity management Guidelines for 
Immune-related Adverse Events associated with Pembrolizumab ..... 222 
 
List of figures 
Figure 3-1 
Part 1: Safety run-in, study design ........................................................ 49 
Figure 3-2 
Part 2: Double-blind, randomized, placebo-controlled, study 
design, including optional crossover during the OLE phase................. 50 
Figure 3-3 
Study flow ............................................................................................. 51 
Figure 4-1 
Simulated PK profiles of canakinumab 200 mg Q3W s.c. and 300 
mg Q4W s.c. .......................................................................................... 55 
Figure 4-2 
Proportions of subjects with hs-CRP < 2.3 mg/ L by baseline hs-
CRP declines in all subjects from the CANTOS study ......................... 56 
Figure 6-1 
Safety run-in part: dose and treatment schedule ................................... 73 
Figure 6-2 
Double-blind, randomized, placebo-controlled part including 
optional crossover in the OLE phase and post implementation of 
protocol amendment 05: dose and treatment schedule ......................... 74 
Figure 12-1 
Graphical gate-keeping procedure to test primary endpoints in 
order to control overall type 1 error .................................................... 146 
 

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List of abbreviations 
ADA 
Anti-drug antibodies 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AJCC 
American Joint Committee on Cancer 
ALK 
Anaplastic Lymphoma Kinase 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANA 
Antinuclear Antibody 
ANC 
Absolute Neutrophil Count 
ASMA 
Anti-Smooth Muscle Antibody 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
b.i.d. 
bis in die/twice a day 
BDR 
Bioanalytical Data Report 
BIRC 
Blinded Independent Review Committee 
BLQ 
Below the Limit of Quantification 
BLRM 
Bayesian Logistic Regression Model 
BMI 
Body Mass Index 
BOR 
Best Overall Response 
BRAF 
B-raf proto-oncogene 
BUN 
Blood Urea Nitrogen 
CANTOS 
Canakinumab Anti-inflammatory Thrombosis Outcomes Study 
CAPS 
Cryopyrin Associated Periodic Syndromes 
Cavg 
Average concentration 
CD-transferrin 
Carbohydrate Deficient-transferrin 
CDS 
Core Data Sheet (for marketed drugs) 
CFR 
Code of Federal Regulation 
CHF 
Congestive Heart Failure 
CI 
Confidence Interval 
Cmax 
Maximum concentration 
Cmin 
Minimum concentration 
CMV 
Cytomegalovirus 
CNS 
Central Nervous System 
COAs 
Clinical Outcome Assessments 
CPD 
Confirmed Progressive Disease 
CR 
Complete Response 
CRF 
Case report form 
CRO 
Contract Research Organization 
CRP 
C-reactive Protein 
CRS 
Case Retrieval Strategy  
CSR 
Clinical Study Report 
CT 
Computer Tomography 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 

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CTCs 
Circulating Tumor Cells 
CTLA-4 
Cytotoxic T-Lymphocyte Antigen 4 
CTx 
Chemotherapy 
CV 
Coefficient of variation 
CVD 
Cardiovascular Disease  
CxDx 
Cycle x Day x 
CYP 
Cytochrome P450  
DBP 
Diastolic Blood Pressure 
DCR 
Disease Control Rate 
DDI 
Drug-Drug Interactions 
DDS 
Dose-Determination Set 
DILI 
Drug Induced Liver Injury 
DLRT 
Dose Level Review Team 
DLTs 
Dose Limiting Toxicities 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of Response 
e.g. 
exempli gratia 
EBV 
Epstein-Barr Virus 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
Electronic Data Capture 
EGFR 
Epidermal Growth Factor Receptor  
ELISA 
Enzyme-linked immunosorbent assay 
EMA 
European medicines agency 
EOI 
End of Infusion 
EORTC 
European Organisation for Research and Treatment of Cancer 
EOT 
End of Treatment 
ePRO 
Electronic Patient Reported Outcomes 
ERCP 
Endoscopic Retrograde Cholangiopancreatography 
EU 
European Union 
EU CTR 
European Union Clinical Trial Regulation  
EWOC 
Escalation With Overdose Control 
FAS 
Full Analysis Set  
FDA 
Food and Drug Administration 
FMF 
Familial Mediterranean Fever  
FPFV 
First Patient First Visit 
G-CSF 
Granulocyte Colony-Stimulating Factor 
gamma(γ)-GT 
gamma-glutamyl transferase 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
GGT 
Gamma-glutamyltransferase 
h 
Hour 
HAV 
Hepatitis A Virus  

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HBV 
Hepatitis B Virus  
hCG 
Human Chorionic Gonadotropin 
HCV 
Hepatitis C Virus  
HEV 
Hepatitis E Virus  
Hgb 
Hemoglobin 
HIDS 
Hyperimmunoglobulin D Syndrome 
HIV 
Human immunodeficiency virus 
HR 
Hazard Ratio 
hs-CRP 
High-sensitivity C-reactive protein 
hs-IL-6 
High sensitivity interleukin 6 
HSV 
Herpes Simplex Virus 
i.e.  
id est 
i.v. 
intravenous 
IB 
Investigator's Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
iCPD 
Immune Confirmed Progressive Disease 
iCR 
Immune related complete response 
iDCR 
Immune related disease control rate 
IEC 
Independent Ethics Committee 
IG 
Immunogenicity 
IgA 
Immunoglobulin A 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IHC 
Immunohistochemistry 
IL-1β 
Interleukin-1β 
IMP 
Investigational Medicinal Product 
IN 
Investigator Notification 
INN 
International Nonproprietary Names 
INR 
International Normalized Ratio  
iORR 
Immune related overall response rate 
iPFS 
Immune related progression-free survival 
iPR 
Immune related partial response 
irAE 
Immune-related adverse events 
IRB 
Institutional Review Board 
iRECIST 
Immune Response Evaluation Criteria in Solid Tumors 
IRT 
Interactive Response Technology 
iSD 
Immune related stable disease 
iSOD 
Immune sum of diameters 
IUD 
Intrauterine Device 
iUPD 
Immune Unconfirmed Progressive Disease 
IUS 
Intrauterine System 
LDH 
Lactate dehydrogenase 
LFT 
Liver Function Test 

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LLN 
Lower Limit of Normal 
LPLV 
Last Patient Last Visit 
MACE 
Major Adverse Cardiovascular Events 
MCV 
Mean Corpuscular Volume  
MDSCs 
Myeloid Derived Suppressor Cells 
MedDRA 
Medical dictionary for regulatory activities 
mg 
milligram(s) 
MI 
Myocardial Infarction 
MKD 
Mevalonate Kinase Deficiency  
mL 
milliliter(s) 
mPFS 
median Progression Free Survival 
MRI 
Magnetic Resonance Imaging 
NASH 
Nonalcoholic steatohepatitis  
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse events 
NE 
Non Estimable 
NF-κB 
Nuclear Factor Kappa Beta 
NLNT 
New Lesion Non-Target 
NLT 
New Lesion Target 
NSAIDs 
Nonsteroidal Anti-Inflammatory Drugs 
NSCLC 
Non-Small Cell Lung Cancer 
OLE 
Open Label Extension 
ORR 
Overall Response Rate  
OS 
Overall Survival 
p.o. 
Per os (oral administration) 
PAS 
Pharmacokinetic Analysis Set  
PBO 
Placebo 
PD 
Pharmacodynamic(s) 
Progressive disease 
PD-L1 
Programmed death-ligand 1 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic(s) 
PR 
Partial Response 
PROs 
Patient Reported Outcomes 
PT 
Prothrombin time 
QMS 
Quality Management System  
QxW 
Every x weeks 
R-value 
ALT/ALP in multiples of ULN 
RBC 
Red blood cell(s) 
RECIST 
Response Evaluation Criteria in Solid Tumors 
ROS-1 
c-ros oncogene 1 
RP2D 
Recommended Phase 2 Dose 
RP3R 
Recommended Phase 3 dose Regimen 
s.c. 
subcutaneous 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 

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SBP 
Systolic Blood Pressure 
sCR 
serum creatinine 
SD 
Stable Disease 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SRI 
Safety run-in 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
T1/2 
The elimination half life associated with the terminal slope (lz) of a semi 
logarithmic concentration time curve (time) 
T1D 
Type 1 Diabetes 
T3 
Triiodothyronine 
T4 
Thyroxine 
TAMs 
Tumor Associated Macrophages 
TB 
Tuberculosis 
TBIL 
Total Bilirubin 
Tmax 
The time at which the maximum observed concentration (Cmax) occurs 
TNF 
Tumor Necrosis Factor 
TNFα 
Tumor necrosis factor alpha  
TP 
Time-point 
TRAPS 
Tumor Necrosis Factor Receptor Associated Periodic Syndrom 
TSH 
Thyroid-Stimulating Hormone 
TTR 
Time To Response 
ULN 
Upper limit of normal 
US 
United States 
USPI 
US-Package Insert 
VATS 
Video-Assisted Thoracic Surgery  
VEGF 
Vascular Endothelial Growth Factor  
vs. 
Versus 
WBC 
White blood cell(s) 
WHO 
World Health Organization 

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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Cohort 
A specific group of subjects fulfilling certain criteria 
Control drug 
A study drug 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. 
Data (Personal data) 
Subject information collected by the Investigator that is transferred to Novartis 
for the purpose of the clinical trial. This data includes subject identifier 
information, study information and biological samples. 
Dosage 
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day) 
Enrollment 
Point/time of subject entry into the study; the point at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described in the 
protocol). 
Implementation of protocol 
amendment 
The implementation of a protocol (or protocol amendment) for a subject at a 
specific site is permitted when relevant Health Authority and/or Ethics 
Committee(s) approvals have been obtained as applicable and when the 
subject has signed the required informed consent(s). 
Investigational drug 
The study drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and Directive 2001/20/EC and is 
synonymous with “investigational new drug” or “test substance” 
Investigational treatment 
All investigational drug(s) whose properties are being tested in the study as 
well as their associated treatment controls. This includes any placebos, any 
active controls, as well as approved drugs used outside of their 
indication/approved dosage or tested in a fixed combination. Investigational 
treatment generally does not include other treatments administered as 
concomitant background therapy required or allowed by the protocol when 
used within approved indication/dosage. 
Medication number 
A unique identifier on the label of each study drug package in studies that 
dispense study drug using an IRT system. 
Part 
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a 
single dose part and a multiple dose part, or a part in patients with 
established disease and in those with newly-diagnosed disease. 
Patient 
An individual with the condition of interest 
Period 
A minor subdivision of the study timeline; divides phases into smaller 
functional segments such as screening, baseline, titration, washout, etc. 
Premature subject withdrawal 
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned. 
Randomization number 
A unique identifier assigned to each randomized subject, corresponding to a 
specific treatment arm assignment 
Screen Failure 
A subject who is screened but is not treated or randomized 
Stage 
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc. 
Study completion 
Point/time at which the subject came in for a final evaluation visit or when 
study drug was discontinued whichever is later. 
Study drug(s) 
Any drug (or combination of drugs) administered to the subject as part of the 
required study treatment; includes investigational drug. 
Study treatment 
All study drugs administered to the subject (includes investigational drug) 

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Study treatment 
discontinuation 
Point/time when subject permanently stops taking study treatment for any 
reason; may or may not also be the point/time of premature subject 
withdrawal. 
Subject 
An individual who has consented to participate in this study. The term Subject 
may be used to describe either a healthy volunteer or a patient. 
Subject number 
A number assigned to each subject who enrolls in the study. When combined 
with the center number, a unique identifier is created for each subject in the 
study. 
Treatment number 
A unique identifier assigned in non-randomized studies to each dosed 
subject, corresponding to a specific treatment arm  
Variable 
Information used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints. 
Withdrawal of informed 
consent and exercise of 
participants’ data privacy 
rights 
Withdrawal of consent from the study occurs only when a subject does not 
want to participate in the study any longer and does not allow any further 
collection of personal data. 

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Amendment 6 (25-Aug-2023) 
Amendment rationale  
As of 25-Aug-2023, there are 18 subjects on treatment, 5 of them receiving canakinumab in 
combination with pemetrexed, 6 receiving canakinumab alone, and 7 receiving pemetrexed 
alone. 
The main objective of amendment 06 is to ensure continuous provision of canakinumab for 
subjects who in the opinion of investigator are still deriving clinical benefit, by adding one 
additional pharmaceutical form for canakinumab.  
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
The following changes are implemented: 
• List of abbreviations: Removed the abbreviation “CMO&PS” as it is replaced with 
“Novartis Safety” throughout the document, in accordance with the global protocol 
template. Added the abbreviation “IMP”. 
• Section 1.2: As of 30-Jun-2023, confirmed that there were no changes to the overall safety 
and tolerability profile of canakinumab, platinum-based chemotherapy and pembrolizumab.  
• Section 3, Figure 3-2: Updated footnote 3 to clarify that OLE phase was never implemented 
since the study did not meet its primary endpoints of Overall Survival (OS) and Progression 
Free Survival (PFS) at final analysis. Additionally, clarified that all subjects will enter 
Safety follow-up period of 130 days once dosing is discontinued.  
• Section 4.1, Table 4-1: Clarified that all subjects will enter Safety follow-up period of 130 
days once dosing is discontinued.  
• Section 4.2.4: Updated with information that the study CPDR001X2102 is completed. 
• Section 4.7: The new section to define the end of the study is added per alignment with 
global protocol template. 
• Section 6.1.1.4: Updated information regarding the status of ongoing subjects. Table 6-6 is 
the new table for investigational and study drugs post implementation of protocol 
amendment 06 and contains two canakinumab pharmaceutical forms (200 mg/1.33 mL 
solution for s.c. injection as pre-filled syringes and 150 mg/1 mL solution for injection in 
vial) and pemetrexed. Consequently, table numbering in Section 6 is updated.  
• Section 6.1.1.5: Updated with the information that canakinumab pharmaceutical form of 
150 mg/1 mL solution for injection in vial will be supplied once protocol amendment 06 is 
implemented and canakinumab 200 mg/1.33 mL solution for s.c. injection as pre-filled 
syringes is no longer available. Also, confirmed that the dose of canakinumab to be given 
in this current study is unchanged (200 mg s.c). The available data to support transition to 
the new ACZ885 drug formulation (150 mg/1 mL solution for s.c. injection in vial) is added. 
Additionally, ACZ885 dosing in Table 6-5 is updated with Q6W frequency. 
• Section 6.7: Updated with information that canakinumab pharmaceutical form of 150 mg/1 
mL solution for injection in vial requires preparation before dosing. 

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• Section 8.3.1, Table 8-6: Clarified that the imaging assessment frequency will be until 
protocol-defined subject discontinuation or sponsor study termination. 
• Section 8.4.1: Clarified that local safety evaluations are aligned with the standard of care of 
current treatment and dosing regimen.  
• Section 9: Updated title and requirements, procedures, and data collection for study 
discontinuation, per the global protocol template. 
• Section 9.2: Addition of the new section to define participant discontinuation from the 
study, per the global protocol template. 
• Section 10.1.1: Provided additional clarification of the adverse events, as per the global 
protocol template. 
• Section 10.1.1.2: Updated version of the ICH guidelines, per the global protocol template.  
• Section 12.5.3: Replaced the abbreviation PAS with the full name (Pharmacokinetic 
Analysis Set). 
• Editorial revisions and text corrections were also included throughout 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 and Health Authority 
approval according to local regulations prior to implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 

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Amendment 5 (01-Dec-2022) 
Amendment rationale  
Enrollment for the safety run-in part was closed on 20-Mar-2019, with 30 subjects enrolled. As 
of 08-Dec-2021, all subjects from the safety run-in have discontinued the study. Enrollment for 
the randomized part was closed on 11-Dec-2019, with 643 subjects randomized. As of 01-Dec-
2022, there are 29 subjects on treatment, 10 of them receiving canakinumab in combination 
with pemetrexed, 9 receiving canakinumab alone, and 10 receiving pemetrexed alone. 
As of 25-Oct-2021, the study did not meet its primary endpoints of Overall Survival (OS) and 
Progression Free Survival (PFS) at final analysis. The trial was unblinded and subjects were 
allowed to continue treatment with pembrolizumab and pemetrexed plus canakinumab (as 
applicable) if the investigator considered this beneficial for the subject. 
The main objectives of amendment 05 are to:  
• Ensure continuous provision of canakinumab for subjects who in the opinion of investigator 
are still deriving clinical benefit, by adding one additional pharmaceutical form for 
canakinumab  
• Align safety and efficacy assessment schedule to standard of care  
• Define the new end of study, as when all subjects discontinue the study treatment and 
complete their safety follow up, die, withdraw consent, or are lost to follow up, whichever 
comes first  
In addition, the following changes are implemented:  
• Replacement of central safety laboratory with local safety laboratory 
• Removal of Patient Reported Outcomes (PRO) collections 
• Removal of all PK, PD, IG samples collections 
• Removal of all biomarkers samples collections 
• Removal of efficacy follow-up 
• Removal of survival follow-up 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
• List of abbreviations: updated with EU Clinical Trial Regulation and removal of Rest of the 
World  
• Glosary of terms: updated with the addition of assessment Implementation of the protocol 
amendment and update of the assessment name Withdrawal of informed consent and 
exercise of participants’ data privacy rights 
• Protocol summary table: updated to reflect the changes post implementation of protocol 
amendment 05 
• Section 1.2: updated with the summary of primary analysis results 

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• Section 3: updated to reflect changes post implementation of protocol amendment 05: all 
subjects will enter or complete the safety follow-up but the subjects in efficacy or survival 
follow-up will discontinue the study 
• Section 3, Figure 3-3: footnote updated for Efficacy follow-up and End of Treatment to 
reflect changes post implementation of protocol amendment 05  
• Section 4.1, Table 4-1: updated with the protocol amendment 05 rationale 
• Section 4.6: added new section “Rationale for public health emergency mitigation 
procedures” 
• Section 6.1.1.4: added dosing regimen post implementation of protocol amendment 05. 
Renumbered Section 6.1.1.4 to Section 6.1.1.5 due to addition of Section 6.1.1.4.  
• Section 6.1.1.4, Table 6-5: addition of the table with the dosing regimen post implementation 
of protocol amendment, and consequently updated Table numbering from Table 6-5 to Table 
6-9  
• Section 6.1.1.5: clarified that post trial unblinding on 25-Oct-2021, canakinumab-matching 
placebo was no longer supplied nor dispensed  
• Section 6.1.1.5, Supply for study treatment: added pharmaceutical form of ACZ885  
• Section 6.1.1.5, Administration of study treatment: removal of information on volume of 
drug syringes  
• Section 6.1.1.5, Figure 6-2: update of the title. Clarified that post trial unblinding on 25-Oct-
2021, canakinumab-matching placebo was no longer supplied nor dispensed 
• Section 6.3: clarified that protocol sections related to subject numbering, treatment 
assignment and randomization are not applicable post implementation of protocol 
amendment 05 
• Section 6.4: clarified that trial was unblinded 25-Oct-2021 prior to the implementation of 
protocol amendment 05 
• Section 6.7: clarified that post trial unblinding on 25-Oct-2021, canakinumab-matching 
placebo was no longer supplied nor dispensed 
• Section 7 and Section 8: added alternative methods of obtaining informed consent and 
providing continuing care during a Public Health emergency as declared by Local or 
Regional authorities 
• Section 8, Table 8-5: added new assessment schedule post implementation of protocol 
amendment 05, and consequently updated Table numbering from Table 8-5 to  
Table 8-10 
• Section 8.3.1: clarified that post implementation of protocol amendment 05, only the 
RECIST 1.1 response assessment will be recorded in the appropriate CRF page. Other 
efficacy assessments will be recorded in the source documentation only 
• Section 8.3.1, Table 8-6: updated to reflect that no more efficacy follow-up will be performed 
post implementation of protocol amendment 05. Clarified that the frequency of tumor 
assessment post implementation of protocol amendment 05 is every 12 weeks 
• Section 8.3.1.4: clarified that efficacy follow-up will not be performed post implementation 
of protocol amendment 05 

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• Section 8.3.3: clarified that survival follow-up will not be performed post implementation 
of protocol amendment 05 
• Section 8.4: clarified safety and survival assessments post implementation of protocol 
amendment 05. Also, added information about alternative methods of safety monitoring 
during a Public Health emergency as declared by Local or Regional authorities 
• Section 8.4.1: clarified that local laboratory will be used instead of central laboratory 
• Section 8.4.1: addition of Table 8-8 with the safety assessment post implementation of 
protocol amendment 05. Updated title of Table 8-7. Also, added information about 
alternative methods of safety monitoring during a Public Health emergency as declared by 
Local or Regional authorities 
• Section 8.4.1.1: clarified how the estimate of GFR will be done  
• Section 8.4.3: clarified that the performance status will no longer be collected post 
implementation of protocol amendment 05. 
• Section 8.4.4: clarified that ECGs should be performed per Table 8-5 
• Section 8.4.5: clarified that only urine pregnancy test will be performed post 
implementation of protocol amendment 05. Also, clarified that serum pregnancy test will 
be used at EOT. Addition of the use of urine pregnancy test kits during a Public Health 
emergency as declared by Local or Regional authorities 
• Section 8.5.1: clarified that ePRO questionnaires will no longer be collected post 
implementation of protocol amendment 05 
• Section 8.5.2: clarified that the sample collection for analysis of PK (and PD/IG as 
applicable) will no longer be performed post implementation of protocol amendment 05 
• Section 8.5.3: clarified that the sample collection for analysis of biomarkers will no longer 
be performed post implementation of protocol amendment 05 
• Section 9.1.1: clarified that assessment schedule post implementation of protocol 
amendment 05 is per Table 8-5: 
• Section 9.1.2: clarified reasons for withdrawal of consent. Addition of instructions of 
documenting the withdrawal of consent at the site level  
• Section 9.1.3: clarified definition of subjects who are lost to follow-up 
• Section 9.1.4: clarified reasons for early study termination. Removal of wording related to 
instructions for contacting the patient when subject should stop the drug since the 
instructions are present in the Section 9.1.1 
• Section 9.2: definition of study end updated by removing the criteria of five years from the 
time of the last subject first treatment in the randomized part  
• Section 10.1.3: updated with instructions on SAE reporting. Clarified that post 
implementation of protocol amendment 05, SAE reported post 130-day safety follow-up. 
Also, update of regulation for SUSARs reporting under EU CTR  
• Section 11.2: addition of section related to data protection. Renumbered Section 11.2 to 
Section 11.3 and Section 11.3 to Section 11.4 due to addition of Section 11.2 
• Appendix 16.6: update of safety follow-up chart for post implementation of protocol 
amendment 05 
• Editorial revisions and text corrections were also included throughout the document 

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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 and Health Authority 
approval according to local regulations prior to implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 

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Amendment 4 (21-Aug-2020)  
Amendment rationale  
Enrollment for the safety run-in part was closed on 20-Mar-2019, with 30 subjects enrolled, of 
which 23 subjects discontinued the study as of 21-Aug-2020. Enrollment for the randomized 
part was closed on 11-Dec-2019, with 643 subjects randomized, of which 328 have 
discontinued the study as of 21-Aug-2020. 
The main objective of amendment 04 is to:  
• Create an open label extension phase (OLE) that all subjects still on treatment or in 
safety/efficacy follow-up will transition into, following unblinding of investigational sites 
to treatment allocation, if OS reaches statistical significance at one of the interim or final 
analyses. If OS is not statistically significant at final analysis but PFS was statistically 
significant at primary analysis, OLE will be initiated after final OS analysis and following 
the unblinding of investigational sites. Subjects will transition to a reduced study assessment 
schedule. 
• Allow subjects that were randomly allocated to the placebo arm the opportunity to cross 
over to the investigational drug (ACZ885), per investigator and subject discretion, during 
the OLE phase.  
• Define the new end of study, as the end of the OLE phase, at 5 years from the time of last 
subject first treatment in the randomized part or when all subjects discontinue the study 
treatment and complete their safety follow up, die, withdraw consent or are lost to follow 
up, whichever comes first.  
In addition, the following changes are implemented: 
• To clarify that all laboratory events meeting the DILI criteria are to be reported as SAE in 
the absence of alternative explanation. 
• To add that confirmed COVID-19 infection should be considered as medically significant 
AE and therefore should be reported as SAE. 
• To add that in case that a female subject becomes pregnant, the study treatment should be 
stopped, and the subject must be asked to read and sign the pregnancy consent form. Also 
to change the newborn follow up period from “at least 12 months” to “up to 12 months”.  
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
• Protocol summary: updated to add the OLE phase 
• Section 3: added new paragraph to describe the design of the OLE 
• Section 3, Figure 3-2: updated title and Figure to include the optional crossover from 
canakinumab matching-placebo to canakinumab during the OLE 
• Section 3, Figure 3-3: updated to include the OLE and clarified that safety follow up is every 
26 days for 130 days after the last dose of the study treatment rather than after EOT  
• Section 4, Table 4-1: added rationale for the OLE and updated wording that pembrolizumab 
treatment will be given for a maximum of 35 administrations and not cycles 

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• Section 6.1.1.3: added new section to describe dosing regimen during the OLE.  
• Section 6, Figure 6-2: Title and footnote updated to include the optional crossover from 
canakinumab matching-placebo to canakinumab during the OLE. 
• Section 6.1.3: added new paragraph to describe the criteria for the optional crossover of 
subjects from canakinumab matching-placebo to canakinumab during the OLE. 
• Section 6.1.4: clarified that subjects randomized to the canakinumab matching-placebo arm 
will be allowed to cross over to canakinumab if the investigator determines this is in the 
subject’s best interest and per subject discretion, provided they fullfill crossover criteria 
• Section 6.1.4.1: Pembrolizumab treatment duration is a maximum of 35 administrations 
instead of cycles. 
• Section 6.3.2: clarified that transition to OLE and crossover (if applicable) will be 
performed on the IRT system. 
• Section 6.4: clarified that following unblinding of investigational sites and provided the 
primary objective is met, all subjects will transition to OLE 
• Section 6.5.4.2: clarified that all laboratory events meeting the DILI criteria are to be 
reported as SAE in the absence of alternative explanation. 
• Section 6.6.2: clarified that emergency unblinding will no longer be applicable following 
investigational site unblinding.  
• Section 8, Table 8-2, Table 8-3, and Table 8-4: clarified that safety follow up is every 26 
days for 130 days after the last dose of the study treatment rather than after EOT.  
• Section 8, Table 8-4: added new assessment schedule for OLE, and consequently updated 
Table numbering from Tables 8-4 to 8-7. 
• Section 8.3.1: clarified that imaging data for OLE should not be submitted to the imaging 
CRO. 
• Section 8, Table 8-5: updated to clarify that the imaging assesment schedule during the OLE 
will remain the same as in SRI or randomized part until Week 159 (aprox. 3 years) after the 
study C1D1and then change to every 24 weeks. 
• Section 8.3.1.2: clarified that the imaging assesment schedule during the OLE will remain 
the same as in SRI or randomized part until Week 159 (aprox. 3 years) after the study C1D1 
and then change to every 24 weeks. 
• Section 8.4.1: clarified that only local laboratory testing will be performed during the OLE 
• Section 8, Table 8-6: updated to clarify which labolatory parameters are not applicable for 
the OLE. 
• Section 8.4.5: clarified that only urine pregnancy testing is applicable during the OLE, and 
serum pregnancy test will be performed at EOT. 
• Section 8.5.1: clarified that ePRO assesment will follow the same schedule as tumour 
assessments during the OLE.  
• Section 8.5.2: clarified that there will be no PK, IG and PD sample collection during the 
OLE. 
• Section 9.2: updated for the addition of the OLE phase and to define the new end of study. 
• Section 10.1.2: added that confirmed COVID-19 infection should be considered medically 
significant and reported as SAE 

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• Section 10.1.4: clarified that in case of a female subject pregnancy, the study treatment 
should be stopped and the pregnancy form read and signed. 
• Section 10.1.4: changed the newborn follow up period from at least 12 months to up to 12 
months.  
• Section 12: added that any additional data for ongoing subjects in the randomized part 
following the final OS analysis and data for subjects in OLE (if initiated) will be further 
summarized in a final study report. 
Editorial revisions and text corrections were also included throughout 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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Amendment 3 (08-Jan-2020)  
Amendment rationale  
Enrollment for the safety run-in part was closed on 20-Mar-2019, with 30 subjects enrolled. As 
of 08-Jan-2020, 15 subjects from the safety run-in part have discontinued the study. Enrollment 
for the randomized part of the study started on 10-Jun-2019 and finished on 11-Dec-2019. As 
of 08-Jan-2020, 637 subjects have been randomized, of which 73 have discontinued the study, 
while 12 subjects are still undergoing screening.  
The main objective of amendment 03 is:  
• To implement the Health Authority request that patients who have discontinued 
pembrolizumab due to toxicity or completed 35 cycles of pembrolizumab per protocol and 
develop RECIST 1.1 progressive disease while receiving chemotherapy combined with 
canakinumab/matching placebo cannot continue treatment with canakinumab/matching 
placebo with chemotherapy (during induction or maintenance), as there is no evidence to 
suggest that drug administration will provide clinical benefit in this setting. Chemotherapy 
refers to platinum-based doublet chemotherapy during induction or pemetrexed 
chemotherapy during maintenance.  
In addition, the following changes are implemented: 
• To clarify exclusion criterion #3 by removing the specific EGFR mutations listed in 
parenthesis, as exon 20 is not a EGFR sensitizing mutation. 
• To clarify that female partners of male participants are also informed of the study treatment 
risk in case of pregnancy during the study 
• To clarify that if a patient is not able to self-administer the ePRO questionnaires (e.g. due 
to illiteracy or blindness) the questionnaires will not be completed. 
• To clarify that for subjects who continue receiving study treatment beyond initial RECIST 
1.1 PD, radiation therapy is allowed.  
• To replace the Adverse Event of Special Interest (AESI) name ‛DILI (Hepatic transaminases 
and bilirubin elevations)’ with the new AESI name ‛Abnormal Liver Parameters’ so as to 
reflect MedDRA search more accurately  
• To clarify the scope of optional pharmacogenetic analysis.  
• To add that if a pregnancy occurs while on study treatment, the newborn will be followed 
for at least 12 months.  
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
• Section 4, Table 4-1: updated to add reference to section 6.1.4.1. 
• Section 5.2: Exclusion #3 updated to remove reference to specific EGFR mutations, 
previously in parenthesis. 
• Section 6.1.3: updated to clarify that all patients are expected to continue to maintenance 
canakinumab/matching placebo in combination with pembrolizumab and to remove 
reference to treatment beyond RECIST 1.1. PD 

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• Section 6.1.4.1: updated to clarify that if pembrolizumab is discontinued before RECIST 
1.1 PD then canakinumab/matching placebo with chemotherapy (during induction or 
maintenance) is not allowed beyond RECIST 1.1 PD. Also removed previous provisions for 
treatment beyond RECIST 1.1 PD when pembrolizumab is discontinued during induction 
or during maintenance.  
• Section 6.2.1.1.1: updated to clarify that after RECIST 1.1 PD, radiation therapy is allowed. 
• Section 7: added the words “ and female partners of male participants” to clarify that female 
partners of male participants are also informed of the study treatment risk in case of 
pregnancy during the study. 
• Section 8.3.1.2: added reference to section 6.1.4.1. 
• Section 8.5.1: updated to clarify that if a patient is not able to self-administer the ePRO 
questionnaires (e.g. due to illiteracy or blindness) then questionnaires will not be completed. 
• Section 8.5.3.3: deleted the words “AE-related” so that the scope of pharmacogenetic 
research is better reflected.  
• Section 9.1.1: updated to add that study treatment must be discontinued at RECIST 1.1 PD 
if it occurs when pembrolizumab was previously discontinued. Also, to remove previous 
provision for continuation of treatment until induction is complete for patients with 
squamous histology.  
• Section 10.1.1.1 updated to replace the Adverse Event of Special Interest (AESI) name 
‛DILI (Hepatic transaminases and bilirubin elevations)’ with the new AESI name 
‛Abnormal Liver Parameters’. 
• Section 10.1.4 updated to add that if a pregnancy occurs while on study treatment, the 
newborn will be followed for at least 12 months.  
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 2 (12-Jul-2019)  
Amendment rationale  
A total of 30 subjects were enrolled and treated in the safety run-in part. Enrollment for the 
safety run-in part was closed on 20-Mar-2019. The Recommended Phase 3 Regimen (RP3R) of 
canakinumab in combination with pembrolizumab plus platinum-based doublet chemotherapy 
has been determined and communicated to all investigators on 10-Jun-2019. Enrollment for the 
randomized part of the study started on 10-Jun-2019. As of 12-Jul-2019, 127 subjects have been 
screened and 25 subjects have been randomized.  
The main objective of amendment 02 is:  
• To clarify treatment beyond disease progression (PD):  
• Any subject who presents with PD based on RECIST 1.1 prior to completion of the 4 cycles 
of induction treatment is allowed to complete the induction cycles (as long as 
canakinumab/matching placebo is not administered as single agent) if it is in the best interest 
of the subject, as determined by the investigator.  
• Subjects with non-squamous histology who present with RECIST 1.1 PD during 
maintenance will be allowed to continue pemetrexed beyond PD if it is in the best interest 
of the subject, as determined by the investigator. 
• Study treatment beyond iRECIST confirmed progression (iCPD) may be allowed if the 
investigator determines that it is in the best interest of the subject. In such cases, approval 
by a Novartis study physician is required. 
In addition, the following changes are implemented:  
• Update of exclusion criteria #5, #7 and #13 to ensure consistency with prior studies and 
based on advice received by the Steering Committee:. 
• Exclusion criterion #5 is updated to allow subjects with known untreated, asymptomatic 
brain metastases (i.e. no neurological symptoms, no requirements for corticosteroids, no or 
minimal surrounding edema, no lesion >1.0 cm and a maximum of 3 lesions) to be enrolled.  
• Exclusion criterion #7 is updated to allow subjects with history of auto-immune disease or 
known auto-immune disease who have not been treated with systemic therapy in the past 2 
years before study entry to be enrolled in the study. 
• Exclusion criterion #13 is updated to clarify that subjects with history of non-infectious 
pneumonitis who did not require steroids (grade 1) can be enrolled in the study. Subjects 
with history of (non-infectious) pneumonitis who required steroids or have current 
pneumonitis are excluded from the study.  
• To clarify that subjects with a tumor of adenosquamous histology can be treated as either 
squamous or non-squamous histology, as per Section 6.3.2. The chemotherapy treatment 
selected must match the histology selected in the Interactive Response Technology (IRT) 
system at time of randomization (squamous or non-squamous).  
• To add two circulating tumor DNA (ctDNA) sample collection time points (C8D1 and 
C12D1). The sequencing of specific gene panels and determination of mutation load will be 
performed using ctDNA. Therefore, the additional ctDNA sample collection time points 
will allow a better longitudinal follow up of the patients as well as the evaluation of liquid 

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biopsy as an early detection method of progression. In addition, this longitudinal analysis 
will allow the understanding of potential mechanisms of resistance to treatment. 
• To clarify as requested per Chinese authorities, that the biomarker assessments are not to be 
done unless approval in China has been obtained by all relevant Chinese authorities. As of 
the release of this amendment, no site has been initiated and no subject has been screened 
or has been enrolled in this study in China. 
• To remove reference to number of slides or blood volume needed for biomarker 
assessments, as these are already detailed in the Central Laboratory Flowchart. Reference 
to Flowchart was added.  
• To clarify that use of steroids is allowed in case of immune-related adverse events (irAE) 
since these events can be caused by pembrolizumab. 
Editorial revisions, clarifications and corrections are made throughout the protocol to improve 
consistency. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
• Protocol summary, Table 8-3 and Section 8.5.3: updated to clarify that biomarkers samples 
will not be done in China unless approval has been obtained by all relevant Chinese 
authorities.  
• Figure 3-3, Table 4-1, section 6.1.4.1, Section 7, Table 8-4, Section 8.3.1.2 and  
Section 9.1.1: language updated from “pembrolizumab +/- canakinumab/matching placebo” 
to “study treatment”. 
• Section 4: Table 4-1 language updated to clarify treatment beyond RECIST 1.1 PD and 
iCPD. 
• Section 5.2: Exclusion criteria #5, #7 and #13 updated.  
• Section 6.1.1.2: updated to clarify treatment of subjects with adenosquamous histology. 
• Section 6.1.3: updated to clarify treatment beyond RECIST 1.1 PD. Also to clarify treatment 
with pemetrexed for subjects with non-squamous histology beyond disease progression. 
• Section 6.1.4: added reference to section 6.1.4.1. 
• section 6.1.4.1: updated to clarify study treatment beyond RECIST 1.1 PD and to add that 
in some cases study treatment beyond iCPD might be allowed. Also, to clarify treatment 
beyond disease progression when pembrolizumab has been discontinued for toxicity. 
• Section 6.2.2.1: updated to clarify that use of steroids to treat immune-related adverse events 
is allowed.  
• Section 6.3.2: updated to clarify stratification for subjects with adenosquamous histology. 
• Section 6.5.3.1: language for adverse drug reactions simplified.  
• Table 6-7: added footnote clarifying exceptions to general guidance for mandatory dose 
modification. 
• Section 6.6.2: added clarification that investigator will provide study drug name (if 
available) in case of emergency unblinding, as requested by Italian Health Authority. 

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• Section 7: added clarification for study treatment beyond iRECIST iCPD. 
• Section 8: Table 8-2 and Table 8-3 updated to add a footnote to clarify SAE data collection 
during safety follow up and to remove the footnote referring to number of slides required 
for biomarker assessments at screening. Table 8-3further updated to add two additional time 
points for ctDNA collection and a footnote to clarify biomarker assessments for China.  
• Section 8.4.1: added clarification that a subject on-site visit may not be required and local 
laboratory testing is allowed for visits with safety laboratory assessments only.  
• Section 8.5.3 updated to clarify biomarker assessments for China to include reference to 
Central Laboratory Flowchart.  
• Section 8.5.3.1 and 8.5.3.3: updated to remove reference to number of slides or blood 
volume needed for biomarker assessments 
• Section 9.1.1: updated to add study treatment discontinuation if RECIST 1.1 PD occurs 
when canakinumab/matching placebo is administered as a single agent. Also, to clarify 
study treatment discontinuation for subjects with squamous histology who discontinued 
pembrolizumab due to toxicity during induction and have RECIST 1.1 disease progression 
during induction  
• Section 9.2: language on post-study treatment simplified.  
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 

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Amendment 1 (12-Dec-2018) 
Amendment rationale 
As of 12-Dec-2018, no site has been initiated. No subject has been screened and no subject has 
received study treatment. 
The main objective of the amendment 01 is: 
• To implement the Health Authority request to obtain subject informed consent before 
continuing with canakinumab/matching placebo as a single agent prior to disease 
progression by RECIST 1.1. A separate informed consent will be created to be signed by 
subjects who will receive canakinumab/matching placebo as single agent before disease 
progression per RECIST 1.1, per physician discretion, in case all other study drugs 
(pembrolizumab and chemotherapy) were permanently discontinued.  
Additional main objectives for the amendment 01 are: 
• To modify the tumor assessment frequency in the maintenance treatment phase, where the 
tumor assessments will be done “every 9 weeks through week 75” instead of “every 9 weeks 
(for the next 21 weeks)” and thereafter after week 75, it will be done every 12 weeks. This 
modification is aligned with the current protocol median PFS assumptions and will ensure 
that the targeted improvement in median PFS will be detected more accurately.  
• To align the assessment schedule in the safety run-in part with the one in the randomized 
part of the study by adding safety assessments on Cycle 5 Day 1.  
In addition, the following modifications have been implemented: 
• Clarification of some inclusion/exclusion criteria and also modification of some of them in 
order to allow more flexibility for the enrollment/randomization  
• NSCLC staging was updated to be aligned with AJCC v.8 
• The inclusion criteria for lipase was changed from lipase < ULN to lipase ≤ 1.5x ULN 
(grade 1), since the criteria was considered to be too restrictive for enrollment of cancer 
patients 
• For subjects with squamous NSCLC molecular testing at screening (EGFR and/or 
ALK) are not required  
• A sub-bullet point has been added to clarify that patients with known ROS-1 
rearrangement or BRAF V600 mutation will be excluded, if required by local 
guidelines. 
• Tuberculosis exclusion criteria was updated to clarify that the need for tuberculosis 
treatment should be based on local guidelines 
• Update of the interstitial lung disease/ pneumonitis exclusion criteria to only exclude 
cases of grade ≥ 2; in alignment with the exclusion used for pembrolizumab studies.  
• Revision of the assessment schedules for the safety run-in and the randomized part of the 
study, by removing safety laboratory assessments (hematology and chemistry) of Day 15 
on Cycle 5 and subsequent Cycles for subjects on pemetrexed, to reduce patient burden. 
There are country-specific local differences on how these assessments are managed when 
taking pemetrexed, thus the protocol guidance is that pemetrexed use is to be managed 
according to the locally approved label and local practice. 

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• Updates performed per Novartis Hepatoxicity Clinical safety Guideline (2018) for the Table 
6-7 Criteria for mandatory dose interruption and re-initiation for canakinumab/matching-
placebo for adverse drug reactions, the Section 6.5.4.2 Follow up on potential drug-induced 
liver injury (DILI) cases, and the Table 6-8 Guidance on specific clinical and diagnostic 
assessments has been added. 
• Updated sentence in the section 10.1.1 Adverse events per regulatory requirement: 
“Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors), should not be reported as a 
serious adverse event, except if the investigator considers that progression of malignancy is 
related to study treatment”. 
• Updated Section 6.2.1.1.2 to add cautionary language regarding the use of concomitant 
therapies that are substrates of CYP450 enzymes with a narrow therapeutic index, as the use 
of canakinumab may reverse cytokine induced suppression of CYP450. 
In addition, editorial revisions, clarifications and corrections are made throughout the protocol 
to improve consistency. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
• Protocol Summary, Tables 8-2, 8-3 and 8-4, Section 8.3.1.2: Modified the tumor assessment 
frequency in the maintenance treatment phase, where the tumor assessments will be done 
“every 9 weeks through week 75” instead of “every 9 weeks (for the next 21 weeks)” and 
thereafter after week 75, it will be done every 12 weeks. 
• Section 1.1.1.1: mPFS abbreviation when describing KEYNOTE-189 results has been 
corrected to median PFS, correct number of patient randomized in the KEYNOTE-407 has 
been added and update on the pembrolizumab approval status included. 
• Section 1.1.1.1: The reference for pemetrexed SmPC in European Union has been added. 
• Section 1.1.1.1, 3, 4.1, 5.1: Revised NSCLC staging to align with AJCC v.8.  
• Section 3: Number of the referenced sections has been corrected. 
• Section 3: Figures 3-1 and 3-2: Number of the referenced sections has been corrected. 
• Section 3: Figure 3-1: Updated to add pemetrexed per investigator's decision for non-
squamous subjects only (Cohort C) in maintenance phase. 
• Section 4.2.2: Figure 4-2: Title has been updated to reflect correct unit of hs-CRP level. 
• Section 5.1: Inclusion criteria #9 laboratory value “serum lipase" updated to allow 
 grade 1. 
• Section 5.2: Exclusion criteria #3 specification for EGFR mutations has been updated to 
clarify mentioned examples are not limited to those. 
• Section 5.2: Exclusion criteria #3 sub-bullet has been updated to clarify that molecular 
testing (EGFR and ALK) are not needed for subjects with pure squamous cell histology, 
and a sub-bullet point has been added to clarify that patients with known ROS-1 
rearrangement or BRAF V600 mutation will be excluded, if required by local guidelines. 

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• Section 5.2: Exclusion criteria #8 has been updated to clarify the need for tuberculosis 
treatment to be based on local guidelines. 
• Section 5.2: Exclusion criteria #13: History of interstitial lung disease or pneumonitis 
updated to exclude only cases of grade ≥ 2 in alignment with the exclusion used for 
pembrolizumab studies. 
• Section 5.2: Exclusion criteria # 19: clarification brought to tubal ligation. 
• Section 6.1.1.1: Tables 6-1, 6-2: Footnote added to clarify that pemetrexed can be continued 
for the non-squamous subjects after the induction cycles as determined by the investigator 
according to local approved label and local practice. 
• Section 6.1.1.1: Table 6-3: Pemetrexed added in the table and footnote to clarify that 
pemetrexed for non-squamous subject can be started after the induction cycles as 
determined by the investigator according to local approved label and local practice. 
• Section 6.1.1.3: Figures 6-1 and 6-2: Updated with correct the number of the sections 
referenced. 
• Section 6.1.3: Updated to clarify that subjects with less than 4 cycles of induction treatment 
can also continue into maintenance treatment, that only subjects with non-squamous 
histology can receive pemetrexed in maintenance treatment and subjects with RECIST PD 
during induction can continue the maintenance with pembrolizumab +/- canakinumab (or 
canakinumab matching placebo) but without pemetrexed. 
• Section 6.1.4: Updated to clarify when a subject can continue canakinumab/matching 
placebo treatment even if pembrolizumab and other study drugs have been discontinued due 
to unacceptable toxicity. 
• Section 6.1.4: Added that a separate informed consent is to be signed by subjects who will 
receive canakinumab/matching placebo as single agent before disease progression per 
RECIST 1.1 (see rationale for main objectives for amendment 01). 
• Section 6.1.4.1: Criteria for treatment beyond progression have been clarified . 
• Section 6.2.1.1.2: Clarification on the use of CYP450 substrates with a narrow therapeutic 
index per Health Authority request. 
• Section 6.2.1.1.2: Clarification on the use of warfarin or warfarin-like treatment with narrow 
therapeutic index. Text moved from section 6.2.1 to Section 6.2.1.1.2. 
• Section 6.2.2.1: Updated to clarify that any antineoplastic therapy are not allowed from start 
to the end of study treatment. 
• Section 6.5.1.2: Clarification on evaluability criteria for safety run-in subjects in case 
canakinumab dose is de-escalated to Q6W regimen 
• Section 6.5.2: Pharmacodynamics (PD) removed from the criteria being looked at for the 
RP3R determination. 
• Section 6.5.3: Updated to clarify pembrolizumab dosing in case chemotherapy needs to be 
interrupted due to toxicity. 
• Section 6.5.3.1: Table 6-7: Updated with revised Novartis hepatoxicity clinical safety 
guidance. 
• Section 6.5.4.2: Table 6-8: Added table detailing guidance on specific clinical and 
diagnostic liver assessments 

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• Section 6.5.4.2: Updated to include the revised DILI language per revised Novartis 
hepatoxicity clinical safety guidance. 
• Section 6.7: Added information related to the instructions for use of canakinumab/matching 
placebo. 
• Section 8: Table 8-1 (visit windows): Specific time window for physical examination and 
serum pregnancy test removed to simplify assessment scheduling. In addition updated to 
clarify that all safety follow-up assessments are applicable. 
• Section 8: Table 8-2 (Assessment Schedule, Safety run-in part): Visit name 
“Prior/concomitant medications” row corrected by replacing the term “non-drug therapies” 
with “prior/concomitant medication”.  
• Section 8: Table 8-2 (Assessment Schedule, Safety run-in part): Safety assessments for 
Cycle 5 Day 1 added (see rationale for main objectives for amendment 01. 
• Section 8: Table 8-2 (safety run-in part)and 8-3 (randomized part): Updated by removing 
safety laboratory assessments (hematology and chemistry) from Day 15 on Cycle 5 and 
subsequent cycles for subjects on pemetrexed (see rationale for main objectives for 
amendment 01). 
• Section 8: Tables 8-2 (safety run-in part) and 8-3 (randomized part): Pregnancy test and 
footnotes updated to clarify that screening assessments are to be done for all female subjects 
and post-baseline only for women with child-bearing potential. 
• Section 8: Table 8-2 (safety run-in part) and 8-3 (randomized part): Antineoplastic therapies 
since discontinuation of study treatment updated to specify the assessment to be done during 
follow up period. 
• Section 8: Table 8-3 (randomized part): Brain CT or MRI specification updated to align 
with Table 8-2 and 8-4. 
• Section 8: Table 8-3 (randomized part), Section 8.5.1: Updated to state ePROs will be 
completed on Day 1 of each cycle, at EOT, + 7 and +28 days post confirmed RECIST 1.1 
PD, and during efficacy follow up (for subjects who discontinue study treatment for reasons 
other than RECIST 1.1 PD). 
• Section 8: Table 8-3 (randomized part): Drug administration updated to specify timepoints 
for subjects on nab-paclitaxel only. 
• Section 8: Table 8-3 (randomized part): Updated Cycle 1 Day 2 to reflect updated PK 
sampling. 
• Section 8: Table 8-3 (randomized part): Updated by adding Cycle 2 Day 2 to reflect updated 
PK sampling. 
• Section 8: Table 8-3 (randomized part): Footnote for hs-CRP updated to guide reader to the 
corresponding subsection for more details. 
• Section 8.2: Updated to clarify that serum pregnancy testing is for all female subjects at 
screening. Definition of vital signs was added per Health Authority request. 
• Section 8.4.1: Table 8-5: Updated to include “pancreatic amylase (as needed)”. 
• Section 8.4.4: Updated to clarify ECG assessments may be taken any time pre-dose, not 
required to be taken within 20 minutes of PK collection. 

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• Section 8.4.5: Updated to clarify the serum and urine pregnancy test frequency for women 
of child bearing potential. 
• Section 8.5.1: Clarification added on ePRO (Patient Reported Outcome) data collection. 
• Section 8.5.2: Table 8-7: Updated to specify and simplify frequency of the PK blood 
sampling of chemotherapy drugs in order to reduce patient burden. 
• Section 8.5.3: Clarification on the methodology of the blood collection for biomarker 
sample. 
• Section 8.5.3.2: Updated to clarify that biomarker results will be blinded and won’t be 
communicated to the investigational sites. 
• Section 9.2: Updated to clarify the strategy of final analysis in the CSR for safety run-in. 
• Section 10.1.1: Updates to add the exception of the related progressive disease reported as 
a SAE and update to remove redundancies. 
• Section 12: Updated to clarify when the final analysis of the study data for safety run-in will 
be reported in the CSR. 
• Section 12.1.3: Clarification on the minimum exposure criterion for safety run-in subjects 
in case canakinumab dose is de-escalated to Q6W regimen. 
• Section 12.7: Modify p<0.00001 values for the 1st interim OS boundaries to reflect the exact 
p-values in decimals. 
• Section 15: Some references have been updated. 
• Section 16.2: Updated to include the new version of the "Guidelines for iRECIST". 
• Section 16.3.1.3: Updated to remove duplication. 
• Section 16.5: Appendix 5 "Medications to be used with caution with canakinumab while on 
the study", Table 16-19 was added to list CYP450 substrates with a narrow therapeutic index. 
• Section 16.7: Appendix 7: Table 16-20 "Dose modifications Guidelines for Pembrolizumab 
drug related Adverse Events" has been fully revised 
The protocol summary has been updated to reflect the changes throughout the document as well 
as the list of abbreviations, the glossary of terms. 
At last, minor editorial changes (e.g. typographical mistakes, grammatical changes, rewording) 
to improve flow and consistency, and correction of spelling errors or typographical errors, have 
been made throughout the protocol. 
IRB Section 
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 Consents. Sites are required to update and submit for 
approval revised Informed Consents that takes into account the changes described in this 
protocol amendment. 

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Protocol summary 
Protocol 
number 
CACZ885U2301 
Full Title 
A randomized, double-blind, placebo-controlled, phase III study evaluating the efficacy and 
safety of pembrolizumab plus platinum-based doublet chemotherapy with or without 
canakinumab as first line therapy for locally advanced or metastatic non-squamous and 
squamous non-small cell lung cancer subjects (CANOPY-1) 
Brief title 
Study of efficacy and safety of pembrolizumab plus platinum-based doublet chemotherapy 
with or without canakinumab in previously untreated locally advanced or metastatic non-
squamous and squamous NSCLC subjects 
Sponsor and 
Clinical Phase 
Novartis, Phase III 
Investigation 
type 
Drug 
Study type 
Interventional 
Purpose  
To evaluate the efficacy, safety and pharmacodynamics of canakinumab versus 
canakinumab matching-placebo in combination with pembrolizumab and platinum-based 
doublet chemotherapy in NSCLC. 
Rationale 
The rationale for treating subjects with canakinumab is based upon the key role 
inflammation plays in the development and spread of NSCLC and the ability of 
canakinumab to suppress elevated C-reactive protein (CRP), which correlates with NSCLC 
stage. CANTOS, a cardiovascular study demonstrated that not only was the composite 
endpoints of stroke and myocardial infarction decreased by canakinumab, but also the 
occurrence of and mortality from NSCLC was decreased. Additionally, CRP suppression 
correlated with responses in NSCLC patients treated with atezolizumab. 
Primary 
Objective(s)  
Safety run-in part: 
• 
To determine the recommended Phase 3 dose regimen (RP3R) of canakinumab in 
combination with pembrolizumab plus platinum-based doublet chemotherapy. 
Double-blind, randomized, placebo-controlled part: 
• 
To compare progression free survival (PFS) between the two treatment arms 
• 
To compare overall survival (OS) between the two treatment arms. 
Secondary 
Objectives 
Safety run-in part:  
• 
To characterize the pharmacokinetics of canakinumab in combination with 
pembrolizumab plus platinum-based doublet chemotherapy  
• 
To characterize the safety and tolerability of canakinumab in combination with 
pembrolizumab plus platinum-based doublet chemotherapy 
• 
To characterize the immunogenicity (anti-drug antibodies) of canakinumab and 
pembrolizumab 
• 
To assess the preliminary clinical anti-tumor activity (overall response rate, disease 
control rate and duration of response) of canakinumab in combination with 
pembrolizumab plus platinum-based doublet chemotherapy 
Double-blind, randomized, placebo-controlled part: 
• 
To evaluate overall response rate (ORR), disease control rate (DCR), time to 
response (TTR) and duration of response (DOR) 
• 
To characterize the safety profile of the two treatment arms. 
• 
To characterize the pharmacokinetics of canakinumab, pembrolizumab and 
chemotherapy 
• 
To characterize the immunogenicity (anti-drug antibodies, ADA) of canakinumab and 
pembrolizumab. 
• 
To assess PROs in the two treatment arms 
Study design 
Safety run-in part 

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This is an open label part to determine RP3R of canakinumab in combination with 
pembrolizumab and platinum-based doublet chemotherapy. 
Double-blind, randomized, placebo controlled part 
This is a double-blind, randomized, placebo-controlled part to evaluate the efficacy and safety 
of canakinumab vs. canakinumab matching-placebo in combination with pembrolizumab plus 
platinum-based doublet chemotherapy followed by maintenance therapy. 
Open label extension phase 
This is an open label extention (OLE) phase. If OS reaches statistical significance at one of 
the interim or final analyses, all subjects still on treatment or in safety/efficacy follow up will 
transition to the OLE phase, following unblinding of investigational sites to treatment 
allocation. If OS is not statistically significant at final analysis but PFS was statistically 
significant at primary analysis, OLE will be initiated after final OS analysis, following the 
unblinding of investigational sites. 
Subjects will transition to a reduced study assessment schedule. Subjects randomized to 
canakinumab matching-placebo will be given the opportunity to cross over to canakinumab if 
the investigator determines this is in the subject’s best interest and per subject discretion 
provided they fulfill crossover criteria. 
Post implementation of protocol amendment 05, subjects will transition into an assessment 
schedule aligned to standard of care with their current treatment and dosing regimen. 
Population 
The study will include adult subjects with locally advanced or metastatic NSCLC 
Approximately 27 subjects up to 54 subjects, in case next dose regimen level should be 
assessed, will be enrolled in the safety run-in part and approximately 600 subjects will be 
randomized in a 1:1 ratio (approximately 300 subjects in each treatment arm) in the double-
blind, randomized, placebo-controlled part. 
Key Inclusion 
criteria 
• 
Histologically confirmed locally advanced or metastatic NSCLC 
• 
Measurable disease by RECIST 1.1 
• 
Known PD-L1 status 
• 
ECOG performance status (PS) 0 or 1 
Key Exclusion 
criteria 
• 
Previous immunotherapy or treatment with IL-1β inhibitor. 
• 
Subjects with epidermal growth factor receptor (EGFR) sensitizing mutations and/or 
anaplastic lymphoma kinase (ALK) rearrangement 
• 
History of severe hypersensitivity reaction to monoclonal antibodies, platinum 
containing drugs, nab-paclitaxel, paclitaxel, pemetrexed or any known excipients of 
these drugs. 
Study 
treatment 
Safety run-in part: 
Canakinumab 200 mg s.c. injection in combination with pembrolizumab 200 mg i.v. infusion 
and platinum-based doublet chemotherapy: 
• 
Cohort A (for non-squamous): carboplatin AUC 5 mg/mL*min i.v. infusion plus 
pemetrexed 500 mg/m2 i.v. infusion 
• 
Cohort B (for non-squamous): cisplatin 75 mg/m2 i.v. infusion plus pemetrexed 500 
mg/m2 i.v. infusion 
• 
Cohort C (for squamous or non-squamous): carboplatin AUC 6 mg/mL*min i.v. 
infusion plus paclitaxel 200 mg/m2 i.v. infusion 
Double-blind, randomized, placebo-controlled part 
• 
Investigational treatment arm: canakinumab 200 mg s.c. injection (Q3W) in 
combination with pembrolizumab 200 mg i.v. infusion (Q3W) and platinum-based 
doublet chemotherapy (Q3W):  
• 
For non-squamous: carboplatin AUC 5 mg/mL*min i.v. infusion or cisplatin 75 
mg/m2 plus pemetrexed 500 mg/m2 i.v. infusion 
• 
For squamous: carboplatin AUC 6 mg/mL*min i.v. infusion plus paclitaxel 200 
mg/m2 or nab-paclitaxel 100 mg/m2 i.v. infusion 

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• 
Control treatment arm: canakinumab matching-placebo s.c. injection in combination 
with pembrolizumab 200 mg i.v. infusion and platinum-based doublet chemotherapy 
(same as for the investigational treatment arm). 
Note: subjects with adenosquamous histology can be treated as either squamous or 
non-squamous histology; see Section 6.3.2. The chemotherapy treatment selected 
must match the histology selected in the IRT system at time of randomization 
(squamous or non-squamous). 
Open label extension phase 
Subjects enrolled in the safety run-in and subjects randomized to the canakinumab arm in 
the randomized part will transition into the OLE with their current treatment and dosing 
regimen. Subjects randomized to the canakinumab matching-placebo arm in the randomized 
part will be allowed to cross over to canakinumab (in combination with the other study drugs), 
per 
investigator 
and 
subject 
discretion 
provided 
they 
fulfill 
crossover 
criteria  
(Section 6.1.3). 
Post implementation of protocol amendment 05, subjects will transition into an assessment 
schedule aligned to standard of care with their current treatment and dosing regimen.  
Efficacy 
assessments 
• 
Radiological tumor assessments by investigator (RECIST 1.1 and immune 
RECIST): At screening and every 6 weeks for the first 12 weeks, then every 9 weeks 
(through week 75) and every 12 weeks thereafter Note: In OLE, the same tumor 
assessment schedule as in safety run-in (SRI) and randomized part will be followed 
until 159 weeks (approximately 3 years) after the study Cycle 1 Day 1; thereafter, 
every 24 weeks. 
• 
Survival phone calls: every 12 weeks after safety and efficacy follow-up period 
Post implementation of protocol amendment 05, the efficacy follow-up and survival follow-
up will no longer be collected. 
Safety 
assessments 
• 
Physical examination 
• 
ECOG performance status, body weight and vital signs 
• 
Laboratory assessments, including hematology, biochemistry, coagulation, thyroid 
function, hepatitis testing and urinalysis 
• 
Pregnancy tests for women of child-bearing potential (serum pregnancy test at 
screening for all women) 
• 
Electrocardiogram (ECG) 
• 
Adverse events (AEs) the severity, the relationship with to study treatment and the 
seriousness 
Post implementation of protocol amendment 05, coagulation, thyroid function, hepatitis 
testing, urinalysis and ECOG performance status will no longer be collected.  
Other 
assessments 
• 
Pharmacokinetics of canakinumab, pembrolizumab, carboplatin, cisplatin, paclitaxel, 
nab-paclitaxel and pemetrexed 
• 
Immunogenicity (ADA) of canakinumab and pembrolizumab 
• 
Pharmacodynamics (PD) IL-1β and PD biomarkers* (including hs-CRP, hs-IL-6) 
• 
Patient reported outcomes (PROs) assessments by the European Organization for 
Research and Treatment of Cancer quality of life (EORTC QLQ-C30 and EORTC 
QLQ-LC13) and EuroQoL (EQ-5D-5L) questionnaires 
*For China only: biomarker tests will not be done unless approval has been obtained by all 
relevant Chinese authorities. 
Post implementation of protocol amendment 05, all assessments listed above will be 
stopped.  
Data analysis 
Safety run-in part - Identification of recommended regimen 
The primary analysis will be conducted when at least 6 evaluable subjects (among 
approximately 9 subjects enrolled) in each of the 3 treatment cohorts have been observed 
for dose limiting toxicity (DLT) for the first 42 days. A lower recommended regimen may be 
explored based on other safety and PK data from the current study (Section 6.5.1.2) 
Bayesian adaptive approach 

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The determination of RP3R will be guided by a Bayesian analysis of DLT data for each 
cohort for the first 42 days (6 weeks) during which subjects receive the combination of 
canakinumab pembrolizumab plus platinum-based doublet chemotherapy. The relationship 
between dose and the probability of DLT is modeled using logistic regression. Details of the 
Bayesian logistic regression model (BLRM) are given in  Section 16.3 . 
The dose limiting toxicity (DLT) relationship of canakinumab in combination with 
pembrolizumab plus platinum-based doublet chemotherapy is modeled by a BLRM for each 
dose regimen that comprises single agent toxicity parts and interaction part. Single agent 
toxicity is modeled using logistic regression for the probability of a subject experiencing a 
DLT against log-dose. The odds of a DLT for each dose regimen are then calculated 
Starting dose 
The starting dosing regimen are the following ( Section 6.5.1.1 ): 
• 
Cohort A: canakinumab 200 mg Q3W in combination with pembrolizumab 200 mg, 
carboplatin AUC 5 mg/mL*min and pemetrexed 500 mg/m2 Q3W 
• 
Cohort B: canakinumab 200 mg Q3W in combination with pembrolizumab 200 mg, 
cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 Q3W 
• 
Cohort C: canakinumab 200 mg Q3W in combination with pembrolizumab 200 mg, 
carboplatin AUC 6 mg/mL*min and paclitaxel 200 mg/m2 Q3W. 
For this starting dose level of canakinumab (i.e. 200 mg Q3W), the prior risk of excessive 
toxicity is 15%, 10%, and 22% for cohorts A, B, and C, respectively, which satisfies the 
escalation with overdose control (EWOC) criterion. 
Dose recommendation 
Dosing regimen decisions are guided by the EWOC principle. A dosing regimen may only 
be used for newly enrolled subjects if the risk of excessive toxicity at that dosing regimen is 
< 25% (Rogatko et al 2007). 
Double-blind, randomized, placebo-controlled part  
Progression free survival (PFS) 
Assuming a proportional hazards model for PFS, the null hypothesis will be tested at one-
sided 1% level of significance. If OS is statistically significant at either interim or final analysis, 
then the 1.5% alpha assigned to OS will be transferred to PFS and PFS will be tested at one-
sided 2.5% level of significance ( Section 12.4 ) 
In the primary analysis, PFS will be tested using the log-rank test stratified by randomization 
stratification factors when approximately 253 PFS events are observed. 
The distribution of PFS will be estimated using the Kaplan-Meier method. The median PFS 
and PFS rate at different timepoints along with 95% confidence intervals (CIs) will be 
presented by treatment arms. A Cox regression model stratified by randomization 
stratification factors will be used to estimate the hazard ratio (HR) of PFS, along with 95% CI 
based on the Wald test. 
Overall survival (OS) 
Assuming a proportional hazards model for OS, the null hypothesis will be tested at one-
sided 1.5% level of significance. If PFS by investigator assessment per RECIST1.1 is 
statistically significant at 1% level of significance, then the 1 % alpha assigned to PFS will 
be transferred to OS and OS will be tested at one-sided 2.5% level of significance 
( Section 12.4 ). 
In the primary analysis, OS will be tested using the log-rank test stratified by randomization 
stratification factors. The distribution of OS will be estimated using the Kaplan-Meier 
method. The median OS and OS rate at different timepoints along with 95% confidence 
intervals (CIs) will be presented by treatment arms. A Cox regression model stratified by 
randomization stratification factors will be used to estimate the hazard ratio (HR) of OS, 
along with 95% CI based on the Wald test. 
Secondary endpoints (overall response rate (ORR), disease control rate (DCR), time to 
response (TTR) and duration of response (DOR)) will be also presented by treatment group 
( Section 12.5.1 ) 
Open Label Extension (OLE) phase  

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Any additional data for ongoing subjects in the randomized part following the primary OS 
analysis and data for subjects in OLE (if initiated) will be further summarized in a final study 
report. 
Key words 
ACZ885, canakinumab, pembrolizumab, carboplatin, cisplatin, paclitaxel, nab-paclitaxel, 
pemetrexed, NSCLC, squamous, non-squamous, hs-CRP, IL-1β, PD-L1, CANOPY 

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1 
Introduction 
1.1 
Background 
1.1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
1.1.1.1 
Background on NSCLC and use of immunotherapy 
An estimated 1.8 million people were diagnosed globally with lung cancer in 2012 and there 
were 1.6 million deaths from this disease (Globocan 2012). The number of new lung cancer 
cases is expected to grow by about 70% over the next 2 decades (Globocan 2012). Non-small 
cell lung cancer (NSCLC) accounts for 85% of the lung cancer diagnoses and approximately 
70% of patients present with advanced disease (Molina et al 2008). The majority of subjects 
present with advanced disease; only 25-30% of subjects have surgically resectable disease and 
only half of these resected subjects are disease-free at 5 years (Molina et al 2008, 
Maeda et al 2010, American Community Survey 2012). Surgery is the treatment of choice for 
subjects with NSCLC stages I through IIIA. Subjects with stage IIIB, IIIC and IV NSCLC 
without targetable oncogenic drivers are usually treated with chemotherapy with the option of 
surgery and/or radiotherapy; however, patients with known alterations (such as EGFR, ALK, 
B-Raf proto-oncogene; BRAF, or c-ros oncogene 1; ROS-1) are candidates for targeted 
treatments (NCCN v1. 2018) 
The first-line standard-of-care for locally advanced and metastatic NSCLC patients without a 
targetable oncogenic driver is pembrolizumab in combination with platinum-based doublet 
chemotherapy. In the United States (US), pembrolizumab is approved in the first-line setting in 
non-squamous NSCLC as a single agent (PD-L1 expression in tumor of ≥ 50%) and in 
combination with platinum-based doublet chemotherapy. The median overall survival of these 
patients treated with platinum–based doublet chemotherapy is only 8-10 months, with 
approximately 50-70% of patients having disease stabilization or tumor shrinkage in response 
to first-line chemotherapy (Schiller et al 2002, Scagliotti et al 2002, Scagliotti et al 2008). 
Although there are differences in toxicity, cost, schedule and convenience; clinical advantage 
of any platinum-based doublet chemotherapy regimens is trivial. 
Maintenance therapy is used in non-squamous NSCLC treatment to prolong response to therapy 
for patients responding or whose disease is stable after first-line therapy. Maintenance can be 
categorized into switch-maintenance (the maintenance therapy is different from the first line) 
or continuation therapy (one of the components of the first line is continued in the maintenance 
phase). Currently, pemetrexed is the only compound formally approved for maintenance 
therapy of non-squamous NSCLC in US (Alimta®USPI 2004) and European Union (EU) 
(Alimta®SmPC 2009). 
Immunotherapy has further shaped the treatment landscape of advanced NSCLC patients, both 
in the pretreated and treatment-naive setting. Monoclonal antibodies targeting PD-1 and PD-L1 
(nivolumab, durvalumab, pembrolizumab, and atezolizumab) have each demonstrated 
significant activity as monotherapy and superiority over single agent chemotherapy in 
pretreated NSCLC either PD-L1 selected or unselected and have been recently approved by the 
Health Authorities in this setting (Barlesi 2016, Langer et al 2016, Antonia et al 2017). 

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Pembrolizumab currently requires PD-L1 testing in some countries for use in approved 
indications (e.g. United States and Japan). 
Nivolumab is approved in many countries for patients who have previously received 
chemotherapy for both squamous and non-squamous lung cancer on the basis of two 
randomized phase III trials (Borghaei et al 2015, Brahmer et al 2015) that demonstrated 
superior OS for nivolumab over docetaxel in both squamous and non-squamous NSCLC. In the 
first-line setting, nivolumab was not superior to platinum-based doublet chemotherapy in 
patients with PD-L1 ≥ 1% based on the CheckMate 26 study (Carbone et al 2017). A second 
study, 
CheckMate-227, 
demonstrated 
PFS 
improvement 
of 
the 
combination 
of 
nivolumab+ipilimumab over chemotherapy in patients with high tumor mutational burden 
NSCLC (regardless of PD-L1 levels) (Hellmann et al 2018). 
Atezolizumab was also approved for previously treated NSCLC with progression on or 
following a platinum-containing regimen based on superior OS over docetaxel chemotherapy 
(Rittmeyer et al 2017) regardless of the PD-L1 expression and of the histology. 
In first-line treatment for non-squamous advanced NSCLC patients, atezolizumab in 
combination with bevacizumab plus platinum based chemotherapy demonstrated PFS benefit 
over bevacizumab plus chemotherapy (Reck et al 2016), with an improvement in OS 
(Socinski et al 2018) regardless of PD-L1 expression and EGFR or ALK genetic aberration. 
Additionally, these studies did not demonstrate any significant OS or PFS benefit in this setting 
between the additions of either atezolizumab or bevacizumab to a platinum based chemotherapy. 
In first-line treatment of squamous NSCLC the addition of atezolizumab to carboplatin plus 
nab-paclitaxel in a phaseIII trial, IMpower 131, demonstrated a PFS benefit and the OS data is 
still awaited (Jotte et al 2018).  
Pembrolizumab is also approved in many countries for the treatment of advanced NSCLC after 
platinum-based doublet chemotherapy in patients whose tumor have PD-L1 expression on ≥1% 
of tumor cells on the basis of KEYNOTE-010 study (Herbst et al 2016). Here the median 
overall survival was significantly longer for each of the pembrolizumab arms over the docetaxel 
and the OS benefit was consistent across all histologies. In first-line NSCLC treatment, 
pembrolizumab was initially approved as monotherapy for NSCLC patients whose tumor have 
a PD-L1 expression ≥50% based on the results of KEYNOTE-024 (Reck et al 2016) that 
demonstrated superiority of pembrolizumab over platinum-based doublet chemotherapy in the 
first-line setting. More recently, pembrolizumab was approved in combination with platinum-
based doublet chemotherapy in non-squamous NSCLC as first line treatment in KEYNOTE-
189 (Gandhi et al 2018): patients were to receive either four cycles of pembrolizumab or 
matching placebo + chemotherapy (pemetrexed + carboplatin or cisplatin) followed by 
pembrolizumab or matching placebo + pemetrexed maintenance. The pembrolizumab 
containing arm compared to chemotherapy significantly prolonged median Progression Free 
Survival (mPFS): 8.8 vs. 4.9 months, HR=0.52 (95% CI: 0.43 to 0.64, p<0.001) regardless of 
PD-L1 status (Gandhi et al 2018). In addition, overall survival (OS) was prolonged at 12 
months: 69.2% versus 49.4%, HR=0.49 (95% CI: 0.38 to 0.64, p<0.001). The results of 
KEYNOTE-407 in first-line squamous NSCLC (Paz-Ares 2018), 559 patients were randomized 
to receive either pembrolizumab in combination with carboplatin plus taxane or placebo in 
combination with carboplatin plus taxane for four cycles followed by maintenance therapy with 
pembrolizumab or placebo until disease progression. The pembrolizumab arm was statistically 

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significantly superior for the primary endpoints of PFS and OS (median PFS (6.4 months versus 
4.8 months, HR 0.56, 95% CI: 0.45 to 0.70, p<0.0001) and median OS (15.9 months versus 
11.3 months, HR 0.64, 95% CI: 0.49 to0.85, p=0.0008)) and for the secondary endpoint, overall 
response rate 58.4% versus 35.0%, p=0.0004). All PD-L1 tumor cell expression subgroups 
experienced similar benefit (<1%, 1%-49%, ≥ 50 %). Based on the results of study KEYNOTE-
189, the combination of pembrolizumab and chemotherapy is approved in the EU and US in 
the first line setting for metastatic non-squamous NSCLC. Additionally, the combination of 
pembrolizumab and chemotherapy is approved in the US in the first-line setting for metastatic 
squamous NSCLC based on the results of KEYNOTE-407.  
Taken together, the addition of an immune checkpoint blocker to platinum-based doublet 
chemotherapy over chemotherapy alone leads to an improvement in efficacy, regardless of 
histologic subtype or PD-L1 status (Herzberg et al 2017). However, PFS and OS remain short 
and highlight the need for additional therapeutic options. Based on the body of evidence 
pembrolizumab in combination with standard platinum-based doublet chemotherapy is an 
appropriate control and therefore will be used as a comparator arm for the study. 
1.1.1.2 
The role of inflammation and IL-1β in NSCLC 
Chronic inflammation plays an important role in the development of NSCLC. Key etiological 
risk factors such as smoking (Bracke et al 2006), second-hand smoke exposure, chronic 
infections, and exposure to environmental toxins cause a chronic inflammatory milieu that plays 
a critical role in carcinogenesis, particularly, in lung cancer (Krysan et al 2008, 
O'Callaghan et al 2010). 
The cytokine interleukin-1β (IL-1β) is one of the mediators of pulmonary inflammation that 
promotes lung cancer. Genetic evidence also links IL-1β to lung cancer risk (Bhat et al 2014). 
Polymorphisms in the promoter region of the IL-1 gene result in altered levels of IL-1β 
expression and are associated with an increase in lung cancer risk (Li and Wang 2013). 
Extensive preclinical data supports the role of IL-1β in several distinct steps in carcinogenesis. 
These 
steps 
include 
tumor 
initiation, 
promotion, 
angiogenesis, 
and 
metastasis 
(O'Byrne et al 2000, 
O'Byrne and Dalgleish 2001, 
Dalgleish and O'Byrne 2006, 
Mantovani et al 2008). Tumor initiation is the first step in carcinogenesis and involves the 
acquisition of mutations in normal cells that allow a selective growth advantage. IL-1β is 
thought to create a microenvironment that promotes tumor initiation (Wu et al 2016). In a 
mouse model of tumor initiation, the genetic loss of IL-1β resulted in an attenuation of 3-
methylcholanthrene (MCA)-induced tumor formation (Krelin et al 2007, Voronov et al 2010). 
The ability of IL-1β to promote tumor initiation is thought to be mediated through the induction 
of Nuclear Factor Kappa Beta (NF-κB) expression (Kasza 2013). The second step in 
carcinogenesis is tumor promotion. This step is characterized by the growth of a primary tumor 
from a single transformed cell. This step is mediated in part by tumor associated macrophages 
(TAM) and cytokines that these TAMs produce, such as tumor necrosis factor alpha (TNFα), 
IL-6, and IL-1β (Becker 2006). The third step in carcinogenesis is angiogenesis, in which blood 
vessel formation is induced to generate a vascular network for the primary tumor. In this process, 
IL-1β is thought to play a critical role, as tumors in mice deficient in IL-1β failed to induce 
vascular endothelial growth factor 
(VEGF) expression and tumor angiogenesis 
(Apte et al 2006). The final step in carcinogenesis is metastasis. IL-1β is thought to play an 
important role in this step as well via the induction of genes critical for invasion and cell 

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adhesion. Using a mouse model of lung cancer metastasis, Yano and colleagues demonstrated 
that tumors genetically programmed to express high levels of IL-1β developed lung metastasis 
more rapidly than controls, with treatment with an anti-IL-1β antibody inhibited formation of 
lung metastasis (Yano et al 2003). Taken together, these results suggest an important role for 
IL-1β in multiple steps of carcinogenesis. 
Activation of the inflammation and elevated levels of CRP have been shown to negatively 
impact several components of the immune system (Chaturvedi et al 2010). Mature IL-1β can 
promote the infiltration of immunosuppressive cells into the tumor microenvironment, 
including myeloid derived suppressor cells (MDSCs) and TAMs (Guo et al 2014). Elevated 
CRP levels, induced by the expression of IL-1β and IL-6, have also been shown to directly and 
negatively impact the immune cell environment. Both in vitro and transgenic mouse models 
have demonstrated the ability of CRP to suppress the differentiation and proliferation of T-cells, 
and inhibit the maturation, migration and function of dendritic cells (Frenzel et al 2007, 
Zhang et al 2015, Jimenez et al 2018). Moreover, a shift towards increased number of 
suppressive MDSCs was demonstrated in a human CRP expression mouse model 
(Pegues et al 2016). Taken together, these findings indicate a role for CRP/IL-1β towards a 
more immunosuppressive microenvironment, contributing to immune evasion and tumor 
progression. Counteracting these effects through inhibition of the CRP/IL-1β axis may result in 
a microenvironment more susceptible to IO agents such as anti-PD-(1) inhibitors used in 
combination. To this end, recently reported results from the atezolizumab in second and third 
line NSCLC studies demonstrated that decreases in CRP correlated with RECIST 1.1 responses, 
prolonged PFS and OS for atezolizumab but not docetaxel treated subjects (Patil et al 2018).  
Given the evidence for the importance of IL-1β signaling in carcinogenesis, treating cancer with 
IL-1β blockade has been proposed (Wu et al 2016, Jenkins 2017). 
1.1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) 
1.1.2.1 
Canakinumab in NSCLC 
Canakinumab (ACZ885) is a high-affinity human anti-interleukin-1β (IL-1β) monoclonal 
antibody that belongs to the Immunoglobulin G1 (IgG1)/κ isotype subclass. Canakinumab is 
manufactured in a murine SP2/0 cell line. Currently canakinumab is approved and marketed as 
Ilaris® for the treatment of IL‑1β driven auto-inflammatory diseases: gouty arthritis, Still's 
disease, Cryopyrin Associated Periodic Syndromes (CAPS), Systemic Juvenile Idiopathic 
Arthritis (SJIA), Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS), 
Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD), Familial 
Mediterranean Fever (FMF). IL-1β, a proinflammatory cytokine, is a key mediator of 
atherosclerotic plaque formation and the atherothrombotic process. 
The secondary prevention of major adverse cardiovascular events (MACE, a composite 
endpoint of cardiovascular death, non-fatal MI and non-fatal stroke in patients with a history of 
MI and inflammatory atherosclerosis) was investigated in the CANTOS (Canakinumab ANti-
inflammatory Thrombosis Outcomes Study) study. In this randomized, placebo-controlled 
study with 10,061 patients with a history of prior myocardial infarction and inflammatory 
atherosclerosis and elevated hs-CRP at baseline were enrolled and were treated with either 

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placebo or 50, 150 or 300 mg s.c. every three months. The administration of canakinumab 
demonstrated a clinically and statistically significant effect in reducing the risk of MACE. Since 
treatment with immune suppression in transplant medicine and in rheumatic disorders has been 
found to cause cancers (Turesson and Matteson 2013, Geissler 2015), a safety analysis in 
CANTOS to evaluate the development of cancer as an adverse event was included as a 
prespecified analysis. This analysis showed that canakinumab reduced the occurrence of lung 
cancer and lung cancer mortality compared to placebo in a dose-dependent manner 
(Ridker et al 2017). The median hs-CRP at baseline for patients who were subsequently 
diagnosed with cancer was 6.0 mg/L. Canakinumab treatment also resulted in dose-dependent 
decrease in hs-CRP of 26-41% and IL-6 decrease of 25-43%; lung cancer incidence was less 
frequent in the treated groups that was dose dependent (Ridker et al 2017). Lung cancer 
mortality was significantly less in the canakinumab 300 mg treated group than in the placebo 
group (HR=0.23 [95% CI 0.10-0.54]) and in the pooled canakinumab patients (p=0.0002 for 
trend across all active-treated patients) (Ridker et al 2017). Total cancer mortality was 
significantly lower in the pooled canakinumab groups versus the placebo group (p=0.0007), but 
only the 300 mg every 12 weeks canakinumab group had statistically significant lowering 
(HR=0.49, 95% CI: 0.31-0.75, p=0.0009). All-cause mortality did not differ significantly 
between the canakinumab and placebo groups, HR=0.94 (95% CI; 0.83-1.06) 
(Ridker et al 2017). Circulating tumor deoxyribonucleic acid (DNA) was detected at baseline 
in 66% (44/67) of lung cancer patients from CANTOS, suggesting that these patients may have 
had pre-existing cancer at baseline. 
One hypothesis to explain the lower lung cancer incidence and lower lung cancer mortality is 
that canakinumab reduced the rate of progression, invasiveness and metastatic spread of already 
existing tumors, which were too small to be detected at study entry (Ridker et al 2017). This 
data along with the preclinical information that IL-1β supports tumorigenic inflammation 
provides the rationale to investigate the therapeutic role of canakinumab. The dose of 
canakinumab to be given in this current study, 200 mg s.c. every 3 weeks, was selected by PK 
modeling simulations and available human safety data (Section 4.2 ). 
Table 1-1 
Canakinumab characteristics 
Chemical name: 
Recombinant human monoclonal antibody 
ACZ885 
INN: 
canakinumab 
Proprietary name: 
ILARIS® 
Drug class: 
Anti-inflammatory 
Laboratory code: 
ACZ885 
For further details on canakinumab, especially on non-clinical pharmacokinetics and drug 
metabolism, non-clinical pharmacology and toxicology, please refer to Section 4 of the current 
[canakinumab IB]. 
1.1.2.2 
Pembrolizumab in NSCLC 
Pembrolizumab (Keytruda®) is a monoclonal humanized antibody designed to identify and 
block the PD-1 receptor. By blocking PD-1, the T-cells can “find” and destroy the cancer cells. 
Pembrolizumab is approved for the treatment of advanced NSCLC ( Section 1.1.1.1 ) 
(Herbst et al 2016, Reck et al 2016, Langer et al 2016, Gandhi et al 2018, Paz-Ares 2018). 

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1.1.2.3 
Pembrolizumab and canakinumab combination 
There are no data available defining the recommended doses of pembrolizumab and 
canakinumab when given in combination. No drug-drug interaction is expected between 
pembrolizumab and canakinumab ( Section 1.1.3 ) and full doses of both drugs (200 mg i.v. 
Q3W for pembrolizumab and 200 mg s.c. Q3W for canakinumab) will be used as the starting 
doses based on the ongoing study CPDR001X2103 which used 600 mg s.c. Q8W as the 
expansion dose for canakinumab and 400 mg i.v. Q4W as the dose for PDR001, a PD-1 inhibitor 
under development ( Section 4.2.4 ). Data available from this study showed no excess toxicity 
with the combination canakinumab and PDR001 was observed, with the AE profile of the 
combination being representative of the individual AE profiles of each compound 
( Section 4.2.4 ). The safety profile of PDR001 is similar to other PD-(L)1 inhibitors. 
1.1.3 
Potential for drug-drug interactions 
1.1.3.1 
Canakinumab in combination with chemotherapeutic agents and in 
combination with pembrolizumab and chemotherapy 
Specific studies to investigate drug-drug interactions (DDI) have not been conducted with 
canakinumab. Given canakinumab is a therapeutic monoclonal antibody, it is expected to be 
catabolized into amino acids by general protein degradation process and is not anticipated to be 
directly eliminated through hepatic/renal metabolism and excretion to compete with the 
elimination of the majority of the platinum-based doublet chemotherapy agents studied in this 
trial, which are mainly eliminated through metabolism and renal excretion. Therefore, the risk 
of DDI between canakinumab and chemotherapeutic agents is anticipated to be low. DDI 
potential between canakinumab and pembrolizumab is also considered to be low given both 
antibodies are eliminated by non-metabolism dependent pathway. 
Antibodies that modulate cytokines, which may regulate cytochrome P450 (CYP450) enzymes, 
may cause DDI with small molecule drugs because of the potential to alter CYP-mediated 
metabolism (Harvey and Morgan 2014). Anti-cytokine antibodies such as canakinumab that 
target and neutralize these proinflammatory cytokines or their receptors are capable of 
restoration of CYP450 enzymes to normal levels (Ashino et al 2007). However, since most of 
the platinum-based doublet chemotherapeutic agents (except for paclitaxel and nab-paclitaxel) 
are not eliminated by CYP, the risk of DDI between canakinumab and platinum-based doublet 
chemotherapy agents is anticipated to be low. Conversely, the platinum-based doublet 
chemotherapy agents are not expected to affect canakinumab clearance, which is mainly 
governed by protein catabolism pathways. 
1.1.3.2 
Pembrolizumab 
Similar to canakinumab, since pembrolizumab is cleared from the circulation through protein 
catabolism, no metabolic DDI is expected. Nevertheless, PK of pembrolizumab will be 
characterized in this study, so that DDI, if any, between pembrolizumab, canakinumab and 
chemotherapeutic agents in this trial, can be explored. The use of systemic corticosteroids or 
immunosuppressants before starting pembrolizumab should be avoided because of their 
potential interference with the pharmacodynamic activity and efficacy of pembrolizumab. 
However, systemic corticosteroids or other immunosuppressants can be used after starting 
pembrolizumab to treat immune-related adverse reactions. 

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1.1.3.3 
Chemotherapeutic agents 
Except for paclitaxel and nab-paclitaxel, none of the chemotherapeutic agents have major CYP 
enzyme involvement and are primarily eliminated by the kidney. The metabolism of 
paclitaxel/nab-paclitaxel is catalyzed by CYP2C8 and CYP3A4. Caution should be exercised 
when administering paclitaxel or nab-paclitaxel concomitantly with medicines known to inhibit 
or induce either CYP2C8 or CYP3A4 (Section 6.2.1.1.2). 
PK of platinum-based doublet chemotherapy agents, in addition to canakinumab and 
pembrolizumab, will be characterized in this study, so that the DDI, if any, between these drugs 
can be explored. As chemotherapeutic agents (paclitaxel, nab-paclitaxel, cisplatin, carboplatin, 
and pemetrexed) are intended to be used in combination with canakinumab and pembrolizumab 
in this study, this evaluation is particularly important since chemotherapeutic agents have 
narrow therapeutic range (FDA Guidance 2012). 
1.2 
Purpose 
The purpose of this multicenter, randomized, double-blind, placebo-controlled phase III study 
is to evaluate the efficacy and safety of canakinumab vs. canakinumab matching-placebo in 
combination with pembrolizumab in addition to 4 cycles of platinum-based doublet induction 
chemotherapy, followed by maintenance therapy in subjects with the overall response of stable 
disease (SD) or better after completion of induction therapy, in subjects with locally advanced 
stage or metastatic NSCLC. The double-blind, randomized, placebo-controlled part will be 
preceded by a safety run-in part where the recommended dose of the combination of 
canakinumab with pembrolizumab plus platinum-based doublet chemotherapy will be 
confirmed.  
As of 25-Oct-2021 study CACZ885U2301 did not meet the primary endpoints of PFS and OS 
at final analysis. Canakinumab combined with pembrolizumab plus platinum doublet 
chemotherapy did not improve PFS and OS, when compared to placebo in the first line 
treatment of subjects with advanced/metastatic NSCLC without ALK or EGFR aberrations. 
Prespecified thresholds for statistical significance between arms were not crossed (for PFS: HR 
= 0.85 [95% CI: 0.67, 1.09]; one-sided stratified log-rank test p = 0.102; and for OS: HR = 0.87 
[95% CI: 0.70, 1.10]; one-sided stratified log-rank test p = 0.123). The median PFS and OS 
were 6.77 (95% CI: 5.62, 7.75) and 20.83 months (95% CI: 16.26, Non Estimable) in the 
canakinumab arm, respectively; and 6.77 (95% CI: 5.52, 6.93) and 20.17 months (95% CI: 
16.23, 22.37) in the placebo arm, respectively. 
Potential canakinumab benefit trends were reported in some subgroups. No differences were 
reported in the secondary endpoints (ORR, DCR, DOR). The median TTR was not reached in 
either arm and the probability of TTR at 6 months was comparable between arms. 
The overall safety and tolerability profile observed in this study with the combination of 
canakinumab, platinum-based chemotherapy and pembrolizumab as of 30-Jun-2023 was as 
expected and consistent with the known safety profile of each agent. No new safety signals or 
unexpected safety findings were identified with study treatment. The observed adverse events 
were as expected in this patient population and clinically manageable. 

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2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
Safety run-in part: To determine the RP3R of 
canakinumab in combination with 
pembrolizumab plus platinum-based doublet 
chemotherapy 
• 
Incidence of dose limiting toxicities in the first 42 
days of study treatment 
• 
Double-blind, randomized, placebo-
controlled part: To compare PFS by local 
investigator assessment as per RECIST1.1 and 
OS between the two treatment arms. 
• 
PFS based on local investigator assessment as per 
RECIST 1.1 and OS are multiple primary endpoints 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
Safety run-in part: To assess the preliminary 
clinical anti-tumor activity (overall response 
rate, disease control rate and duration of 
response) of canakinumab in combination with 
pembrolizumab plus platinum-based doublet 
chemotherapy.  
• 
ORR, DCR, DOR by local investigator’s 
assessment according to RECIST 1.1 
• 
Safety run-in part: To characterize the safety 
and tolerability of canakinumab in combination 
with pembrolizumab plus platinum-based 
doublet chemotherapy. 
• 
Type, frequency and severity of adverse events 
and reactions, changes in laboratory values, vital 
signs, ECGs 
• 
Safety run-in part: To characterize the 
pharmacokinetics of canakinumab in 
combination with pembrolizumab plus platinum-
based doublet chemotherapy. 
• 
Concentration and PK parameters of canakinumab, 
pembrolizumab and chemotherapy 
• 
Safety run-in part: To characterize the 
immunogenicity (anti-drug antibodies) of 
canakinumab and pembrolizumab 
• 
Anti-drug antibodies (ADA) prevalence at baseline 
and ADA incidence on-treatment of canakinumab 
and pembrolizumab 
• 
Double-blind, randomized, placebo-
controlled part: To evaluate overall response 
rate (ORR), disease control rate (DCR), time to 
response (TTR) and duration of response 
(DOR) by local investigator assessment per 
RECIST 1.1 in the treatment arms. 
• 
ORR, DCR, TTR and DOR based on local 
investigator assessment as per RECIST 1.1 
• 
Double-blind, randomized, placebo-
controlled part: To characterize the safety 
profile of the two treatment arms. 
• 
Frequency of adverse events, serious adverse 
events, AEs leading to treatment discontinuation, 
proportion of patients with laboratory abnormalities, 
ECG, and vital signs.  
• 
Double-blind, randomized, placebo-
controlled part: To characterize the 
pharmacokinetics of canakinumab, 
pembrolizumab and chemotherapy. 
• 
Concentration and PK parameters of canakinumab, 
pembrolizumab and chemotherapy  
• 
Double-blind, randomized, placebo-
controlled part: To characterize the 
immunogenicity (anti-drug antibodies, ADA) of 
canakinumab and pembrolizumab. 
• 
Anti-drug antibodies (ADA) prevalence at baseline 
and ADA incidence on-treatment of canakinumab 
and pembrolizumab 
• 
Double-blind, randomized, placebo-
controlled part: To assess PROs (EORTC 
QLQ-C30 with the QLQ-LC13 lung cancer 
module and EQ-5D-5L) including symptoms, 
physical functioning and health-related quality 
of life in the two treatment arms. 
• 
Time to definitive 10-point deterioration symptom 
scores for chest pain, cough and dyspnea per 
QLQ-LC13 questionnaire as three primary PRO 
variables of interest and time to definitive 
deterioration in global health status/QoL, shortness 
of breath and pain per QLQ-C30 as secondary 
PRO variables of interest. 

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Objective(s) 
Endpoint(s) 
Exploratory objective(s) 
Endpoint(s) for exploratory objective(s) 
• 
Double-blind, randomized, placebo-
controlled part: To assess the relationship 
between PK of canakinumab, and PD 
biomarkers, safety and efficacy. 
• 
Canakinumab PK by inflammatory markers (e.g. 
hs-CRP and hs-IL-6), safety (e.g. AEs and 
laboratory abnormalities) and efficacy (PFS and 
OS). 
• 
Double-blind, randomized, placebo-
controlled part: To assess the predictive and 
prognostic value of baseline levels of blood-
based and tissue-based biomarkers on 
efficacy . 
• 
PFS and OS by biomarkers at baseline 
• 
Double-blind, randomized, placebo-
controlled part: To explore iPFS, iORR, iDCR 
based on iRECIST as per local investigator in 
the two treatment arms. 
• 
iPFS, iORR and iDCR based on iRECIST criteria 
as determined by investigator  
• 
Double-blind, randomized, placebo-
controlled part: To explore the long term 
benefit intermediate to PFS and OS by 
assessing PFS2 in the two treatment arms. 
• 
PFS2 
• 
Double-blind, randomized, placebo-
controlled part: To characterize the impact of 
immunogenicity (anti-drug antibodies, ADA) on 
PK, safety and efficacy. 
• 
Antidrug antibodies (ADA) prevalence at baseline 
and ADA incidence on-treatment vs PK, AEs, lab 
abnormalities and efficacy endpoints (PFS, OS) 
3 
Study design 
This is a double-blind, randomized, multicenter phase III study evaluating the efficacy and 
safety of canakinumab vs. canakinumab matching-placebo in combination with pembrolizumab 
in addition to 4 cycles of platinum-based doublet induction chemotherapy, followed by 
maintenance therapy in subjects with AJCC v. 8 stage IIIB/IIIC (not eligible for definite 
chemoradiation therapy) or stage IV (metastatic) NSCLC regardless of PD-L1 levels and 
histology (squamous and non-squamous). Subjects who completed 4 cycles of induction 
treatment and fulfill eligibility criteria as defined in  Section 6.1.3 will enter the maintenance 
treatment phase. For dosing regimen, please refer to  Section 6.1.1 . 
This is a 2-part study: 
Part 1: Safety run-in part The safety run-in part will determine the recommended regimen of 
canakinumab (recommended Phase 3 dose regimen, RP3R) in combination with 
pembrolizumab and platinum-based doublet chemotherapy. Approximately 9 subjects will be 
enrolled in each cohort to get at least 6 evaluable subjects (for evaluability definition refer 
to  Section 6.5.1.2 ), as described in below  Figure 3-1 . For choice of chemotherapy 
medications and dosing regimen please refer to  Section 6.1  and  Section 6.1.3 . 
 

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Figure 3-1 
Part 1: Safety run-in, study design 
 
1 1 cycle = 3 weeks, 2 for Non-Squamous subjects only  
Part 2: Double-blind, randomized, placebo-controlled part 
Once the RP3R for canakinumab in combination with pembrolizumab and platinum-based 
doublet chemotherapy is confirmed in the safety run-in part, the double-blind, randomized, 
placebo-controlled part of the study will open. 
The randomization will be stratified based on PD-L1 status (Tumor Proportion Score (TPS) 
<1% vs. ≥1%), geographic region (East Asia vs. North America + Western Europe vs. Rest of 
the world) and histology (squamous vs. non-squamous). PD-L1 unevaluable subjects will be 
included with the TPS <1% group. Approximately 600 subjects will be randomized in a 1:1 
ratio to two treatment arms as described in below  Figure 3-2 . 
No cross-over treatment from canakinumab matching-placebo treatment arm to canakinumab 
treatment arm will be allowed. 
Open Label Extension (OLE) phase  
If OS reaches statistical significance at one of the interim or final analyses, all subjects on 
treatment or in safety/efficacy follow up will transition to the open label extension (OLE) phase 
following unblinding of investigational sites to treatment allocation. If OS is not statistically 
significant at final analysis but PFS was statistically significant at primary analysis, OLE will 
be initiated after final OS analysis, following the unblinding of investigational sites. Subjects 
will transition to a reduced study assessment schedule, as specified in Table 8-4. 
Subjects enrolled in the safety run-in part and subjects randomized to the canakinumab arm in 
the randomized part will transition into the OLE phase with their current treatment and dosing 
regimen (Section 6.1.1.3).  
Subjects randomized to the canakinumab matching-placebo arm in the randomized part will be 
allowed to cross over to canakinumab if the investigator determines this is in the subject’s best 
interest and per subject discretion, provided they fulfill crossover criteria (Section 6.1.3). 

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Subjects should cross over to canakinumab in combination with the other study drugs, i.e. 
pembrolizumab and maintenance chemotherapy, where applicable. Crossover is optional; 
subjects who do not wish to cross over to canakinumab will transition into the OLE phase with 
the other study drugs (Section 6.1.1.3). 
Any enrolled or randomized subjects who have already discontinued study treatment and are in 
efficacy and/or safety follow-up will also transition into the OLE and follow the reduced study 
assessment schedule, as specified in Table 8-4.  
Subjects in survival follow-up will not transition into OLE and will continue survival follow-
up as specified in Table 8-2 and Table 8-3. All subjects in OLE will be followed up for 5 years 
from the time of last subject first treatment in the randomized part or until all subjects 
discontinue the study treatment and complete their safety follow up, die, withdraw consent or 
are lost to follow up, whichever happens first.  
Figure 3-2 
Part 2: Double-blind, randomized, placebo-controlled, study design, 
including optional crossover during the OLE phase  
 
 
1 cycle = 3 weeks; 2 canakinumab/matching-placebo at RP3R; CTx = chemotherapy; R = Randomization. 
3Applicable during the OLE phase. OLE phase was never implemented since the study did not meet its primary 
endpoints of Overall Survival (OS) and Progression Free Survival (PFS) at final analysis. 
After treatment discontinuation, all subjects (enrolled in part 1 or randomized in part 2) will 
enter in the safety follow-up period and in an efficacy follow-up (as applicable) and then in a 
survival follow-up as described in the study flow Figure 3-3. Post implementation of protocol 
amendment 05, all subjects who discontinue study treatment will enter or complete the safety 
follow-up and the subjects in efficacy or survival follow-up will discontinue the study. For 
further details, please refer to study completion and post-study treatment Section 9.2. 

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Figure 3-3 
Study flow 
 
 
1:1
Safety 1
Safety 1
Safety 2
Safety 2
Safety 3
Safety 3
Safety 4
Safety 4
Safety 5
Safety 5
Randomization
(double-blind, 
randomized, placebo-
controlled part)
Treatment Period
Maintenance Treatment (until RECIST PD)1
(Canakinumab/placebo in combination with Pembrolizumab +/- pemetrexed)
Follow-up Period
PD as per RECIST1
(by investigator)
NO PD as per RECIST1
(by investigator)
pre-treatment
Period
End of post-treatment Follow-up
Survival Follow-up
Open Label Extension phase2
(Canakinumab in combination with Pembrolizumab +/- pemetrexed)
Screening 
(up to 28 days prior C1D1)
End of Treatment (EOT)3
Safety Follow-up
(every 26 days for 130 days after last dose of 
study treatment)
Efficacy Follow-up
(until RECIST PD)1
Safety Follow-up
(every 26 days for 130 days after last dose of 
study treatment)
Induction Treatment (4 cycles)
(Canakinumab/placebo in combination with Pembrolizumab and CTx +/- pemetrexed)
Enrollment
(safety run-in part)
Stratification factors:
PD-L1 expression: (<1% vs. ≥1%)
Histology: squamous vs. non-squamous
Geographic region: East Asia vs North America + 
Western Europe vs RoW

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1For subjects who continue study treatment beyond RECIST 1.1 PD as per investigator, tumor assessments will 
be done until immune confirmed PD (iCPD) as per iRECIST per investigator or discontinuation of study treatment, 
whichever occurs first. CTx = Chemotherapy. 2OLE will be initiated following unblinding of investigational sites if 
OS reaches statistical significance at one of the interim or final analyses. If OS is not statistically significant at final 
analysis but PFS was statistically significant at primary analysis, OLE will be initiated after final OS analysis 
following unblinding of investigational sites. 3Post implementation of protocol amendment 05, all subjects who 
discontinue study treatment will be followed for safety assessments for 130 days post EOT 
4 
Rationale 
As described in  Section 1.1.1.2 , chronic inflammation plays an important role in the 
development 
of 
cancer (Dalgleish and O'Byrne 2006, 
Mantovani et al 2008, 
Bhat et al 2014). CRP is an inflamatory marker that has been associated with a higher risk of 
developing lung cancer (Chaturvedi et al 2010). CRP has also been shown to be elevated in 
NSCLC and correlates with tumor size and stage, and points to poor outcome and prognosis 
(Aref H and Refaat 2014). 
CRP is a downstream target of IL-1β and is therefore often used as a surrogate marker for IL-
1β inhibition (Ridker 2016). 
Countering the elevated activities of IL-1β pathway could potentially reduce the occurrence of 
lung cancer and lung cancer mortality a hypothesis that was corroborated by data from the 
CANTOS study ( Section 1.1.2.1 ) 
High CRP levels were associated with inferior Overall Survival after Immunotherapy (OSI) in 
lung cancer patients treated with nivolumab (Naqash AR 2017); these data support the 
hypothesis that inhibition of the IL-1β may lead to a microenvironment more susceptible to 
anti-PD-(1) inhibitors used in combination. Furthermore, recent pooled data from the 
atezolizumab studies in second and third line NSCLC patients demonstrated that decrease in 
CRP levels correlated with RECIST 1.1 responses and prolonged PFS and OS in the 
atezolizumab-treated arm (Patil et al 2018). 
Taken together, these data reinforce the importance of inflammation as a target in cancer 
treatment and support the hypothesis that canakinumab, an IL-1β inhibitor, may synergize with 
PD-(L)1 inhibitors in the treatment of advanced or metastatic NSCLC. Given the positive results 
of pembrolizumab in combination with chemotherapy in first-line NSCLC , the current study 
(CACZ885U2301) is designed to evaluate the safety and efficacy of canakinumab in 
combination with pembrolizumab and platinum-based doublet chemotherapy to test this 
hypothesis. 
4.1 
Rationale for study design 
The study will compare the addition of canakinumab to pembrolizumab plus platinum-based 
doublet chemotherapy as first line treatment for stage IIIB/IIIC (locally advanced) or stage IV 
(metastatic) NSCLC. The safety run in part establishes the RP3R and the safety profile for the 
canakinumab combination and is followed by a double blind randomized placebo controlled 
trial to determine the efficacy of adding canakinumab to the current standard of care. 
Stratification factors based on PD-L1 expression, histologic subtype and geographic region 
balances the predictive and prognostic factors. The double blind placebo controlled design 
minimizes the bias in the assessments of efficacy, safety and PROs.  

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Rationale for study design features is described in  Table 4-1 .  
Table 4-1 
Rationale for study design 
Study Design Aspect 
Rationale 
Randomization stratification factors: 
• 
PD-L1 expression (<1% vs. ≥1%) 
• 
Histology (squamous vs. Non-
squamous) 
• 
Geographic region 
The stratification factors have been selected to balance potential 
predictive and/or prognostic factors between the two arms: 
• 
PD-L1 expression has been shown to correlate with response 
to checkpoint inhibitors. This has been further confirmed by 
results from KEYNOTE-189, where the least benefit was 
observed in subjects with PD-L1 expression <1% 
(Gandhi et al 2018). Hence, randomization is stratified based 
on PD-L1 expression based on a 1% cut-off threshold. 
• 
Although anti-PD-1/PD-L1 activity is observed in both 
squamous and non-squamous histology, the magnitude of 
benefit and the absolute outcomes may differ slightly in the 
two histologies (Brahmer et al 2015, Borghaei et al 2015, 
Herbst et al 2016, Reck et al 2016, Herzberg et al 2017), 
therefore randomization is stratified based on disease 
histology. 
• 
Geographic region (East Asia vs. North America + Western 
Europe vs. Rest of the world) to account for possible 
differences in standard of care. 
No treatment cross-over from 
canakinumab matching-placebo to 
canakinumab arm after disease 
progression as per RECIST 1.1 will be 
allowed. 
This is to reduce confounding due to cross-over in OS outcome 
(primary objective) 
Study treatment beyond initial disease 
progression by RECIST 1.1 will be 
permitted if it is in the best interest of the 
subject per physician discretion (details in 
Section 6.1.4.1). Canakinumab as single 
agent after RECIST 1.1 progression is 
not allowed.  
Study treatment will be discontinued 
upon confirmation of progression (iCPD) 
as per iRECIST. 
Note: Treatment beyond iRECIST 
confirmed progression (iCPD) may be 
allowed if considered to be in the best 
interest of the subject by the investigator. 
In such cases, approval by a Novartis 
study physician is required . 
This is to ensure that those subjects who derive clinical benefit 
from study treatment (are clinically stable, tolerate the treatment 
and have no confirmed PD by immune response criteria (iCPD by 
iRECIST)) can continue to receive treatment. Timely follow-up 
after the initial PD will ensure that subjects with confirmed/rapid 
progression will be discontinued and can initiate adequate 
subsequent therapies. Continuation of study treatment will be 
allowed after RECIST 1.1 progression and until iCPD by iRECIST 
if the investigator assesses that the subject is deriving clinical 
benefit. Note that pembrolizumab treatment will be given for a 
maximum of 35 administrations (4 administrations of induction + 
31 administrations of maintenance as per Keynote 189 study; 
Gandhi et al 2018)  
Open Label Extension phase (OLE): if 
OS reaches statistical significance at one 
of the interim or final analyses, all 
subjects will transition to the open label 
extension (OLE) phase following 
unblinding of investigational sites to 
treatment allocation. If OS is not 
statistically significant at final analysis but 
PFS was statistically significant at 
primary analysis, Subjects will transition 
to a reduced study assessment schedule. 
Subjects randomized to canakinumab-
matching placebo will be allowed to cross 
over to canakinumab, as per investigator 
 The OLE phase will allow: 
• 
 Subjects who continue to derive clinical benefit from the 
treatment, based on the investigator’s evaluation, to continue 
to receive trial treatment.  
• 
 Subjects in the placebo arm to receive added benefit from 
canakinumab treatment 
• 
A reduced schedule of assessments 

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Study Design Aspect 
Rationale 
and subject discretion, provided they 
fulfill crossover criteria. Crossover is 
optional.  
Post implementation of protocol 
amendment 05, subjects will continue 
with an assessment schedule aligned to 
standard of care. The efficacy follow-up 
and survival follow-up will no longer be 
collected. All subjects who discontinue 
study treatment will enter or complete the 
safety follow-up and the subjects in 
efficacy or survival follow-up will 
discontinue the study. 
Protocol Amendment 05 will allow subjects to continue the study 
with a safety and efficacy assessment schedule aligned to to 
standard of care. 
4.2 
Rationale for dose/regimen and duration of treatment 
In the safety run-in part, canakinumab dose will start at 200 mg every three weeks (Q3W) which 
is the dosing regimen selected for the development program in NSCLC. This dosing regimen is 
chosen on the basis of the pharmacokinetic (PK) and pharmacodynamics (PD) properties of 
canakinumab, the observed safety, biomarker and efficacy data from the CANTOS study, and 
the safety data from completed and ongoing canakinumab studies. 
4.2.1 
Pharmacokinetics (PK) consideration 
Canakinumab displays PK properties typical of an IgG1 antibody, with a mean terminal half-
life of 26 days (Ilaris® USPI). Every 3 weeks dosing schedule of canakinumab is feasible based 
on its half-life of 26 days, and its ability to suppress CRP for at least 1 month as previously 
demonstrated in two single-dose phase II studies with dose ranges of 0.03 to 10 mg/kg i.v. and 
25 to 300 mg s.c. (Study [CACZ885A2213] in diabetes and Study [CACZ885H2251] in gouty 
arthritis). Population PK analysis and simulation were also performed to compare the steady-
state PK of 200 mg Q3W versus 300 mg Q4W. 300 mg Q4W was selected as reference for 
comparison, because it is the highest approved regimen for canakinumab. As shown 
in  Figure 4-1 , the simulated PK profiles of canakinumab at 200 mg Q3W and 300 mg Q4W 
are comparable, indicating that the safety margin with the 200 mg Q3W regimen is expected to 
be in line with the one from the currently approved regimen of 300 mg Q4W. Specifically, the 
maximum plasma concentration (Cmax) of 200 mg Q3W is not exceeding that of 300 mg Q4W. 

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Figure 4-1 
Simulated PK profiles of canakinumab 200 mg Q3W s.c. and 300 mg 
Q4W s.c. 
 
Line and band: median of individual simulated concentrations with 2.5-97.5% prediction interval. Values reported 
are median (solid line) and the 95% prediction interval (shaded area, 2.5th-97.5th percentile). 
4.2.2 
Efficacy and pharmacodynamics (PD) considerations 
CANTOS study evaluated whether IL-1β inhibition might alter cancer occurrence and mortality 
as there is a strong inflammatory component to certain cancers, especially lung cancer. The 
results show that canakinumab, as compared to placebo, was associated with dose-dependent 
risk reductions in lung cancer and lung cancer mortality. There is a clear differentiation in 

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clinical benefits across all three dosing regimens, with the greatest risk reduction in lung cancer 
mortality achieved with the highest dose, 300 mg s.c. every three months. Hazard ratios (95% 
confidence interval, P-value) were 0.67 (0.37-1.20, P=0.18), 0.64 (0.36-1.14, P=0.13), and 0.23 
(0.10-0.54, P=0.0002) for the 50 mg, 150 mg, and 300 mg s.c. dose groups, respectively as 
reported by (Ridker et al 2017). The dose-dependent pattern of hs-CRP reduction among 
subjects with lung cancer is also aligned with the clinical results, with the 300 mg group 
demonstrating the largest magnitude of reduction, relative to the other two treatment groups and 
placebo, with no saturating effect at 300 mg s.c. every three months. 
The different median baseline hs-CRP levels among canakinumab-treated subjects in CANTOS 
who were subsequently diagnosed with cancer compared to those who did not (median 6.0 mg/L 
[Interquartile Range (IQR): 3.5-11.5 mg/L] versus 4.2 mg/L [IQR: 2.8-7.1 mg/L], P<0.0001) 
(Ridker et al 2017) likely reflect the different inflammatory status and risk for cancer. Notably, 
for subjects with higher baseline hs-CRP, the proportion of subjects with hs-CRP normalized 
to post-treatment target level (2.3 mg/L) is less, compared to subjects with lower baseline hs-
CRP ( Figure 4-2 ). This finding suggests that raising the dose and/or shortening the dosing 
interval which will increase canakinumab steady-state PK may lead to better control of 
inflammation in subjects with higher baseline hs-CRP and deliver greater efficacy in subjects 
with higher baseline hs-CRP. Publications examining hs-CRP levels in NSCLC subjects show 
that higher hs-CRP levels is correlated with higher stage and poor prognosis (Alifano et al 2011, 
Hara et al 2010, Vagulienė et al 2011). 
Figure 4-2 
Proportions of subjects with hs-CRP < 2.3 mg/ L by baseline hs-CRP 
declines in all subjects from the CANTOS study  
  
Median hs-CRP at 3 months was 2.3 mg/L based on all subjects in the Full Analysis Set. 
4.2.3 
Safety considerations 
The combination of canakinumab + pembrolizumab + pemetrexed for subjects with non-
squamous NSCLC is expected to be administered at full dose of each of the drugs as no additive 
toxicity is anticipated from this triple combination based on the following rationale: 

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• the combination of pembrolizumab + chemotherapy is well tolerated at full doses used in 
the phase III trials, KEYNOTE-189 trial (Gandhi et al 2018) and KEYNOTE 407 
(Paz-Ares 2018) 
• the combination of PDR001 + canakinumab was well tolerated at full doses of each 
component in the ongoing Phase Ib study, [CPDR001X2103]. Hence, it is expected the 
combination of pembrolizumab + canakinumab will also be well tolerated; 
• the main toxicities related to canakinumab administration possibly overlapping with 
pemetrexed are infection and neutropenia. These two side effects were however of low 
added frequency as compared to placebo in the CANTOS study. 
The safety of combination of canakinumab at 200 mg s.c. Q3W with pembrolizumab + 
carboplatin + pemetrexed, pembrolizumab + cisplatin + pemetrexed and pembrolizumab + 
carboplatin + paclitaxel will be evaluated in the safety run-in part. The resulting canakinumab 
regimen will be used in the double-blind, randomized, placebo-controlled part of the study. 
Overall, canakinumab safety and tolerability findings across the three dosing regimens in 
CANTOS showed no new or unexpected signals and are similar to that reported in other 
populations, which shows a well-tolerated safety profile following a wide range of dosing 
regimens [canakinumab Investigator’s Brochure]. There were no meaningful differences 
between any of the canakinumab treatment groups and placebo in the overall incidence of AE 
or of serious adverse events (SAEs) in CANTOS. Based on ~ 570 subjects treated with 
canakinumab in interventional trials in approved indications, the most frequently reported 
adverse drug reactions (ADRs) were infections, predominantly of the upper respiratory tract. 
Majority of the events were mild to moderate, although serious infections were observed. Early 
recognition of infection symptoms and immediate use of antibiotics with appropriate measures 
can prevent serious outcome of infections. No neutralizing antibodies have been detected so far 
(Ilaris®, SmPC-2017). 
As described in the canakinumab IB across the completed and ongoing studies, higher 
canakinumab doses (4 mg/kg [max. 300 mg] s.c. Q4W, 300 mg s.c. Q2W or 600 mg i.v. loading 
dose plus 300 mg s.c. Q2W) have been used before for other indications. These studies did not 
reveal clinically relevant differences in the types and severity of reported adverse events across 
different dose groups. The AEs observed were mostly mild and moderate in severity, and similar 
to that of the placebo group. 
4.2.4 
Consideration for combination with pembrolizumab and 
chemotherapy 
Several canakinumab trials are ongoing in oncology: in particular, canakinumab is being 
evaluated in subjects with advanced NSCLC in an ongoing phase Ib study, [CPDR001X2103]. 
The rationale for the choice of the doses of canakinumab is also based on the outcomes of a 
phase Ib study (CPDR001X2103) where the combination of spartalizumab (PDR001, a PD-1 
inhibitor from Novartis) and canakinumab are being evaluated. Available data on pharmacology, 
pharmacokinetics, and safety suggest that PDR001 behaves similarly to other approved PD-L1 
inhibitors. In study [CPDR001X2103], a review of the safety and tolerability data showed that 
canakinumab at 600 mg s.c. Q8W is safe to be combined with PDR001 administered at 400 mg 
i.v. Q4W (Recommended Phase 2 Dose, RP2D) (refer the safety summary details in the next 
paragraph). Based on preliminary population PK simulation, 600 mg s.c. Q8W canakinumab 

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generates steady-state Cmax greater than that attained at the 200 mg s.c. Q3W; PDR001 at 400 
mg i.v. Q4W is also expected to achieve steady-state exposure similar to those of 
pembrolizumab at 200 mg i.v. Q3W [PDR001 Investigational Brochure]. Therefore, no 
unexpected safety issues are expected with the administration of pembrolizumab in combination 
with canakinumab. 
Overview of combination of PDR001 and canakinumab 
Data for the combination of canakinumab is available from Study [CPDR001X2103], a Phase 
Ib study to characterize the safety, tolerability and pharmacodynamics of PDR001 in 
combination with CJM112, EGF816, canakinumab, or trametinib. As of the data cut-off (31-
Jul-2017), 16 patients were enrolled and treated in the dose escalation part of the study, using 
three dose levels: 100 mg canakinumab s.c. Q8W (n=6), 300 mg canakinumab s.c. Q8W (n=7) 
and 600 mg canakinumab s.c. Q8W (n=3), all in combination with 400 mg Q4W PDR001. 
Fifteen patients (94%) experienced AEs of any grade, regardless of causality. The most 
common AEs were decreased appetite (6 patients, [37%]), fatigue (5 patients, [31%]), anemia 
and dyspnea (each in 4 patients, [25%]), and back pain, dizziness and nausea (each in 3 patients, 
[18%]). The majority of AEs were Grade 1/2. Six (37%) experienced AEs of any grade, 
suspected to be related to study treatment. The most frequent AEs suspected to be related to 
study treatment were fatigue (5 patients, [18%]) and decreased appetite (2 patients, [12%]). 
Seven patients (44%) experienced Grade 3/4 AEs regardless of causality. No patient had a 
Grade 3/4 AE that was suspected to be related to study treatment. Eight SAEs have been 
reported for 5 (31%) patients: Large Intestinal Obstruction, Urinary Tract Infection, Cystitis, 
Herpes Zoster, Lipase Increased (LT/Grade 4), Cancer Pain, Intercostal Neuralgia, Acute 
Respiratory Failure (LT/Grade 4). All 8 SAEs were assessed as not suspected of being related 
to study treatment. There were no DLTs observed, and this Phase Ib study is completed. 
4.2.5 
Conclusion for dose regimen selection 
Every 3 weeks dosing schedule of canakinumab is feasible based on its half-life of 26 days, and 
its ability to suppress CRP for at least 1 month as previously demonstrated in two single-dose 
phase II studies with dose ranges of 0.03 to 10 mg/kg i.v. and 25 to 300 mg s.c. Study 
[CACZ885A2213] in diabetes and Study [CACZ885H2251] in gouty arthritis respectively. 
More importantly, given the evidence of the efficacy profile from the CANTOS study in which 
canakinumab shows no plateau effect in lung cancer risk reduction at 300 mg s.c. quarterly 
(Q12W), and the comprehensive and well-established safety profile of canakinumab across a 
wide range of doses and dosing intervals studied in interventional trials, a 200 mg s.c Q3W 
dosing schedule for canakinumab, which has an approximately equivalent total dose amount 
and similar predicted PK range as 300 mg s.c. Q4W (a regimen already used in certain approved 
indications), is selected for the NSCLC development program to ensure a positive benefit/risk 
ratio. The protocol includes appropriate safety assessment to monitor and manage these risks 
( Section 6.5  for further details). The full dose of pembrolizumab (200 mg Q3W) and 
pemetrexed (500 mg/m2) is expected to be administered as no additive toxicity is anticipated 
from this triple combination. 
If canakinumab dosed at 200 mg s.c. Q3W is deemed intolerable in this triple combination 
based on data from the safety run-in part, an alternative canakinumab schedule will be 
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( Section 6.5.1.1 ). Based on population PK simulation, 200 mg s.c. Q6W is predicted to 
generate steady-state PK parameters (i.e. minimum concentration (Cmin), Cmax, average 
concentration (Cavg) that are lower than those from 200 mg s.c. Q3W, but still higher than 
those from the CANTOS top dose of 300 mg s.c. Q12W to ensure sufficient clinical benefit 
given the exposure-dependent risk reductions in lung cancer and lung cancer mortality observed 
from CANTOS. 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
Two phase III studies KEYNOTE 189 and KEYNOTE 407 (Section 1.1) establishes the 
combination of pembrolizumab in combination with platinum-based doublet chemotherapy in 
the first-line treatment for NSCLC. Despite these advances, the PFS and OS remain short and 
there is a need to improve efficacy. IL-1β inhibition is a new mechanism of action that is 
expected to bring benefit to NSCLC patients as suggested by the CANTOS study outcome. 
Additionally, the demonstrated correlation between the IL-1β pathway, CRP levels and PD-L1 
expression provides a rationale for combining PD-1 inhibitors with an IL-1β pathway antagonist 
(Akamine et al 2018, Guo et al 2017). In studies that included 33567 and 10408 cancer-free 
individuals, elevated baseline levels of hs-CRP were demonstrated to be associated with 
increased mortality from lung cancer (Ko et al 2012, Allin et al 2009). Based on the 
immunomodulatory properties of IL-1β inhibition, it is expected that the maintenance treatment 
combination of canakinumab and pembrolizumab will lead to better outcomes than 
pembrolizumab alone as maintenance following induction treatment with platinum-based 
doublet chemotherapy plus pembrolizumab. Additionally, recent pooled data from the 
atezolizumab in second and later treatment line NSCLC studies demonstrate that decreases in 
CRP correlate with higher RECIST 1.1 responses and prolonged PFS and OS in the 
atezolizumab-treated arm, reinforcing the importance of inflammation as a target in cancer 
treatment (Patil et al 2018). 
Rationale for choice of chemotherapies tested in safety run-in part (part 1) 
The overlapping toxicities between canakinumab and the chemotherapies (carboplatin/cisplatin 
+ pemetrexed; paclitaxel/nab-paclitaxel + carboplatin) include myelosuppression, febrile 
neutropenia and the increased risk of serious infections. Frequency of neutropenia, febrile 
neutropenia, thrombocytopenia and sepsis from selected Phase III studies of pemetrexed, nab-
paclitaxel and paclitaxel in advanced NSCLC are summarized in  Table 4-2 . For further details 
for the rationale for the choice of chemotherapy tested in safety run-in part refer 
to  Section 1.1.1.1 . 
Since the hematological events and febrile neutropenia events are similar for nab-paclitaxel and 
paclitaxel regardless of the NSCLC histology, paclitaxel will be used in the safety run-in to 
evaluate the safety of canakinumab added to pembrolizumab + paclitaxel + carboplatin. Results 
from the paclitaxel combination will be applied to nab-paclitaxel combination.  
Based on the low number of all grade neutropenia and sepsis events observed with canakinumab 
monotherapy treatment in CANTOS study, it is expected that the addition of canakinumab to 
the combination of pembrolizumab and chemotherapy may only slightly increase the frequency 
of hematologic and infection related adverse events. 

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Table 4-2 
Summary of key hematological and infection adverse events for 
different treatment combinations for NSCLC 
Combination 
N 
Neutropenia 
% 
CTC grade 
3/4 
Febrile 
Neutropenia 
% 
Thrombopenia 
% 
CTC grade 3/4 
Infection 
% 
CTC grade 
3/4 
Reference 
Pembrolizumab 
+ Pemetrexed + 
platinum vs. 
Placebo + 
Pemetrexed + 
platinum 
607 
Safety 
Data set 
15.8 vs. 
11.9* 
Not Reported 
(febrile 
neutropenia 
was the only 
adverse event 
of grade 3 or 
higher that 
was more 
frequent in 
pembrolizuma
b-combination 
group*) 
7.9 vs. 6.9 
Not 
reported 
Gandhi et al 
2018 
Paclitaxel + 
cisplatin vs. 
Paclitaxel + 
carboplatin 
608 
Safety 
Data set 
51 vs. 54 
4 vs. 6 
2 vs. 8 
5 vs. 5 
Rosell et al 
2002 
Paclitaxel + 
carboplatin vs. 
nab-paclitaxel + 
carboplatin 
1038 
Safety 
Data set 
58 vs. 47 
<2 vs. <2 
9 vs. 18 
Not 
reported 
Socinski et al
 2012 
CANTOS 
Canakinumab 
300 mg, 150 
mg, 50 mg – 
Total 
vs. placebo 
10061 
CANTOS 
study,  
events 
of all 
grades 
All Grades: 
2.0,1.4,1.1-
1.5 
vs. 
0.9 
Not Reported 
All Grades 
2.7, 2.0, 2.0-
2.2 
vs. 
1.6 
Events of 
sepsis: 
2.2, 2.1, 
1.8-2.0 
vs. 
1.3 
CANTOS 
study CSR 
* Gandhi et al 2018 pembrolizumab included grade 5 in neutropenia data set. 
4.4 
Purpose and timing of interim analyses/design adaptations 
The statistical basis for claim of efficacy in favor of the canakinumab arm is based on either 
statistical significance for PFS or statistical significance for OS as detailed in Section 12.4.2. 
The timing of the final PFS analysis and interim OS analyses are detailed in Section 12.4.2 and 
Section 12.7 . 
4.5 
Risks and benefits 
The double-blind, randomized, placebo-controlled part of this Phase III study is preceded by a 
safety run-in, to define the dose of canakinumab to be used as RP3D. Appropriate eligibility 
criteria, specific dose-limiting toxicity definitions, and specific dose modification and stopping 
rules, are included in this protocol. Recommended guidelines for prophylactic or supportive 
management of study-drug induced adverse events are provided in Section 6 . 
The risk to subjects in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, as well as close clinical monitoring, and the periodic review of safety 
data by an independent data monitoring committee (DMC).  

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Cancer subjects receiving chemotherapy are at an increased risk of infection due to 
myelosuppression. Canakinumab treatment also predisposes subjects to an increased risk of 
infection. Nadir complete blood counts with differentials will be followed carefully during 
induction chemotherapy and urinalyses will be routinely performed on study visits to allow 
early diagnosis of potential urinary tract infections. Subjects are informed by their signed 
informed consent to notify their physician and seek medical attention immediately if they 
experience a fever (>38.0°C) or any signs/symptoms of infection. Refer to the [Investigator’s 
Brochure]. 
Women of child-bearing potential and sexually active males must be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 
study, and agree that in order to participate in the study they must adhere to the contraception 
requirements outlined in the exclusion criteria. If there is any question that the subject will not 
reliably comply, they should not be entered or continue in the study. 
Imaging studies (computed tomography (CT), magnetic resonance or X-rays) will be used in 
this study to assess response of tumors to administered treatments. The frequency is consistent 
with the standard of care assessments every 6 weeks of chemotherapy. Tumor assessments 
required by the trial allow for magnetic resonance imaging (MRI) and CT; the ability to use of 
MRI instead of CT for the brain and abdomen decreases the radiation exposure. Only in the 
chest is CT preferable to MRI. Contrast enhancement is a standard tool to evaluate potential 
metastatic lesions; subjects with contrast allergy are exempted from its use. The ordering 
physician should assure that subjects are well hydrated and precautions taken to avoid renal 
injury due to contrast agents. 
Advanced/metastatic NSCLC is an incurable disease, which has a median life expectancy of 
less than 20 months. Given that canakinumab or canakinumab matching-placebo is being added 
the most current standard of care for this disease, pembrolizumab in combination with platinum-
based doublet chemotherapy, with subject safety overseen by a DMC, the risk benefit ratio 
favors canakinumab. 
4.6 
Rationale for public health emergency mitigation procedures 
In the event of a public health emergency as declared by local or regional authorities (i.e. 
pandemic, epidemic or natural disaster), mitigation procedures may be required to ensure 
subject safety and trial integrity and are listed in relevant sections of the study protocol. 
Notification of the public health emergency will be discussed with Novartis by Investigator 
/Site prior to implementation of mitigation procedures and permitted/approved by local or 
regional Health Authorities and Ethics Committees as appropriate. 
4.7 
End of study definition 
Study completion is defined when the last participant finishes their last study visit and any 
repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator (e.g., each participant will be required to complete the study 
in its entirety and thereafter no further study treatment will be made available to them in the 
scope of the trial). The study will end when all participants discontinue the study treatment and 
complete their safety follow up, die, withdraw consent, or are lost to follow up, whichever 
comes first. 

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5 
Population 
The study population will include adult subjects to be treated in the first-line setting, advanced 
or metastatic non-small cell lung cancer (NSCLC), without EGFR or ALK alteration. 
The investigator or designee must ensure that only subjects who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study. 
5.1 
Inclusion criteria 
Subjects eligible for inclusion in this study must meet all of the following criteria: 
1. Written informed consent must be obtained prior to any screening procedures 
2. Adult male/female ≥ 18 years of age at the time of informed consent 
3. Histologically confirmed locally advanced stage IIIB/IIIC (and is not eligible for definitive 
chemo-radiation curative therapy) or stage IV (metastatic) NSCLC for treatment in the first-
line setting 
• Subjects who received previous neo-adjuvant or adjuvant systemic therapy (other than 
immunotherapies) will be eligible if neo-adjuvant or adjuvant therapy was completed 
at least 12 months prior to the development of metastatic disease. Last dose of neo-
adjuvant or adjuvant therapy must be more than 12 months prior to 
enrollment/randomization 
4. Subject is a suitable candidate for platinum-doublet chemotherapy and pembrolizumab, and 
does not have any contraindication(s) to these drugs as per locally approved label. 
5. Known PD-L1 status determined by a Novartis designated central laboratory. 
• A newly obtained tissue biopsy or an archival biopsy (block or slides) is required for 
PD-L1 determination (PD-L1 IHC 22C3 pharmDx assay), prior to study randomization. 
• Note: For the safety run-in part, known PD-L1 status is not required. 
6. ECOG performance status (PS) of 0 or 1. 
7. At least 1 measurable lesion by RECIST 1.1 in solid tumors criteria; a previously irradiated 
lesion may only be counted as a target lesion if there is clear sign of progression since the 
irradiation. 
8. Subject must have recovered from all toxicities related to prior systemic therapy to grade ≤ 
1 (CTCAE v5.0). Exception to this criterion: patients with any grade of alopecia 
9. Subjects must have adequate bone marrow organ function including the following 
laboratory values at the screening visit: 
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (without growth factor support) 
• Platelets ≥ 100 x 109/L (without growth factor support or transfusion) 
• Hemoglobin (Hgb) > 9 g/dL (4 weeks without transfusions or erythropoietin) 
• Creatinine clearance greater than 60 mL/min by calculation using Cockcroft-Gault 
formula 
• Total bilirubin (TBIL) ≤ 1.5 x ULN 
• Aspartate aminotransferase (AST) ≤ 3 x ULN 
• Alanine aminotransferase (ALT) ≤ 3 x ULN 
• Serum amylase ≤ 2 x ULN or pancreatic amylase ≤ 1.5 x ULN 

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• Serum lipase ≤ 1.5 x ULN 
10. Subject is able to communicate with the investigator, and has the ability to comply with the 
requirements of the study procedures. 

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5.2 
Exclusion criteria 
Subjects meeting any of the following criteria are not eligible for inclusion in this study. 
1. Previous immunotherapy (e.g. anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, 
or any other antibody or drug specifically targeting T-cell co-stimulation or immune 
checkpoint pathways). 
2. Prior treatment with canakinumab or drugs of a similar mechanism of action (IL-1β 
inhibitor). 
3. Subjects with epidermal growth factor receptor (EGFR) sensitizing mutations , and/or ALK 
rearrangement by locally approved laboratory testing (If local testing is not available, a 
Novartis designated central laboratory will perform EGFR and/or ALK testing). 
• Subjects with NSCLC of pure squamous cell histology can initiate treatment without 
molecular testing or result, however, subjects with pure squamous cell histology that 
are known to have EGFR/ALK sensitizing mutations are excluded. 
• Subjects with known BRAF V600 mutation or ROS-1 rearrangement will be excluded, 
if required by local guidelines 
4. History of severe hypersensitivity reaction to monoclonal antibodies, platinum containing 
drugs, paclitaxel, nab-paclitaxel, pemetrexed or any known excipients of these drugs (i.e. 
Polysorbate-80-containing infusions, mannitol, histidine). 
5. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.  
• Subjects with previously treated brain metastases may participate provided they are 
clinically stable for at least 2 weeks and, have no evidence of new or enlarging brain 
metastases and also are off steroids ≥ 2 weeks (unless receiving a dose equivalent to 
prednisone ≤5 mg) prior to dosing with study medication. Stable brain metastases by 
this definition should be established prior to the first dose of study medication.  
• Subjects with known untreated, asymptomatic brain metastases (i.e., no neurological 
symptoms, no requirements for corticosteroids, no or minimal surrounding edema, no 
lesion >1.0 cm and a maximum of 3 lesions) may participate but will require regular 
imaging of the brain as a site of disease.  
6. Presence or history of a malignant disease, other than NSCLC, that has been diagnosed 
and/or required therapy within the past 3 years prior to randomization. Exceptions to this 
exclusion include the following: completely resected basal cell and squamous cell skin 
cancers, and completely resected carcinoma in situ of any type 
7. Active autoimmune disease that has required systemic treatment in the past 2 years prior to 
randomization (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Control of the disorder with replacement therapy (e.g., 
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc) is permitted. 
8. Subject with suspected or proven immunocompromised state or infections, including: 
•  Evidence of active or latent tuberculosis (TB) as determined by locally approved 
screening methods. If the results of the screening per local treatment guidelines or 
clinical practice require treatment, then the patient is not eligible.  
• Chronic or active hepatitis B or C 

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• Known history of testing positive for Human Immunodeficiency Virus (HIV) infections. 
For countries where HIV status is mandatory: testing positive for HIV during screening 
using a local test. 
• Any other medical condition (such as active infection, treated or untreated), which in 
the opinion of the investigator places the patient at an unacceptable risk for participation 
in immunomodulatory therapy.  
• Note: Subjects with localized condition unlikely to lead to a systemic infection e.g. 
chronic nail fungal infection are eligible. 
• Allogeneic bone marrow or solid organ transplant 
• Treatment with any immune modulating agent in doses with systemic effects e.g.:  
• Prednisone > 20 mg (or equivalent) oral or intravenous daily for > 14 days; 
• Prednisone > 5 mg and ≤ 20 mg (or equivalent) daily for > 30 days; 
• Equivalent dose of methotrexate > 15 mg weekly 
• Subject receiving any biologic drugs targeting the immune system (for example, 
TNF blockers, anakinra, rituximab, abatacept, or tocilizumab). 
• Note: Daily glucocorticoid-replacement for conditions such as adrenal or pituitary 
insufficiency is allowed. 
• Note: Topical, inhaled, or local steroid use in doses that are not considered to cause 
systemic effects are permitted. 
• Note: Steroids for pre-medication related to chemotherapy as per local standard of 
care are permitted. 
9. Subject has received live vaccination within 3 months prior to first dose of study drug. 
10. Subject has had major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 
4 weeks prior to starting study drug or has not recovered from side effects of such procedure 
(≥ grade 2 AE related to such procedure). Video-assisted thoracic surgery (VATS) and 
mediastinoscopy will not be counted as major surgery and subject can be enrolled in the 
study ≥ 1 week after the procedure. 
11. Thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting the study treatment or 
subjects who have not recovered from radiotherapy-related toxicities (≥ grade 2 AE related 
to such procedure). For all other anatomic sites (including radiotherapy to thoracic vertebrae 
and ribs) radiotherapy ≤ 2 weeks prior to starting the study treatment or has not recovered 
from radiotherapy-related toxicities. Palliative radiotherapy for bone lesions ≤ 2 weeks prior 
to starting study treatment is allowed. 
12. Clinically significant, uncontrolled heart disease and/or recent cardiac event (within 6 
months), such as: 
• Unstable angina or myocardial infarction within 6 months prior to screening 
• History of documented congestive heart failure (New York Heart Association 
functional classification III-IV) 
• Clinical significant cardiac arrhythmias 
• Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg 
and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, unless controlled prior to 
screening. 

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13. History of (non-infectious) pneumonitis that required steroids or current pneumonitis.  
14. Subject has any other concurrent severe and/or uncontrolled medical condition that would, 
in the investigator’s judgment, cause unacceptable safety risks, contraindicate subject 
participation in the clinical study, or compromise compliance with the protocol (e.g. chronic 
pancreatitis, uncontrolled diabetes mellitus). 
15. Known active or recurrent hepatic disorder including cirrhosis. 
16. Patient is concurrently using other anti-cancer therapy 
17. Participation in a prior investigational study (drug or device) within 30 days prior to 
enrollment or randomization or within 5-half lives of the investigational product, whichever 
is longer, or those who are expected to receive any other investigational drug or device 
during the conduct of the study. 
18. Pregnant or breast-feeding (lactating) women, or women who plan to become pregnant or 
breast-feed during the study, where pregnancy is defined as the state of a female after 
conception and until the termination of gestation, confirmed by a positive hCG laboratory 
test. 
19. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective contraception during the study 
and 6 months after study treatment discontinuation. Highly effective contraception methods 
include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the subject . 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) 
and withdrawal are not acceptable methods of contraception) 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or bilateral tubal ligation at least 6 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 patients on the study, 
the vasectomized male partner should be the sole partner for that patient. 
• Use of oral (estrogen and progesterone), injected or implanted combined hormonal 
methods of contraception or placement of an intrauterine device (IUD) or intrauterine 
system (IUS), or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal hormone 
contraception. 
In case of use of oral contraception women should have been stabilized on the same pill 
for a minimum of 3 months before taking study treatment. 
Women are considered post-menopausal and not of child bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy) or bilateral tubal ligation at least 6 weeks ago. In the case 
of oophorectomy alone, only when the reproductive status of the woman has been confirmed 
by follow up hormone level assessment is she considered not of child-bearing potential. 
20. Sexually active males unless they use a condom during intercourse while taking 
chemotherapy drug(s) and for 6 months after stopping chemotherapy treatment, and should 
not father a child in this period or as per the local label. A condom is required to be used 

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also by vasectomized men in order to prevent delivery of the chemotherapy drug(s) via 
seminal fluid. 
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible subjects 
6 
Treatment 
6.1 
Study treatment 
In this study, the “study treatment” refers to the combination of study drugs: 
canakinumab/canakinumab 
matching 
placebo, 
pembrolizumab, carboplatin, 
cisplatin, 
paclitaxel, nab-paclitaxel, and pemetrexed. The term “investigational drug” refers to the 
Novartis study drug, canakinumab (ACZ885). 
For all non-investigational drugs (pembrolizumab, carboplatin, cisplatin, paclitaxel, nab-
paclitaxel, and pemetrexed), the locally approved label and local practice are to be followed. 
The choice of the chemotherapy medications (as described in the following sections) will be 
determined by the investigator prior to enrollment/randomization. This choice will be made 
based on the histology of the patients (and depending on what part the study the subject is 
participating to) and as per local practice and cannot be changed afterward. Of note, the choice 
to treat non-squamous subjects with pemetrexed after the 4 induction cycles will be determined 
by the investigator according to locally approved label and local practice. 
All dosages prescribed and dispensed to the subject and all dose changes during the study must 
be recorded on the appropriate eCRF page. 
6.1.1 
Investigational and control drugs 
6.1.1.1 
Dosing regimen for Part 1: Safety run-in part 
In the safety run-in (Part 1), 3 study treatment regimens will be tested in 3 cohorts of subjects 
(cohort A, cohort B, and cohort C) as defined in  Table 6-1 . Subjects with non-squamous 
histology can be enrolled either in cohort A, B, or C. The choice of the chemotherapy 
medications in cohort A and B (see also  Figure 3-1 ) will be determined by the investigator 
prior to enrollment (as per local practice). Subjects with squamous histology must be enrolled 
in cohort C. 
Please note that canakinumab dose level (-1), canakinumab Q6W, may be investigated after 
review of the data collected for the Q3W regimen ( Section 6.5 ). 
Table 6-1 
Part 1 (safety run-in part) - Cohort A: Dose and treatment schedule 
(non-squamous subjects only) 
Study treatment 
Pharmaceutical 
Dosage Form and 
route of 
administration 
Strength 
Dose 
Frequency and/or 
regimen 
Canakinumab 
(ACZ885) 
Solution for s.c. 
injection in prefilled 
syringe 
150 mg/1 mL AND 
50 mg/0.5 mL 
200 mg 
Q3W (or Q6W) 

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Study treatment 
Pharmaceutical 
Dosage Form and 
route of 
administration 
Strength 
Dose 
Frequency and/or 
regimen 
Pembrolizumaba 
Concentrate for 
solution for i.v. 
infusion in vial 
100 mg/4 mL (25 
mg/mL) 
200 mg 
Q3W 
Lyophilized 
powder for solution 
for infusion in vial 
50 mg 
Carboplatin 
Concentrate for 
solution for i.v. 
infusion in vial 
As per local label 
and practices 
AUC 5 mg/mL*min 
Pemetrexedb 
500 mg/m2 
a Either concentrate solution or lyophilized powder formulations of pembrolizumab can be used if approved by 
local country regulations . b Pemetrexed can be given as maintenance therapy for patients with non-squamous 
NSCLC after induction treatment per investigator discretion according to local approved label and local 
practice. 
Table 6-2 
Part 1 (safety run-in part) - Cohort B: Dose and treatment schedule 
(non-squamous subjects only) 
Study Treatment 
Pharmaceutical 
Dosage Form and 
route of 
administration 
Strength 
Dose 
Frequency and/or 
regimen 
Canakinumab 
(ACZ885) 
Solution for s.c. 
injection in prefilled 
syringe 
150 mg/1 mL AND 
50 mg/0.5 mL 
200 mg 
Q3W (or Q6W) 
Pembrolizumaba 
Concentrate for 
solution for i.v. 
infusion in vial 
100 mg/4 mL (25 
mg/mL) 
200 mg 
Q3W 
Lyophilized 
powder for solution 
for infusion in vial 
50 mg 
Cisplatin 
Concentrate for 
solution for i.v. 
infusion in vial 
As per local label 
and practices  
75 mg/m2 
Pemetrexedb 
500 mg/m2 
a Either concentrate solution or lyophilized powder formulations of pembrolizumab can be used if approved by 
local country regulations. b Pemetrexed can be given as maintenance therapy for patients with non-squamous 
NSCLC after induction treatment per investigator discretion according to local approved label and local 
practice. 
Table 6-3 
Part 1 (safety run-in part) - Cohort C: Dose and treatment schedule 
(squamous or non-squamous subjects) 
Study treatment 
Pharmaceutical 
Dosage Form and 
route of 
administration 
Strength 
Dose 
Frequency and/or 
regimen 
Canakinumab 
(ACZ885) 
Solution for s.c. 
injection in prefilled 
syringe 
150 mg/1 mL AND 
50 mg/0.5 mL 
200 mg 
Q3W (or Q6W) 
Pembrolizumaba 
Concentrate for 
solution for i.v. 
infusion in vial 
100 mg/4 mL (25 
mg/mL) 
200 mg 
Q3W 

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Study treatment 
Pharmaceutical 
Dosage Form and 
route of 
administration 
Strength 
Dose 
Frequency and/or 
regimen 
Lyophilized 
powder for solution 
for infusion in vial 
50 mg 
Carboplatin 
Concentrate for 
solution for i.v. 
infusion in vial 
As per local label 
and practices 
AUC 6 mg/mL*min 
Paclitaxel 
200 mg/m2 
Pemetrexedb 
Concentrate for 
solution for i.v. 
infusion in vial 
As per local label 
and practices 
500 mg/m2 
a Either concentrate solution or lyophilized powder formulations of pembrolizumab can be used if approved by 
local country regulations. b Pemetrexed can be given as maintenance therapy for patients with non-squamous 
NSCLC after induction treatment per investigator discretion according to local approved label and local 
practice. 
6.1.1.2 
Dosing regimen for Part 2: double-blind, randomized, placebo-
controlled part 
In the double-blind, randomized, placebo-controlled part (Part 2), subjects will be randomized 
into 2 study treatment arms with canakinumab or canakinumab matching-placebo. The study 
treatment will be canakinumab/matching placebo in combination with pembrolizumab and 
platinum-based doublet chemotherapy (with or without pemetrexed). The platinum-based 
doublet chemotherapies (carboplatin plus paclitaxel/nab-paclitaxel vs. pemetrexed plus 
carboplatin/cisplatin) are dependent on the tumor histology of the subject (squamous vs. non-
squamous) as defined in  Table 6-4 . Note: subjects with adenosquamous histology can be 
treated as either squamous or non-squamous histology; see Section 6.3.2. The chemotherapy 
treatment selected must match the histology selected in the IRT system at time of randomization 
(squamous or non-squamous).  
Table 6-4 
Part 2 (double-blind, randomized, placebo-controlled part): Dose and 
treatment schedule 
Study 
treatment 
Pharmaceutica
l Dosage Form 
and route of 
administration 
Strength 
Dose 
Frequency 
and/or 
regimen 
Histology 
Canakinumab 
(ACZ885) 
Solution for s.c. 
injection in 
prefilled syringe 
150 mg/1 mL 
AND 50 mg/0.5 
mL 
200 mg 
Q3W or Q6Wb 
Squamous AND 
non-squamous 
Canakinumab 
matching-
placebo 
(ACZ885) 
0 mg/1 mL AND 
0 mg/0.5 mL 
0 mg 
Pembrolizumab
a 
Concentrate for 
solution for i.v. 
infusion in vial 
100 mg/4 mL 
(25 mg/mL) 
200 mg 
Q3W 
Lyophilized 
powder for 
solution for 
infusion in vial 
50 mg 

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Study 
treatment 
Pharmaceutica
l Dosage Form 
and route of 
administration 
Strength 
Dose 
Frequency 
and/or 
regimen 
Histology 
Carboplatin OR 
cisplatin 
Concentrate for 
solution for i.v. 
infusion in vial 
As per local 
label and 
practices 
AUC 5 
mg/mL*min 
(carboplatin) 
OR 
75 mg/m2 
(cisplatin) 
Non-squamous 
Pemetrexed 
500 mg/m2 
Carboplatin 
AUC 6 
mg/mL*min 
Squamous 
Paclitaxel OR 
nab-paclitaxel 
200 mg/m2 
(paclitaxel) OR 
100 mg/m2 
(nab-paclitaxel) 
a Either concentrate solution or lyophilized powder can be used per locally approved label and local practice; b 
Depending on RP3R (recommended phase 3 regimen) defined during safety run-in part (Part 1) 
6.1.1.3 
Dosing regimen for the Open Label Extension phase 
Subjects enrolled in the SRI part and subjects randomized to the canakinumab arm in the 
randomized part will transition into the OLE with their current treatment and dosing regimen.  
Subjects randomized to the canakinumab matching-placebo arm in the randomized part will be 
allowed to cross over to canakinumab, per investigator and subject discretion, provided they 
fulfill crossover criteria (Section 6.1.3). Subjects who cross over to canakinumab are 
recommended to start canakinumab at 200mg s.c. Q3W dosing regimen.  
6.1.1.4 
Dosing regimen post implementation of protocol amendment 06 
As of 05-Sep-2022, there are no more subjects on treatment taking pembrolizumab. All subjects 
enrolled in the SRI part have discontinued treatment. The trial was unblinded as of 25-Oct-2021 
and subjects were allowed to continue treatment with pembrolizumab and pemetrexed plus 
canakinumab (as applicable) if the investigator considered this beneficial for the subject. As of 
25-Aug-2023, there are 18 subjects on treatment, 5 of them taking canakinumab in combination 
with pemetrexed, 6 taking canakinumab alone, and 7 taking pemetrexed alone. 
Table 6-5 
Dose and treatment schedule post implementation of protocol 
amendment 05 
Study 
treatment 
Pharmaceutical 
Dosage Form 
and route of 
administration 
Strength 
Dose 
Frequency 
and/or 
regimen 
Histology 
Canakinumab 
(ACZ885) 
Solution for s.c. 
injection in 
prefilled syringe 
150 mg/1 mL 
and 50 mg/0.5 
mL 
200 mg 
Q3W (or Q6W) 
Squamous and 
non-squamous 
 
Solution for s.c. 
injection in 
prefilled syringe  
200 mg/1.33 
mL 

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Study 
treatment 
Pharmaceutical 
Dosage Form 
and route of 
administration 
Strength 
Dose 
Frequency 
and/or 
regimen 
Histology 
Pemetrexed 
Concentrate for 
solution for i.v. 
infusion in vial 
As per local 
label and 
practices 
500 mg/m2 
Q3W 
Non-squamous 
Table 6-6 
Investigational and study drug post implementation of protocol 
amendment 06 
Treatment Title 
Canakinumab (ACZ885) 
Canakinumab (ACZ885) 
Pemetrexed 
Treatment 
Description 
Canakinumab 
Canakinumab 
Pemetrexed 
Type 
biologic 
biologic 
chemotherapy 
Dose Formulation 
Solution for s.c. injection 
in prefilled syringe 
Solution for s.c. injection 
in vial  
As per local label and 
practices 
Unit Dose 
Strength(s) 
200 mg/1.33 mL 
150 mg/1 mL  
500 mg/m2 
Q3W 
Dosage Level(s) 
200 mg 
Q3W (or Q6W) 
200 mg 
Q3W (or Q6W) 
500 mg/m2 
Q3W 
Route of 
Administration 
Subcutaneous Injection 
Subcutaneous Injection 
i.v. infusion  
Use 
experimental 
experimental 
additional study drug 
IMP 
Yes 
Yes 
No 
Sourcing 
Provided centrally by the 
sponsor 
Provided centrally by the 
sponsor 
Locally sourced 
Packaging and 
Labeling 
Study treatment will be 
provided as solution for 
s.c. injection in pre-filled 
syringe. Each pre-filled 
syringe will be labeled as 
required per country 
requirement. 
Study treatment will be 
provided as solution for 
s.c. injection in vial. Each 
vial will be labeled as 
required per country 
requirement. 
As per local label and 
practices 
6.1.1.5 
Supply and administration of study treatment 
Post trial unblinding on 25-Oct-2021, canakinumab-matching placebo was no longer supplied 
nor administered.  
Supply of study treatment 
Canakinumab and canakinumab matching-placebo will be supplied by Novartis or its 
designee in the pharmaceutical form of solution for s.c. injection as ready-to-use pre-filled 
syringes. 
Post implementation of protocol amendment 05, once 150 mg/1 mL and 50 mg/0.5 mL solution 
for s.c. injection as pre-filled syringes are no longer available, canakinumab will be supplied in 
the pharmaceutical form of 200 mg/1.33 mL solution for s.c injection as ready-to-use pre-filled 
syringes (Table 6-5).  
Post implementation of protocol amendment 06, once 200 mg/1.33 mL solution for s.c. injection 
as pre-filled syringes is no longer available, canakinumab will be supplied in the pharmaceutical 

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form of 150 mg/1 mL solution for s.c. injection in vial (Table 6-6). The dose of canakinumab 
to be given in this current study part 2 (double-blind, randomized, placebo-controlled part) is 
unchanged (200 mg s.c). 
 
 
 A bioequivalence study, CACZ885A2104, demonstrated the 
bioequivalence of solution for injection in a pre-filled syringe and lyophilized form of 
canakinumab. Additionally, population PK analysis of PK data from study CACZ885N2301 
showed no effect of formulation between lyophilized form of canakinumab and solution for s.c 
injection in vial on the PK of canakinumab.
 
 
  
The 150 mg/1 mL solution for injection in vial, 150 mg/1 mL solution for injection in prefilled 
syringe and 200mg/1.33 mL solution for injection in prefilled syringe have the same 
formulation. 
An analytical comparability assessment between the 150 mg/1 mL solution for injection in vial, 
150 mg/1 mL solution for injection in the prefilled syringe, and 200 mg/1.33 mL solution for 
injection in prefilled syringe was performed which demonstrated they are comparable from a 
quality perspective. 
The drug substance is manufactured with the same process and at the same manufacturing site 
that is approved for the marketed product Ilaris 150 mg/1 mL solution for injection in vial. 
Pembrolizumab and the chemotherapies (carboplatin, cisplatin, paclitaxel, nab-paclitaxel, and 
pemetrexed) will be provided locally by the study site, subsidiary or designee as commercially 
available or centrally by Novartis, in each participating country according to local practices and 
local regulations.  
For dose and treatment schedule refer to  Figure 6-1  and  Figure 6-2, and for allowable visit 
windows refer to  Table 8-1.  
Administration of study treatment 
Canakinumab or canakinumab matching-placebo will be administered by study site personnel 
via s.c. injections once every 3 weeks or 6 weeks as determined in part 1 (safety run-in part).  
The administration and infusion durations of the study drugs (pembrolizumab, platinum-based 
doublet chemotherapy, and pemetrexed) should follow the locally approved label and local 
practice. 
All study drugs should be administered sequentially, on the same day as reported 
in  Figure 6-1  and  Figure 6-2 . 
CCI
CCI

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Figure 6-1 
Safety run-in part: dose and treatment schedule 
  
Note: The infusion times reported for chemotherapies, and pembrolizumab (30 min: -5 min/+10 min), 
are suggestions only. The locally approved labels and local practice are to be followed. 

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Figure 6-2 
Double-blind, randomized, placebo-controlled part including optional 
crossover in the OLE phase and post implementation of protocol 
amendment 05: dose and treatment schedule 
  
aRP3R defined during safety run-in. Placebo (PBO) is not applicable during the OLE phase. Post trial 
unblinding on 25-Oct-2021, canakinumab-matching placebo was no longer supplied nor administered. 
Note: The infusion times reported for chemotherapies, and pembrolizumab (30 min: -5 min/+10 min), 
are suggestions only. The locally approved labels and local practice are to be followed. 

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6.1.2 
Additional study treatments 
All subjects receiving pemetrexed as part of study treatment (non-squamous NSCLC histology 
only) should be premedicated with folic acid, vitamin B12 and glucocorticoids as required per 
locally approved label and local practice. 
Alternative premedication dosing or schedule may be administered as per locally approved label 
and local practice. 
6.1.3 
Guidelines for continuation of treatment 
Guidelines for management of toxicities and doses modifications instructions  
Please refer to  Section 6.5.3 . 
Criteria for continuation of study treatment from induction to maintenance 
All subjects are expected to receive 4 cycles of induction treatment: canakinumab (or 
canakinumab matching-placebo) in combination with pembrolizumab plus platinum-based 
doublet chemotherapy. After induction, all subjects are expected to continue in maintenance 
with canakinumab/matching placebo in combination with pembrolizumab. 
Only subjects with non-squamous histology who achieve stable disease (SD) or better 
radiological response after induction treatment will be eligible to continue pemetrexed during 
maintenance.  
However, treatment beyond RECIST 1.1 progressive disease is allowed, please refer to 
Section 6.1.4.1  for details. 
Criteria for crossover from canakinumab matching-placebo arm to 
canakinumab in the OLE phase 
During the OLE phase, subjects randomized to the canakinumab matching placebo arm will be 
allowed to cross over to canakinumab, if the investigator determines this is in the subject’s best 
interest and per subject discretion (Section 3). Crossover is optional. 
A subject is eligible to cross over if the following criteria are met:  
1. No evidence of active infection – subjects with active infections must wait until the 
infection is resolved and antibiotic therapy (if initiated) is completed prior to crossover. 
Note: subjects with localized condition unlikely to lead to a systemic infection, e.g. 
chronic nail fungal infection are eligible. 
2. Subjects with neutropenia and/or thrombocytopenia must wait until these are resolved to ≤ 
grade 2  
3. No suspected or proven immunocompromised state, as per exclusion criterion 8 
4. AST/ALT < 3.0 x ULN  
5. bilirubin < 3.0 x ULN 
6. pancreatitis ≤ grade 2 
Subjects who do not fulfill these requirements and subjects who do not cross over to 
canakinumab within 12 weeks from time of investigational site unblinding, will transition into 

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the OLE with their current treatment only (i.e. pembrolizumab and maintenance chemotherapy, 
where applicable, and not canakinumab matching placebo).  
6.1.4 
Treatment duration 
Subjects will continue to receive study treatment until RECIST 1.1 disease progression is 
radiologically documented by investigator assessment (exceptions are described in  
Section 6.1.4.1), unacceptable toxicity that precludes further treatment, treatment is 
discontinued at the discretion of the investigator, subject withdrawal of consent, pregnancy, lost 
to follow-up, or death (Section 9.1.1 ).  
If pembrolizumab and all other study chemotherapy drugs are permanently discontinued 
because of unacceptable toxicities, the investigator can continue canakinumab/matching-
placebo alone until RECIST 1.1 disease progression as per investigator, as long as:  
• There is no radiological evidence of disease progression by RECIST 1.1, and 
• The subject is continuing to benefit from investigational drug treatment as assessed by 
the investigator, and 
• The subject is tolerating the treatment and clearly understands the risks associated with 
continuing treatment with canakinumab/matching-placebo, and 
• Separate informed consent for canakinumab/matching-placebo alone until disease 
progression per RECIST 1.1 is provided by the subject.  
For subjects randomized in part 2, no cross-over treatment from canakinumab matching-
placebo treatment arm to canakinumab treatment arm will be allowed. However, if the OLE 
phase is initiated, subjects randomized to the canakinumab matching-placebo arm will be 
allowed to cross over to canakinumab if the investigator determines this is in the subject’s best  
interest and per subject discretion, provided they fulfill crossover criteria. Crossover is optional. 
6.1.4.1 
Treatment beyond disease progression  
Subjects who derive clinical benefit are permitted to continue study treatment beyond initial 
RECIST 1.1 disease progression as per investigator provided they meet all of the following 
criteria: 
• Absence of confirmed PD by iRECIST (iCPD) 
• Continuation of study treatment beyond initial RECIST 1.1 disease progression will not 
delay an imminent intervention to prevent serious complications of disease progression 
• Subject performance status is stable 
• Subject exhibits adequate tolerance to study treatment as defined by no grade 3 or 4 
toxicities within the past 21 days on current therapy 
• Separate informed consent for study treatment beyond disease progression per RECIST 
1.1 is provided by the subject  
If the above criteria are met, subjects are permitted to continue study treatment until immune 
confirmed disease progression (iCPD) per iRECIST as per investigator. Pembrolizumab 
treatment duration is a maximum of 35 administrations.  
Canakinumab/matching placebo as single agent after RECIST 1.1 PD is not allowed.  

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If pembrolizumab is discontinued before disease progression per RECIST 1.1, treatment with 
canakinumab/matching placebo with chemotherapy (during induction or maintenance) is not 
allowed beyond RECIST 1.1 PD.  
Study treatment beyond iRECIST confirmed disease progression (iCPD) may be allowed if the 
investigator determines it is in the best interest of the subject. In such cases, approval by a 
Novartis study physician is required. 
All study procedures have to be followed as outlined in Section 8. Eligibility for the subject 
continuing study treatment beyond RECIST 1.1 PD will be documented in the eCRF.  
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
In general, the use of any concomitant medications/non-drug therapies deemed necessary for 
the care of the subject (e.g. G-CSF, anti-emetics, anti-diarrhea) is permitted except when 
specifically prohibited (Section 6.2.2). For pembrolizumab and study chemotherapy drugs, 
please refer to the locally approved label. 
The investigator should instruct the subject to notify the study site about any new medications 
and/or non-drug therapies/procedures he/she takes after signing the informed consent. All 
medications 
including 
herbal/natural 
medications 
and 
significant 
non-drug 
therapies/procedures (including surgeries, physical therapy and blood transfusions) taken 
within 28 days of screening and administered after the subject has signed informed consent 
must be listed on the appropriate eCRF pages. 
Subjects taking concomitant medication chronically should be maintained on the same dose and 
dose schedule throughout the study period, as medically feasible. The days of PK blood 
sampling should be representative of the other study days with regard to the use of the 
chronically administered concomitant medications. However, if a concomitant medication is 
used intermittently during the study, this medication should be avoided on the days of PK 
sampling, if medically feasible (Section 6.2.2). 
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the subject was enrolled into the study must be recorded 
on the appropriate eCRF page.  
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medications. If in doubt, the investigator should contact the Novartis medical monitor before 
enrolling a subject or allowing a new medication to be started. If the subject is already enrolled, 
contact Novartis to determine if the subject should continue participation in the study. 
Note: For Drug-Drug interaction (DDI) potential, please refer to  Section 1.1.3  for DDI 
potential between canakinumab and combination partners. 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
6.2.1.1.1 Permitted radiotherapy 
Limited-field palliative radiation for bone pain is permitted. 

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Radiotherapy should not be delivered to a target lesion and it should not encompass more than 
25% of irradiated bone marrow ( Section 16.1). If palliative radiotherapy is initiated after the 
start of study treatment, the reason for its use must be clearly documented and progression as 
per RECIST 1.1 must be ruled out. No dose modification of study treatment is needed during 
palliative radiotherapy. 
After documented RECIST 1.1 PD, radiation therapy is allowed.  
6.2.1.1.2 Permitted concomitant medications 
Medications required to treat AEs, manage cancer symptoms, concurrent diseases and 
supportive care agents, such as pain medications, anti-emetics and anti-diarrheal are 
allowed. Potential drug interactions between study drugs and concomitant medications should 
always be taken into consideration. 
Except for paclitaxel/nab-paclitaxel, none of the chemotherapy agents (carboplatin, cisplatin, 
and pemetrexed) have major CYP enzyme involvement and are primarily eliminated by the 
kidney. The metabolism of paclitaxel/nab-paclitaxel is catalyzed by CYP2C8 and CYP3A4. 
Caution should be exercised when administering paclitaxel/nab-paclitaxel concomitantly with 
medicines known to inhibit or induce either CYP2C8 or CYP3A4. See Table 16-18 for drugs 
to be used with caution with paclitaxel/nab-paclitaxel while on study. 
CYP450 expression may be normalized when potent cytokine inhibitory therapy, such as 
canakinumab, is introduced (see Section 1.1.3.1). This is clinically relevant for CYP450 
substrates with a narrow therapeutic index. Caution should be exercised when administering 
these agents (see Table 16-19) concomitantly with canakinumab. 
Given the potential DDI via cytokine modulation by canakinumab, subjects who are on warfarin 
or warfarin-like treatment with narrow therapeutic index, should have their international 
normalized ratio (INR) measured locally and warfarin or warfarin-like treatment dose adjusted 
accordingly within one month from starting study treatment. No DDI is expected between 
warfarin and the study chemotherapy drugs, as these drugs are eliminated by different 
elimination pathways (warfarin by CYP2C9, paclitaxel/nab-paclitaxel by CYP2C8 and 
CYP3A4, and other chemotherapy agents mainly via kidney) and are not an inhibitor/inducer 
of each other's metabolism. 
6.2.2 
Prohibited medication 
6.2.2.1 
Prohibited concomitant medications for canakinumab/matching 
placebo 
Use of any treatments below are NOT allowed after the start of study treatment due to potential 
increase in immunosuppressant related concomitant conditions. They are prohibited for the 
duration of the study and for at least 130 days after discontinuation of canakinumab/matching-
placebo.  
Note: steroids are allowed at any dose/duration when necessary to treat immune-related adverse 
events (irAE). Investigators should closely monitor subjects for risk of infections. 
• Any anti retro-virals and / or any biologic drugs targeting the immune system (e.g., TNFa 
blockers, anakinra, rituximab, abatacept, tocilizumab) 

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• Treatment with any immune modulating agent in doses with systemic effects e.g.:  
• Prednisone > 20 mg (or equivalent) oral or intravenous daily for > 14 days; 
• Prednisone > 5 mg and ≤ 20 mg (or equivalent) daily for > 30 days; 
• Equivalent dose of methotrexate > 15 mg weekly 
• Topical, inhaled or local steroid use in doses that are not considered to cause systemic 
effects are permitted 
• Steroids for pre-medication related to chemotherapy are permitted as per the locally 
approved label and local practice 
• Live vaccines within 90 days of study treatment and after initiation of study treatment. 
Subjects must be discontinued from the trial if administered any live vaccine during the 
course of the study. Note: Inactivated vaccines are allowed. 
The following treatments are NOT allowed after the start of study treatment and until the end 
of study treatment: 
• Any additional investigational drugs, devices, chemotherapy, or any antineoplastic 
therapies that may be active against cancer. 
6.2.2.2 
Prohibited concomitant medications for pemetrexed 
Subjects taking Non Steroidal Anti-Inflammatory Drugs (NSAIDs) or salicylates will not take 
the NSAIDs or salicylates (other than an aspirin dose ≤1.3 grams per day) for 2 days before, the 
day of, and 2 days after receiving pemetrexed. Subjects taking NSAIDs or salicylates with a 
long half-life (for example, naproxen, piroxicam, diflunisal, or nabumetone) will not take the 
NSAIDs or salicylates for 5 days before, the day of, and 2 days after pemetrexed. 
6.3 
Subject numbering, treatment assignment, randomization 
The enrollment (safety run-in part) and randomization (randomized part) of the study has been 
completed. The trial was unblinded on 25-Oct-2021. The below Section 6.3.1 Subject 
numbering and Section 6.3.2 Treatment assignment, randomization are no longer applicable.  
6.3.1 
Subject numbering 
Each subject is identified in the study by a Subject Number (Subject No.), that is assigned when 
the subject is first entered into screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential subject 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the ICF, the subject is assigned the next sequential Subject No. available. 
The investigator or designated staff will contact the Interactive Response Technology (IRT) and 
provide the requested identifying information to register the subject. Once assigned, the Subject 
No. must not be reused for any other subject and the Subject No. for that individual must not 
be changed. If the subject fails to be enrolled (safety run-in) or randomized or start treatment 
for any reason, the reason will be entered into the appropriate eCRF page. 

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6.3.2 
Treatment assignment, randomization 
Prior to dosing, for all subjects who fulfill all inclusion/exclusion criteria, the investigator or 
his/her delegate will log on to the IRT system and confirm that the subject fulfills all the 
inclusion/exclusion criteria by completing the key eligibility criteria checklist embedded in the 
system. Note: Cycle 1 Day 1 visit and dosing should occur no later than 3 days after IRT 
registration. 
The choice of the chemotherapy medications ( Figure 3-1 and  Figure 3-2) will be determined 
by the investigator prior to enrollment/randomization based on histology of the patient and as 
per local practice. 
In the safety run-in part (part 1), no randomization will be performed. The assignment of a 
subject to a particular cohort will be coordinated by the investigator based on his/her choice of 
the chemotherapy medication. 
In the double-blind, randomized, placebo-controlled part (part 2), subjects will be randomized 
in a 1:1 ratio to one of the 2 treatments arms ( Section 4 and  Section 6.1). The IRT system will 
generate a randomization number to the subject and provide a unique medication (kit) number 
for dispensation to the subject. The randomization number will not be communicated to the 
investigator or his/her delegate.  
Randomization will be stratified based on PD-L1 status (Tumor Proportion Score (TPS) <1% 
vs. ≥1%), geographic region (East Asia vs. North America + Western Europe vs. Rest of the 
World), and histology (squamous vs. non-squamous). PD-L1 unevaluable subjects will be 
included with the TPS <1% group. Random permuted blocks scheme will be used for this study. 
Subjects with adenosquamous histology should be stratified as squamous or non-squamous 
based on the predominant histology or the histology chosen by the treating physician for 
determining treatment, if medically justified. 
A separate medication randomization list will be produced by the IRT provider under the 
responsibility of Novartis Global Clinical Supply (GCS) using a validated system that 
automates the random assignment of subject numbers to medication packs containing the 
investigational drug. 
Subject transition to OLE and crossover to canakinumab, if applicable, will be performed on 
the IRT system. 
6.4 
Treatment blinding 
Part 1: Safety run-in part 
Not applicable. 
Part 2: Double-blind, randomized, placebo-controlled part 
Only the investigational drug (canakinumab) will be blinded in this study. 
At the time of the final PFS analysis, both PFS and 1st IA for OS will be performed by an 
independent statistician and reviewed by a data monitoring committee (DMC). Unblinded 
results from the final PFS analysis and IA for OS will not be communicated to the Sponsor's 

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clinical team or to any party involved in the study conduct (apart from the independent 
statistician and DMC members) until the DMC has determined that either:(i) final PFS or 
interim OS analyses has crossed the pre-specified boundary for efficacy or (ii) the study needs 
to be terminated due to any cause including safety reasons. If the final PFS and 1st IA for OS 
are not statistically significant, the 2nd IA for OS will also be done by an independent statistician. 
If the final PFS analysis is statistically significant, the sponsor’s clinical team will be unblinded 
and will perform the second OS interim and/or final OS analyses. Subjects, investigator, site 
personnel, persons performing the assessments, will remain blinded to the identity of the 
treatment from the time of randomization until OS results are statistically significant at one of 
the interim or final analyses.  
If OS reaches statistical significance at one of the interim or final analyses, all subjects on 
treatment or in safety/efficacy follow up will transition to the OLE phase following unblinding 
of investigational sites to treatment allocation. If OS is not statistically significant at final 
analysis but PFS was statistically significant at primary analysis, OLE will be initiated after 
final OS analysis, following unblinding of investigational sites (Section 3). To limit the impact 
of unblinding on the scientific validity of the study results, individual subject unblinding is 
prohibited. Unblinding will only be permitted in the case of subject emergencies (Section 6.6.2), 
for regulatory reporting purposes. Unblinding is also permitted under exceptional circumstances 
if treatment assignment is critical to determine the optimal subsequent treatment for the subject 
and only if post-progression therapy with an IL-1ß inhibitor is being considered. In case of 
unblinding for determination of subsequent treatment, approval by a Novartis study physician 
is required.  
Randomization data are kept strictly confidential until the time of unblinding, and will not be 
accessible by anyone else involved in the study with the following exceptions: independent 
biostatistician and programmer who will perform Data Monitoring Committee (DMC) analysis, 
PK bioanalyst, modeler and modeling programmer. The study bioanalyst will receive a copy of 
the randomization schedule to facilitate analysis of the samples. The independent biostatistician 
and programmer and bioanalyst will keep treatment allocation information confidential until 
clinical database lock.  
The trial was unblinded on 25-Oct-2021.  
6.5 
Dose escalation and dose modification 
6.5.1 
Dose confirmation guidelines 
6.5.1.1 
Starting dose 
The starting dose of canakinumab is 200 mg s.c. Q3W for the safety run-in part (Section 6.1.1.1).  
The recommended phase 3 dose regimen (RP3R) from the safety run-in part will be the starting 
dose for the part 2 (double-blind, randomized, placebo-controlled part) . 
6.5.1.2 
Guidelines for safety and tolerability decisions and determination of 
recommended Phase 3 dose Regimen (RP3R) 
The primary objective is to establish the recommended Phase 3 dose regimen (RP3R) of 
canakinumab and pembrolizumab in combination with: pemetrexed and carboplatin in cohort 

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A (non-squamous subjects); pemetrexed and cisplatin in cohort B (non-squamous subjects), and 
paclitaxel and carboplatin in cohort C (squamous or non-squamous subjects). The primary 
variable is the incidence of dose limiting toxicities (DLTs) in the first 42 days of study treatment. 
Determination of the RP3R of canakinumab will be based upon the estimation of the probability 
of DLT for the first 42 days for subjects in the dose-determining set. 
For the purposes of dose de-escalation decisions, each cohort will consist of approximately 9 
enrolled subjects who will be treated at the specified dose level in order to have at least 6 
evaluable subjects for the dose decision. The first dose level will be full dose of canakinumab 
and full dose of other components with possibility to de-intensify the administration of 
canakinumab only. Additional dose levels for dose de-escalation in subsequent cohorts will 
include provisional dose levels of canakinumab given less frequently, e.g. every 6 weeks (Q6W) 
instead of every 3 weeks (Q3W) with dose of other components maintained at the starting full 
dose. 
Dose de-escalation decisions and RP3R decision 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 v5.0 Grade ≥ 2 toxicity data during first 42 days of treatment, and 
Pharmacokinetics (PK) data from the evaluable subjects. Dosing regimen decisions are guided 
by the escalation with overdose control (EWOC) principle (Rogatko et al 2007). The 
recommended canakinumab dose regimen for the next cohort of subjects will be guided by the 
Bayesian logistic regression model (BLRM) with EWOC principle ( Section 16.3 ). 
The adaptive Bayesian methodology provides an estimate of all dose levels in each cohort: 
canakinumab in combination with pembrolizumab, pemetrexed and carboplatin; canakinumab 
in combination with pembrolizumab, pemetrexed and cisplatin; or canakinumab in combination 
with pembrolizumab, paclitaxel and carboplatin, and incorporates all DLT information at all 
dose levels for this estimation. 
If the first 2 subjects in a cohort experience a DLT, further enrollment to that cohort will stop 
and the BLRM will be updated with this new information. Re-evaluation of the available safety 
and PK data will occur. By incorporating information gained at the preceding dose levels, 
additional subjects may be enrolled at this dose level or a lower dose level as agreed by 
Investigators who enrolled subjects and Novartis personnel and if the BLRM predicts that the 
risk that this lower dose exceeds the toxicity remains below 25% (EWOC). Re-escalation may 
then occur if data in subsequent cohorts supports it (EWOC criteria are satisfied) and 
Investigators who enrolled subject and Novartis personnel agree. 
Evaluable subjects will be defined as below: 
• Have received full dose of pembrolizumab for at least 2 cycles and at least 75% of the 
planned dose of the 2 cycles of chemotherapy, and 
• Have received at least 2 doses of canakinumab (for Q3W dosing regimen cohort) or at 
least 1 dose of canakinumab (for Q6W dosing regimen cohort in case the canakinumab 
dose is de-escalated to Q6W) , and 
• Have been followed for the first 42 days (2 cycles) for adverse events starting Cycle 1 Day 
1. 
The RP3R is identified when the following conditions are met in each cohort: 
• At least 6 evaluable subjects have been treated at this dose and observed for 42 days and 

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• This dose satisfies EWOC criteria and 
• The selected dose regimen is recommended either per the model or by review of all 
clinical data by Dose Level Review Team (DLRT) in a dose decision meeting. 
6.5.1.3 
Provisional dose levels 
Table 6-7 
Provisional dose levels 
Dose level (DL) 
Canakinumab  
(s.c. injection) 
Pembrolizumab 
(i.v. infusion) 
Chemotherapy drugs (i.v. infusion) 
DL1 
200 mg Q3W 
200 mg Q3W 
pemetrexed 500 mg/m2 plus carboplatin 
AUC 5 
OR 
pemetrexed 500 mg/m2 plus cisplatin 75 
mg/m2  
OR 
paclitaxel 200 
mg/m2 plus carboplatin AUC 6 
DL-1 
200 mg Q6W 
No change, same as 
above 
No change, same as above 
6.5.1.4 
Implementation of dose regimen decisions 
To implement dose regimen decisions, the available toxicity information (including adverse 
events and laboratory abnormalities that are not DLTs), the recommendations from the BLRM, 
and the available PK/PD (IL-1β) information will all be evaluated by the investigators who 
enrolled subjects and Novartis study personnel (including the study physician and statistician) 
during a dose decision meeting. Drug administration at the next lower dose level (canakinumab 
DL-1) may not be administered if the investigator receives written confirmation from Novartis 
indicating the results of the previous dose level were evaluated and that it is the recommended 
regimen. 
Novartis will communicate the agreed dose decision in writing to the Dose Level Review Team 
(DLRT), data monitoring committee (DMC), steering committee (SC), and all participating 
investigators. Additional communication in a form of teleconference, webcast, or investigator 
meeting may be implemented if needed. 
6.5.1.5 
Implementation of dose escalation decisions 
Not applicable 
6.5.1.6 
Intra-Subject dose escalation 
Intra-subject dose escalation is not permitted at any time. 
6.5.2 
Definitions of dose limiting toxicities (DLTs) 
Dose-limiting toxicities will be collected and used in the safety run-in part of the study (Part 1). 
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value 
assessed as unrelated to disease, disease progression, inter-current illness, or concomitant 
medications that occurs within the first 42 days of treatment with canakinumab and 

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pembrolizumab in combination with additional protocol specified chemotherapy and meets any 
of the criteria included in Table 6-8. The National Cancer Institute Common Terminology 
Criteria for Adverse events (NCI CTCAE v5.0) will be used for all grading. In addition to DLTs, 
the decision about the recommended Phase 3 regimen (RP3R) will be based on a synthesis of 
all relevant data available including all CTCAE v5.0 Grade ≥ 2 and PK data during the first 42 
days of combination treatment from evaluable subjects. For the purpose of dose de-escalation 
decisions, DLTs will be considered and included in the BLRM.  
The investigator must notify the sponsor immediately of any DLT. 
Table 6-8 
Criteria for defining dose-limiting toxicities 
TOXICITY 
DLT CRITERIA (NCI CTCAE v5.0 will be used for grading) 
Hematological 
• 
Grade 4 neutropenia (for >7 consecutive days). For paclitaxel combinations: for > 
14 days* 
• 
Grade 4 febrile neutropenia 
• 
Grade 4 anemia 
• 
Grade 4 thrombocytopenia (<25,000/mm3) any duration. For paclitaxel 
combinations: >7 days or associated with clinically significant bleeding (i.e. life 
threatening and invasive intervention indicated) # 
• 
Grade 3 thrombocytopenia with clinically significant bleeding (i.e. life threatening 
and invasive intervention indicated) regardless of duration or requirement for 
transfusion 
Severe infection 
• 
Drug-related grade 4 
Hepato-biliary 
• 
Grade 4 bilirubin elevation 
• 
For subjects with normal baseline AST and ALT values: AST or ALT > 8.0 × ULN 
• 
For subjects with normal baseline AST and ALT and normal baseline bilirubin 
value: AST or ALT > 3.0 × ULN combined with total bilirubin > 2.0 × ULN without 
evidence of cholestasis 
• 
For subjects with abnormal baseline AST or ALT or abnormal baseline bilirubin 
value: [AST or ALT > 2 × baseline AND > 3.0 × ULN] OR [AST or ALT > 8.0 x 
ULN], combined with [TBIL > 2 × baseline AND > 2.0 × ULN] without evidence of 
cholestasis 
Gastrointestinal 
• 
Nausea and vomiting ≥ Grade 3 for > 3 days despite optimal anti-emetic therapy. 
• 
 ≥ Grade 3 diarrhea for > 5 days despite optimal antidiarrheal treatment (which 
could include steroids). 
Pancreas 
• 
Symptomatic serum amylase or lipase elevation, medical intervention required 
(Pancreatitis Grade 3 or higher) 
Hypertension 
• 
≥ Grade 3 hypertension related to the study medication if it persists > 7 days 
despite optimal anti-hypertensive treatment 
• 
Grade 4 hypertension of any duration 
Cardiac 
• 
≥ Grade 3 cardiac event that is symptomatic or requires medical intervention 
Pneumonitis 
• 
Grade 2 pneumonitis if it persists > 7 days despite treatment with corticosteroids. 
• 
 ≥ Grade 3 pneumonitis of any duration 
Immune-related 
toxicities 
(except 
pneumonitis) 
• 
Grade 3 immune-related toxicities that persist > 14 days with same severity despite 
treatment with corticosteroids. 
• 
Grade 4 immune related toxicities of any duration 
• 
≥ Grade 3 infusion related reaction 
Other Adverse 
Events 
Other clinically significant adverse events: 
• 
≥ Grade 3 adverse events that has not been previously identified for 
pembrolizumab/platinum-based doublet chemotherapy and/or canakinumab. 

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TOXICITY 
DLT CRITERIA (NCI CTCAE v5.0 will be used for grading) 
• 
 ≥ Grade 3 AEs that are known to occur with pembrolizumab/platinum-based 
doublet chemotherapy and/or canakinumab, but cannot be controlled using the 
recommended product-specific management guidelines or leads to ˂50% of 
planned exposure of study medications 
• 
Other clinically significant toxicities, including a single event or multiple occurrences 
of the same event that lead to a dosing delay of > 12 weeks should be considered 
to be DLTs by the Investigators and Novartis, even if not Grade 3 or higher. 
Events which will NOT be considered as DLT for the purpose of this protocol:Clinically insignificant laboratory 
values ≤ Grade 2. For laboratory values ≥ Grade 3, the maximum allowable time limit for correction of 
electrolyte abnormalities to ≤ Grade 1 is 72 hr. Events secondary to disease progression and concomitant 
medications should not be considered DLTs. Decision about RP3R will be made by Dose Level Review Team 
(DLRT) based on a synthesis of all relevant data available from all dose levels evaluated in the ongoing study 
including safety information, DLTs , all CTCAE v5.0 Grade ≥ 2 toxicity, PK, and PD data during the first 42 days 
of combination treatment from evaluable subjects. *Subjects taking paclitaxel can take more than 10 days to 
recover neutrophils count to > 1000/ mm 3 (Lalami et al 2006) # Subjects taking paclitaxel can take~4-6 days to 
recover from thrombocytopenia (Kuter 2015). 
6.5.3 
Dose modifications 
For subjects who do not tolerate the protocol-specified dosing schedule, dose change are 
permitted and must follow the following principles: 
• Canakinumab dose reductions are not permitted, only increase in the dosing interval is 
allowed (from Q3W to Q6W and from Q6W to Q9W only). Once the dosing interval is 
increased it cannot be reverted to the previous dosing interval ( Section 6.5.3.1). 
• Pembrolizumab and chemotherapy agents (carboplatin, cisplatin, paclitaxel, nab-paclitaxel, 
and pemetrexed) will follow locally approved labels (if pembrolizumab is not yet approved 
in your country, refer to Section 16.7 and local clinical practice. 
• If the chemotherapy drugs need to be interrupted due to toxicity, canakinumab/matching-
placebo and pembrolizumab must also be interrupted. 
• If pembrolizumab or canakinumab/matching-placebo are interrupted due to toxicity, the 
other agents may also be interrupted, per investigator discretion. 
• Reduction of one chemotherapy agent and not the other agent is appropriate if, in the opinion 
of the investigator, the toxicity is clearly related to one of the treatments.  
• Pembrolizumab may be interrupted for a maximum of 12 weeks.  
• If one of the study drugs is permanently discontinued the other study drugs ongoing can be 
continued, for treatment beyond RECIST 1.1 disease progression refer to Section 6.1.4.1.  
All dose changes in any study drugs must be recorded on the appropriate eCRF page. 
6.5.3.1 
Guidelines for mandatory dose modifications for 
canakinumab/matching-placebo 
Mandatory dose interruption or discontinuation of canakinumab/matching-placebo in the 
management of adverse reactions are summarized in  Table 6-9. Clinical judgment of the 
treating physician should guide the management plan of each subject based on individual 
benefit/risk 
assessment. 
However, 
for 
events 
requiring 
a 
discontinuation 
in  
Table 6-9, canakinumab/matching-placebo must be discontinued. If a subject experiences 
several toxicities and there are conflicting recommendations, the most conservative dose 

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adjustment recommended should be followed (dose reduction appropriate to the most severe 
toxicity). 
If pembrolizumab and all other study chemotherapy drugs are permanently discontinued 
because of unacceptable toxicities, the investigator can continue canakinumab/ matching-
placebo alone until RECIST 1.1 disease progression ( Section 6.1.4 ). If canakinumab is 
interrupted for more than 12 weeks or a subject misses more than two doses of 
canakinumab/matching placebo due to canakinumab -related toxicities (whichever is longer), 
canakinumab/matching placebo must be permanently discontinued. 
Unscheduled local laboratory assessments may be performed if medically indicated to 
document a (potential) adverse event or when the treating physician cannot wait for central 
laboratory results for decision making (e.g. dose modifications). In this particular situation, if 
possible, the blood sample obtained at the same timepoint should be submitted to the central 
laboratory for analysis in parallel with local analysis. 
Table 6-9 
Criteria for mandatory dose interruption and re-initiation for 
canakinumab/matching-placebo for adverse drug reactions 
Worst toxicity 
(CTCAE v5.0) during a cycle of therapy 
Mandatory dose schedule modifications for 
canakinumab/ matching-placebo 
General guidance for adverse events considered to be related to canakinumab (to be followed whenever 
no other specific guidance is described in this table) 
Grade 1/ Grade 2 
Maintain dose level 
Grade 3 
Interrupt dose until resolved to ≤ Grade 2, then increase 
canakinumab/matching-placebo dosing intervala 
Grade 4 
Permanently discontinue canakinumab/matching-placebo 
Exceptions to the above general guidanceg 
Neutropenia (ANC) 
Grade 2 (ANC < 1500 - 1000/mm3) 
Interrupt until grade 1 or less then maintain dose 
Grade 3 (ANC < 1000 - 500/mm3)/ Grade 4 
(ANC < 500/mm3) 
Interrupt until resolved to ≤ Grade 1, then: 
• 
For subjects receiving chemotherapy, maintain 
canakinumab/matching-placebo dosing interval, only 
delay canakinumab dose to match chemotherapy dosing 
• 
After permanent discontinuation of chemotherapy, 
increase canakinumab/matching-placebo dosing 
interval.a 
Grade 4 (ANC < 500/mm3) for >7 consecutive 
days. 
For paclitaxel/ nab-paclitaxel combinations: for 
> 14 days 
Permanently discontinue canakinumab/matching-placebo 
Grade 4 Febrile neutropenia  
• 
Permanently discontinue canakinumab/matching-placebo 
Thrombocytopenia 
Grade 3 (PLT < 50,000 - 25,000/mm3) 
Interrupt dose until resolved to ≤ Grade 1, then: 
• 
If resolved in ≤ 7 days, then maintain dose level 
• 
If resolved in > 7, permanently discontinue 
canakinumab/matching-placebo 
Serum creatinine 
Grade 3 
Interrupt dose until resolved to ≤ Grade 2 or baseline, then 
re-start at the same dose 

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Worst toxicity 
(CTCAE v5.0) during a cycle of therapy 
Mandatory dose schedule modifications for 
canakinumab/ matching-placebo 
• 
If not resolved within 14 days, then permanently 
discontinue canakinumab/matching-placebo 
Isolated total bilirubin elevationb 
Any elevation > ULN: 
• 
Fractionate bilirubin, evaluate for cholestatic liver injury 
(ALP) or alternative causes of bilirubin elevation (e.g. 
disease progression [imaging]). Treat alternative causes 
according to local institutional guidelines. 
Grade 2 > 1.5 - 3.0 x ULN 
• 
Maintain treatment. Repeat LFTs within 48-72 hours, 
then monitor LFTs weekly until resolution to ≤ Grade 1 or 
to baseline. 
Grade 3 > 3.0 - 10.0 x ULNc 
Interrupt treatment. Repeat LFTs within 48-72 hours, then 
monitor LFTs weekly until resolution to ≤ Grade 1 or to 
baseline.  
• 
If resolved in ≤ 14 days, maintain dose level 
• 
If resolved in > 14 days, then increase 
canakinumab/matching-placebo dosing intervalsa 
Grade 4 > 10.0 x ULNc 
• 
see footnotef - otherwise discontinue study treatment 
Isolated AST or ALT elevationb 
With normal baseline AST/ALT: 
  
Grade 1 > ULN - 3.0 x ULN 
Maintain dose level 
Grade 2> 3.0 - 5.0 x ULN 
Maintain dose level. 
Repeat LFTs within 48-72 h; if still abnormal then monitor 
LFTs at least weekly, until resolved to ≤ 3.0 x ULN e 
Grade 3: AST or ALT > 5.0 - 10.0 x ULN 
Interrupt dose. Repeat LFTs within 48-72 h; monitor LFTs at 
least weekly, until resolved to ≤ 3.0 x ULN. Then: 
• 
If resolved in ≤ 14 days, maintain dose level 
• 
If resolved in > 14 days, then increase 
canakinumab/matching-placebo dosing intervalsa. 
Grade 3: AST or ALT > 10.0 - 20.0 x ULN 
Interrupt canakinumab/matching-placebo. Repeat LFTs 
within 48-72 h; monitor LFTs at least weekly until resolved to 
≤ baseline, then increase canakinumab/matching-placebo 
dosing intervals a.. 
Grade 4: AST or ALT > 20.0 x ULN 
Discontinue canakinumab/matching-placebo. Repeat LFTs 
within 48-72 h; monitor LFTs at least weekly until resolved to 
≤ baseline. 
With abnormal baseline ALT/AST (up to Grade 
1: ≤ 3.0 x ULN): 
  
• ALT/AST > 2.0 x baseline AND > 5.0 x ULN 
• Interrupt treatment. Repeat LFTs within 48-72 hours, then 
monitor LFTs weekly until recovery to baseline. If 
resolved in ≤ 14 days, maintain dose level; if resolved in 
> 14 days, increase canakinumab/matching-placebo 
dosing intervals a. 
• ALT/AST > 3.0 x baseline AND >10 x ULN 
• Interrupt treatment. Repeat LFTs within 48-72 hours, then 
monitor weekly until resolved to baseline, then increase 
canakinumab/matching-placebo dosing intervals a. 
• Grade 4: AST or ALT (>20 x ULN) 
• Permanently discontinue study treatment. 
AST/ALT increase associated with concomitant total bilirubin increaseb 
With normal baseline LFTs: 
  

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Worst toxicity 
(CTCAE v5.0) during a cycle of therapy 
Mandatory dose schedule modifications for 
canakinumab/ matching-placebo 
AST or ALT (>3.0xULN) associated with 
concomitant total bilirubin >2.0 x ULN without 
evidence of cholestasisd (unless Gilbert 
syndrome) 
Interrupt study treatment. Assess if case is true DILI.f 
If DILI confirmed - Permanently discontinue  
If Not DILI – interrupt treatment. Treat the identified cause 
according to institutional guidelines. Repeat LFTs within 48-
72 hours, then monitor weekly, till enzyme levels resolve to 
≤Grade 1 or Baseline. 
*Refer to  Section 6.5.4.2  for additional follow-up of potential 
drug induced liver injury cases as applicable. 
With abnormal baseline LFTs: 
  
ALT or AST >3 x baseline ,OR ALT or AST >8 
x ULN {whichever is lower] combined with total 
bilirubin >2.0x ULN  
After recovery, re-administration of study treatment could be 
considered only if Investigator assesses benefit to outweigh 
the risk. Any decision regarding re-administration of study 
drug/s and dose regimen, should be discussed with the 
Novartis medical and safety team. Refer 
to Section 6.5.4.2  for additional follow-up evaluations as 
applicable.  
Pancreatitis  
Grade 3 
• 
If resolved in ≤ 7 days, then maintain dose level 
• 
If resolved in > 7 days, then discontinue 
canakinumab/matching-placebo 
Hypertension 
Grade 3 
Interrupt dose until resolved ≤ Grade 1, then maintain dose 
level 
Diarrhea - institute appropriate anti-diarrheal treatment and follow general guidelines 
Rash/photosensitivity - initiate/institute appropriate skin toxicity therapy (such as antihistamines and/or 
topical corticosteroids) and follow general guidelines 
Steven Johnson Syndrome, Toxic epidermal necrolysis 
• 
Permanently discontinue canakinumab/matching-placebo 
Tuberculosis or reactivation of hepatitis 
• 
Permanently discontinue canakinumab/matching-placebo 
Asymptomatic laboratory abnormalities- Provide supportive care and replacement therapy 
• 
If clinically significant, follow general guidelines 
LFTs- Liver function Tests 
a canakinumab/matching placebo dosing interval can be increased from Q3W to Q6W or from Q6W to Q9W. 
b Refer to protocol  Section 6.5.4.2  for monitoring of liver toxicity. 
c If total bilirubin > 3.0 x ULN is due to the indirect component only, and hemolysis as the etiology has been 
ruled out as per institutional guidelines continue treatment at the discretion of the investigator. 
dThe subject should be monitored biweekly (including LFTs), or more frequently if clinically indicated, until total 
bilirubin have resolved to baseline or stabilization over 4 weeks. 
eSubject with liver metastasis and baseline values between 3 and 5 x ULN are excluded from repeat 
assessment 
 Note: A CT scan or other imaging study to assess the pancreas, liver, and gallbladder must be performed 
within 1 week of the first occurrence of any ≥ Grade 3 of amylase and/or lipase. 
f An isolated bilirubin elevation is not typical for drug-induced liver injury. Bilirubin can be elevated either as part 
of a “Hy’s law” constellation with a preceding elevation of ALT/AST, or as part of a cholestatic reaction with 
simultaneous elevation of other cholestatic parameters (ALP, GGT). Isolated bilirubin can be seen in 
conjunction with drugs that inhibit bilirubin conjugation or excretion, but both scenarios do not typically 
represent liver injury. Alternative causes of bilirubin elevation should therefore, be ruled out before basing dose 
modification decisions on bilirubin values alone. 
gIf relatedness to canakinumab can be excluded with certainty and there is no risk for the patient (e.g. 
creatinine in a subject taking cisplatin), the dose modification for canakinumab is not mandatory 

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6.5.4 
Follow-up for toxicities 
6.5.4.1 
Follow up for infections 
Infections are the most common adverse event observed with canakinumab treatment. Subjects 
should be followed closely for signs or symptoms of infection and receive prompt appropriate 
treatment for suspected infections. Subjects will have a urinalysis performed at screening and 
on Day 1 of every cycle.  
6.5.4.2 
Follow up on potential drug-induced liver injury (DILI) cases 
DILI Diagnosis 
Subjects with transaminases elevations combined with total bilirubin (TBIL) increase may be 
indicative of potentially severe drug-induced liver injury (DILI). These events should be 
considered as clinically important and should be 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 subject’s baseline AST/ALT and TBIL 
value (Table 6-8 in  Section 6.5.3 ). Subjects meeting any of the following criteria will require 
further follow-up and assessments as outlined below: 
• For subjects with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN 
• For subjects with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 3 x 
baseline] or 8 x ULN, whichever is lower combined with [TBIL > 2 x baseline AND > 2.0 
x ULN] 
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before the diagnosis of DILI is confirmed. 
Hepatic toxicity monitoring includes the following LFTs: albumin, ALT, AST, total bilirubin, 
direct and indirect bilirubin, alkaline phosphatase (fractionated if alkaline phosphatase is grade 
2 or higher), creatine kinase, prothrombin time (PT) or INR and gamma-glutamyltransferase 
(GGT). For subjects with Gilbert Syndrome: total and direct bilirubin must be monitored, 
intensified monitoring applies to changes in direct bilirubin only. 
Evaluate status of liver metastasis (new or exacerbation) or vascular occlusion – CT, MRI, 
duplex sonography. 
Perform relevant examinations (Ultrasound or MRI, ERCP) as appropriate, to rule out if liver 
test elevations (LFTs) are caused by cholestasis (defined as: ALP elevation > 2.0 x ULN with 
R value < 2 in subjects without bone metastasis, or elevation of alkaline phosphatase (ALP) 
liver fraction in subjects with bone metastasis). 
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury). 
Table 6-10  provides guidance on specific clinical and diagnostic assessments to be (OR which 
can be) performed to rule out possible alternative causes of the observed LFT abnormalities. 

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Table 6-10 
Guidance on specific clinical and diagnostic assessments 
Disease 
Assessment 
Hepatitis A, B, C, E 
IgM anti-HAV; HBsAg, IgM & IgG anti-HBc, HBV DNA; anti-HCV, HCV RNA, 
IgM & IgG anti-HEV, HEV RNA 
CMV, HSV, EBV infection 
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV 
Autoimmune hepatitis 
ANA & ASMA titers, total IgM, IgG, IgE, IgA 
Alcoholic hepatitis 
Ethanol history, GGT, MCV, CD-transferrin 
Nonalcoholic steatohepatitis 
Ultrasound or MRI 
Hypoxic/ischemic hepatopathy 
Medical history: acute or chronic CHF, hypotension, hypoxia, hepatic venous 
occlusion. Ultrasound or MRI. 
Biliary tract disease 
Ultrasound or MRI, ERCP as appropriate. 
Wilson disease (if <40 yrs old) 
Ceruloplasmin 
Hemochromatosis 
Ferritin, transferrin 
Alpha-1-antitrypsin deficiency 
Alpha-1-antitrypsin 
Other causes should also be considered based upon patients’ medical history (Hyperthyroidism 
/ thyrotoxic hepatitis – T3, T4, TSH; CVD / Ischemic hepatitis – ECG, prior hypotensive 
episodes; T1D / glycogenic hepatitis). 
Following appropriate causality assessments, as outlined above, the causality of the drug is 
estimated as “probable” i.e. >50% likely, if it appears greater than all other causes combined. 
The term “drug-induced” indicates probably caused by the drug, not by something else, and 
only such a case can be considered 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. 
DILI Management 
In the absence of cholestasis, these subjects should be immediately discontinued from study 
drug treatment, and repeat Liver Function Tests (LFT) within 48 hours. The evaluation should 
include laboratory tests, detailed history, physical assessment, and the possibility of liver 
metastasis or new liver lesions, obstructions/compressions, etc. 
Close observation is recommended in case of AST, ALT, and/or bilirubin increase requiring 
dose interruption, which involves: 
• Repeating liver enzyme and serum bilirubin tests two or three times weekly. Frequency of 
re-testing can decrease to once a week or less if abnormalities stabilize or return to normal 
values. 
• Obtaining a more detailed history of current symptoms. 
• Obtaining a more detailed history of prior and/or concurrent diseases, including history of 
any pre-existing liver conditions or risk factors. 
• Obtaining a history of concomitant drug use (including non-prescription medications, 
herbal and dietary supplements), alcohol use, recreational drug use, and special diets. 

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• Ruling out acute viral hepatitis types A, B, C, D, and E; hepatotropic virus infections 
(CMV, EBV, or HSV); autoimmune or alcoholic hepatitis; NASH; hypoxic/ischemic 
hepatopathy; and biliary tract disease. 
• Obtaining a history of exposure to environmental chemical agents. 
• Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct 
bilirubin). 
• Considering gastroenterology or hepatology consultations. 
• Assessing cardiovascular dysfunction or impaired liver oxygenation, including 
hypotension or right heart failure as possible etiologies for liver dysfunction. 
• Obtaining a PK sample, as close as possible to last dose of study drug, to determine 
exposure to study drug, if PK analysis is performed in the study. 
• Considering a liver biopsy, as clinically indicated to assess pathological change and 
degree of potential liver injury 
These assessments should be done in addition to the assessments of immunological markers 
and total bile acids described in  Section 8  . 
All cases of DILI confirmed on repeat testing meeting the laboratory criteria defined above, 
with no other alternative cause for LFT abnormalities identified, should be considered as 
“medically significant”, thus meeting the definition of SAE ( Section 10.1.2 ), and must be 
reported as SAE using the term “potential drug-induced liver injury”. All events must be 
followed up with the outcome clearly documented. Results of tests as well as other clinically 
important information will be recorded in the eCRF. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
Every time the study treatment is to be administered, IRT must be accessed to assign a 
medication (kit) number (for the investigational drug canakinumab or canakinumab matching-
placebo) and/or registration of the other study drugs dispensed to the subjects. The date and 
time of all study treatment administrations during the study and any deviations from the protocol 
treatment schedule will be captured by the investigator staff or by field monitor on the 
appropriate study treatment dispensing form. 
Exposure to the study treatment will be based on the number of injections or infusions 
administered. Compliance with the study treatment will be assessed by the field monitor at each 
visit and information provided by the pharmacist or by the investigator. 
6.6.2 
Emergency breaking of assigned treatment code 
Emergency unblinding procedures must only be undertaken when it is required to in order to 
treat the subject safely. 
Most often, study treatment discontinuation and knowledge of the possible treatment 
assignments are sufficient to treat a study subject who presents with an emergency condition. 
Emergency treatment code breaks are performed using the IRT system. When the investigator 
contacts the system to break a treatment code for a subject, he/she must provide the requested 

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subject identifying information and confirm the necessity to break the treatment code for the 
subject. The investigator will then receive details of the investigational drug treatment for the 
specified subject and a fax or email confirming this information. The system will automatically 
inform the Novartis monitor for the site and the study team that the code has been broken. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide: 
• Protocol number 
• Study drug name (if available) 
• Subject number 
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time. 
Study treatment must be discontinued once emergency unblinding has occurred. The subject 
will have an End of Treatment (EOT) visit completed and will continue to be followed for 
recurrence as specified in the protocol.  
Following unblinding of the investigational sites to treatment allocation (Section 3), this section 
will no longer be applicable as there will be no need for emergency unblinding.  
6.7 
Preparation and dispensation 
Canakinumab or canakinumab matching-placebo (investigational drug): 
Each study site will be supplied by Novartis with the investigational drug in packaging of 
identical appearance per product volume. Canakinumab in ready for use pre-filled syringes does 
not require preparation. Canakinumab as solution for s.c injection in vial, which will be used 
post implementation of protocol amendment 06, requires preparation. For further information 
on canakinumab injection, please refer to Instruction for use Canakinumab manuals.  
Post trial unblinding on 25-Oct-2021, canakinumab-matching placebo was no longer supplied 
nor dispensed. 
For more details, please refer to Section 6.1.  
Investigator staff will identify the investigational drug packages for the subject at each 
dispensing visit by contacting the IRT and obtaining the medication (kit) number. 
Other study drugs (pembrolizumab, cisplatin, carboplatin, paclitaxel, nab-
paclitaxel and pemetrexed): 
The other study drugs (pembrolizumab, pemetrexed, cisplatin, carboplatin, paclitaxel, and nab-
paclitaxel) will be supplied locally as commercially available by the site pharmacy or by 
Novartis, if so, the drugs will be labeled accordingly to comply with the country legal 
requirements. Preparation and dispensation should follow the locally approved label and local 
practice. 

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6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
Handling of study treatment 
Study drugs supplied by Novartis 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 drugs must be 
stored according to the instructions specified on the labels and in the [Investigator’s Brochure] 
for the investigational drug or as per the locally approved label and local practice for the other 
study drugs. Clinical supplies are to be dispensed only in accordance with the protocol. 
Technical complaints are to be reported to the respective Novartis Country Organization (CO) 
Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. Also, for drugs sourced by Novartis, they will include storage conditions for the study 
treatment but no information about the subject, except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
drugs in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits and at the completion of the trial. At the conclusion of the study, and 
as appropriate during the course of the study, the investigator will return 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. 
The study drugs supply can be destroyed at the local Novartis facility or third party, as 
appropriate, or locally at the site only if permitted by local regulations and authorized by 
Novartis. 
6.7.1.2 
Handling of additional treatment 
Not applicable. 
6.7.2 
Instruction for prescribing and taking study treatment 
Refer to Section 6.1.1.1 and Section 6.1.1.2.  
7 
Informed consent procedures 
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), Institutional Review Board/ Institutional Ethics Committee (IRB/IEC)-
approved informed consent. 
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents. 

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Novartis will provide to investigators, in a separate document, a proposed informed consent 
form that complies with the International Conference on Harmonization Good Clinical Practices 
(ICH GCP) guidelines and regulatory requirements and is considered appropriate for this study. 
Any changes to the proposed consent form suggested by the investigator must be agreed by 
Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB) and/or Core Data Sheet (CDS) for marketed drugs. 
This information will be included in the subject informed consent and should be discussed with 
the subject during the study as needed. Any new information regarding the safety profile of the 
investigational drug that is identified between IB updates will be communicated as appropriate, 
for example, via an investigator notification (IN) or an aggregate safety finding. New 
information might require an update to the informed consent and then must be discussed with 
the subject. 
Women of child bearing potential and female partners of male participants must be informed 
that taking the study treatment may involve unknown risks to the fetus if pregnancy were to 
occur during the study and agree that in order to participate in the study they must adhere to the 
contraception requirements. 
Male subjects must be informed that if a female partner becomes pregnant while he is enrolled 
in the study, contact with the female partner will be attempted to request her consent to collect 
pregnancy outcome information. 
The study includes optional biomarker sample collections and assessments, the option to 
continue study treatment beyond RECIST 1.1 disease progression and, in some cases, the option 
to continue study treatment beyond iRECIST iCPD. These will require a separate signature if 
the subject agrees to participate. It is required as part of this protocol that the investigator 
presents these options to the subjects, as permitted by local governing regulations. The process 
for obtaining consent should be exactly the same as described above for the main informed 
consent. 
Declining to participate in these optional assessments will in no way affect the subject’s ability 
to participate in the main research study. 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
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 (e.g. telephone, videoconference) if allowable by a 
local Health Authority. 
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g. the presence of an impartial witness, sign/dating separate ICFs 
by trial subject and person obtaining informed consent, etc.). 

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8 
Visit schedule and assessments 
The assessment schedules Table 8-2 Safety run-in part, Table 8-3  Double-blind, randomized, 
placebo-controlled part, Table 8-4 Open label extension and Table 8-5 Post implementation of 
protocol amendment 05, list all of the assessments and indicates with an “X”, the visits when 
they are performed and with an "S", the visit when they are to be documented in the subject 
source medical record only. All data obtained from these assessments must be supported in the 
subject’s source documentation. 
Treatment cycles are intended to be 3 weeks (21 days), but the treatment can be delayed in order 
to manage toxicities according to the canakinumab/matching-placebo dose modification criteria 
in  Section 6.5.3 and the locally approved label and local practice for the other study drugs. In 
such cases, all study procedures (except imaging) will be completed at a later date 
corresponding to the delayed treatment. Imaging will be performed every 6 weeks (for the first 
12 weeks) starting from Cycle 1 Day 1 regardless of any treatment delays. Tumor assessments 
post week 12 are specified in Table 8-2, Table 8-3, Table 8-4, Table 8-5  and in  Section 8.3. 
During the course of the study visits, test procedures should occur on schedule whenever 
possible as per allowable visit windows specified in Table 8-1  below. 
Note: If any drug of the study treatment is temporarily interrupted or permanently discontinued 
at any time during the study, efficacy assessments should continue according to the appropriate 
number of calendar days from Cycle 1 Day 1 as per the schedule of assessments.  
Table 8-1 
Allowable visit windows are specified as follows: 
Visit name 
Window 
Screening 
-28 Days 
All assessments including C1D1, during the treatment 
period (except tumor assessments) 
± 3 Days 
Canakinumab or canakinumab matching-
placebo injection (if applicable) 
± 3 Days 
Pembrolizumab infusion (if applicable) 
± 3 Days 
Chemotherapies infusion (if applicable) 
± 3 Days 
PK/IG/PD sampling 
Refer to tables in  Section 8.5.2  
Tumor assessments 
± 7 Days 
26 day safety follow-up visit 
± 7 Days 
52, 78, 104-day safety follow-up visits 
± 7 Days 
130-day safety follow-up visit 
+ 14 Days 
EOT 
≤ 7 Days after permanent discontinuation of study 
treatment 
Survival follow- up 
± 7 Days 
Every effort must be made to follow the schedule of assessments within the windows outlined 
in Table 8-2, Table 8-3,Table 8-4 and Table 8-5, as applicable. If an off-schedule imaging 
assessment is performed, subsequent imaging assessments should be performed in accordance 
with the original imaging schedule. 
Additional assessments may be performed as clinically indicated. 
Missed or rescheduled visits should not lead to automatic discontinuation. Subjects who 
prematurely discontinue the study for any reason should be scheduled for a visit as soon as 

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possible, at which time all of the assessments listed for the final visit will be performed. At this 
final visit, all dispensed investigational product should be reconciled, and the adverse event and 
concomitant medications recorded on the appropriate eCRF. 
All data obtained from these assessments must be supported in the subject's source 
documentation. 
As per Section 4.6, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, alternative 
methods of providing continuing care may be implemented by the Investigator as the situation 
dictates. If allowable by a local Health Authority, national and local regulations and depending 
on operational capabilities, phone calls, virtual contacts (e.g. tele consultation) or visits by site 
staff/ off-site healthcare professional(s) staff to the subject´s home, can replace certain protocol 
assessments, for the duration of the disruption until it is safe for the subject to visit the site again. 
If the Investigator delegates tasks to an off-site healthcare professional, the Investigator must 
ensure the individual(s) is/are qualified and appropriately trained to perform assigned duties. 
The Investigator must oversee their conduct and remain responsible for the evaluation of the 
data collected. 

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Table 8-2 
Assessment Schedule, Safety run-in part 
Period 
Screening 
Induction 
Maintenance 
Follow-up 
Visit Name 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Subsequent 
Cycles 
EOT 
Safety follow-up visit 
(every 26 d for 130 d 
after the last dose of 
the study treatment) 
End of post 
treatment 
follow-up 
Survival 
follow-up 
(every 12 
weeks) 
Days 
-28 to -1 1 
2 
8 
15 
1 
15 1 
15 1 
15 1 8 Day 1 (or as reported) - 
1 
2 
3 
4 
5 
 
 
Main informed consent X 
  
  
  
  
  
  
  
  
  
  
      
  
  
  
  
  
  
 
 
IRT Screening (after 
ICF signature) 
X 
  
  
  
  
  
  
  
  
  
  
      
  
  
  
  
  
  
 
 
IRT Enrollment 
  
X 
  
  
  
  
  
  
  
  
  
      
  
  
  
  
  
  
 
 
Collection of 
concomitant molecular 
alteration data 
(EGFR/ALK) 
S 
  
  
  
  
  
  
  
  
  
  
      
  
  
  
  
  
  
 
 
Archival or newly 
obtained tumor sample 
for ALK/EGFR testing 
by Novartis designated 
laboratory (if no local 
testing available) 
X 
  
  
  
  
  
  
  
  
  
  
      
  
  
  
  
  
  
 
 
Demography 
X 
  
  
  
  
  
  
  
  
  
  
      
  
  
  
  
  
  
 
 
Inclusion / Exclusion 
criteria 
X 
  
  
  
  
  
  
  
  
  
  
      
  
  
  
  
  
  
 
 
Medical history/current 
medical conditions 
X 
  
  
  
  
  
  
  
  
  
  
      
  
  
  
  
  
  
 
 
Diagnosis, stage and 
grade of cancer 
X 
  
  
  
  
  
  
  
  
  
  
      
  
  
  
  
  
  
 
 
Smoking history 
X 
  
  
  
  
  
  
  
  
  
  
      
  
  
  
  
  
  
 
 
Prior/concomitant 
medications 
From 28 days prior to first dose until 130 days after EOT or start of new antineoplastic drugs, whichever is sooner. 
After starting a new antineoplastic drug, only report concomitant medications for AEs/SAEs suspected to be related to 
any study drugs. 
 
 
Non-drug therapies 
and procedures 
From 28 days prior to first dose until 130 days after EOT or start of new antineoplastic drugs, whichever is sooner. 
After starting a new antineoplastic drug, only report non-drug therapies for AEs/SAEs suspected to be related to any 
study drugs. 
 
 

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Period 
Screening 
Induction 
Maintenance 
Follow-up 
Visit Name 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Subsequent 
Cycles 
EOT 
Safety follow-up visit 
(every 26 d for 130 d 
after the last dose of 
the study treatment) 
End of post 
treatment 
follow-up 
Survival 
follow-up 
(every 12 
weeks) 
Days 
-28 to -1 1 
2 
8 
15 
1 
15 1 
15 1 
15 1 8 Day 1 (or as reported) - 
1 
2 
3 
4 
5 
 
 
Prior anti-neoplastic 
therapies (medications, 
surgery, radiotherapy) 
X 
  
  
  
  
  
  
  
  
  
  
      
  
  
  
  
  
  
 
 
Physical Examination 
S 
S 
  
  
  
S 
  
S 
  
S 
  
S   S 
S 
S 
  
S 
  
S 
 
 
ECOG performance 
status 
X 
X 
  
  
  
X 
  
X 
  
X 
  
X   X 
X 
X 
  
X 
  
X 
 
 
Body Height 
X 
  
  
  
  
  
  
  
  
  
  
      
  
  
  
  
  
  
 
 
Body Weight 
X 
X 
  
  
  
X 
  
X 
  
X 
  
X   X 
X 
X 
  
X 
  
X 
 
 
Vital Signs 
X 
X 
  
  
  
X 
  
X 
  
X 
  
X   X 
X 
X 
  
X 
  
X 
 
 
Determination of 
tuberculosis status 
S 
  
  
  
  
  
  
  
  
  
  
      
  
  
  
  
  
  
 
 
HIV history (HIV testing 
where locally required) S 
  
  
  
  
  
  
  
  
  
  
      
  
  
  
  
  
  
 
 
Hematology 
X 
X 
  
  
X 
X 
X 
X 
X 
X 
X 
X   X 
X 
X 
  
X 
  
X 
 
 
Blood Chemistry 
X 
X 
  
  
X 
X 
X 
X 
X 
X 
X 
X   X 
X 
X 
  
X 
  
X 
 
 
Coagulation 
X 
If clinically indicated 
 
 
Total T3, FT4 and TSH X 
X 
  
  
  
  
  
X 
  
  
  
X 
  To be repeated every 
other Cycle beginning 
with Cycle 7 
X 
X 
  
  
  
  
 
 
Hepatitis testing 
X 
If clinically indicated 
  
  
  
  
  
 
 
Urinalysis 
X 
X 
  
  
  
X 
  
X 
  
X 
  
X   X 
X 
X 
  
X 
  
X 
 
 
Serum pregnancy test 
X 
  
  
  
  
  
  
  
  
  
  
      
X1 
  
  
  
  
  
 
 
Urine pregnancy test1 
  
S 
  
  
  
S 
  
S 
  
S 
  
S   S 
  
S 
  
S 
  
S 
 
 
CT or MRI of Chest 
and Abdomen (with 
intravenous contrast 
enhancement)2 
X 
Every 6 weeks (for the first 12 weeks), then every 9 weeks through week 75 and every 12 weeks thereafter3  
 
Brain CT or MRI2 
X 
If clinically indicated and/or positive at baseline, follow same schedule as CT/MRI of chest and abdomen 
 
 

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Period 
Screening 
Induction 
Maintenance 
Follow-up 
Visit Name 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Subsequent 
Cycles 
EOT 
Safety follow-up visit 
(every 26 d for 130 d 
after the last dose of 
the study treatment) 
End of post 
treatment 
follow-up 
Survival 
follow-up 
(every 12 
weeks) 
Days 
-28 to -1 1 
2 
8 
15 
1 
15 1 
15 1 
15 1 8 Day 1 (or as reported) - 
1 
2 
3 
4 
5 
 
 
Whole body bone 
scan2 
X 
If clinically indicated 
 
 
CT scan or MRI of 
other metastatic sites 
(e.g., neck, pelvis, 
etc.)2 
If 
clinically 
indicated 
If clinically indicated and/or positive at baseline, follow same schedule as CT/MRI of chest and abdomen 
 
 
Localized bone CT 
scan, MRI or x-ray (for 
any skeletal lesions 
identified on the whole 
body bone scan that 
are not visible on the 
chest/abdomen and 
pelvis, if applicable, CT 
or MRI)2 
If 
clinically 
indicated 
If clinically indicated and/or positive at baseline, follow same schedule as CT/MRI of chest and abdomen 
 
 
Photography (for any 
skin lesion)2 
If 
clinically 
indicated 
If clinically indicated and/or positive at baseline, follow same schedule as CT/MRI of chest and abdomen 
 
 
Electrocardiogram 
(ECG)4 
  
X5 
  
  
  
  
  
  
  
  
  
    C6D15 
  
  
  
  
  
  
 
 
Adverse Events 
Continuous, up to 130 days after last dose of study treatment or start of new post study treatment antineoplastic 
medication (whichever is sooner) 
 
 
Serious Adverse 
Events 
Continuous, up to 130 days after last dose of study treatment or start of new post study treatment antineoplastic 
medication (whichever is sooner) 
 
SAEs 
related to 
study 
treatment8 
Drug administration6 
  
X 
  
  
  
X 
  
X 
  
X 
  
X   X 
  
  
  
  
  
  
 
 
IRT drug 
discontinuation 
  
  
  
  
  
  
  
  
  
  
  
      
X 
  
  
  
  
  
 
 
Canakinumab PK 
sampling7 
  
X 
X 
X 
X 
X 
  
X 
  
X 
  
X X C6D1, C8D1, C12D1, 
C16D1 
X 
X 
  
X 
  
X 
 
 

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Period 
Screening 
Induction 
Maintenance 
Follow-up 
Visit Name 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Subsequent 
Cycles 
EOT 
Safety follow-up visit 
(every 26 d for 130 d 
after the last dose of 
the study treatment) 
End of post 
treatment 
follow-up 
Survival 
follow-up 
(every 12 
weeks) 
Days 
-28 to -1 1 
2 
8 
15 
1 
15 1 
15 1 
15 1 8 Day 1 (or as reported) - 
1 
2 
3 
4 
5 
 
 
Canakinumab 
Immunogenicity 
sampling7 
  
X 
  
  
  
  
  
  
  
X 
  
    
C8D1, C12D1, C16D1 X 
X 
  
X 
  
X 
 
 
Canakinumab 
Pharmacodynamic / 
Total IL-1β7 
  
X 
  
  
X 
  
  
  
  
  
  
X 
  
C16D1 
X 
X 
  
X 
  
X 
 
 
Pembrolizumab PK 
sampling7 
  
X 
X 
X 
X 
X 
  
X 
  
X 
  
X   C6D1, C8D1, C12D1, 
C16D1 
X 
X 
  
  
  
  
 
 
Pembrolizumab 
Immunogenicity 
sampling7 
  
X 
  
  
  
X 
  
  
  
X 
  
    
C8D1, C12D1, C16D1 X 
X 
  
  
  
  
 
 
Pemetrexed PK 
sampling7 
  
X 
  
  
  
X 
  
  
  
  
  
      
  
  
  
  
  
  
 
 
Cisplatin PK sampling7   
X 
  
  
  
X 
  
  
  
  
  
      
  
  
  
  
  
  
 
 
Carboplatin PK 
sampling7 
  
X 
  
  
  
X 
  
  
  
  
  
      
  
  
  
  
  
  
 
 
Paclitaxel PK 
sampling7 
  
X 
  
  
  
X 
  
  
  
  
  
      
  
  
  
  
  
  
 
 
Antineoplastic 
therapies since 
discontinuation of 
study treatment 
  
  
  
  
  
  
  
  
  
  
  
      
  
At every visit (on site or phone call) during 
safety follow up, efficacy follow up and survival 
follow up. 
Disposition 
Assessment 
X 
  
  
  
  
  
  
  
  
  
  
      
X 
  
  
  
  
  
X 
 
Survival Follow-up 
  
  
  
  
  
  
  
  
  
  
  
      
  
  
  
  
  
  
 
X 

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Period 
Screening 
Induction 
Maintenance 
Follow-up 
Visit Name 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Subsequent 
Cycles 
EOT 
Safety follow-up visit 
(every 26 d for 130 d 
after the last dose of 
the study treatment) 
End of post 
treatment 
follow-up 
Survival 
follow-up 
(every 12 
weeks) 
Days 
-28 to -1 1 
2 
8 
15 
1 
15 1 
15 1 
15 1 8 Day 1 (or as reported) - 
1 
2 
3 
4 
5 
 
 
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 For women with child bearing potential status confirmed only. For further details please refer to Section 8.4.5  
2 For further details please refer to Section 8.3 Efficacy assessments 
3 Tumor assessment at end of treatment (EOT) only for subjects without documented RECIST 1.1 PD and who do not enter the efficacy follow-up phase provided the 
last scan was not conducted within 30 days prior to the end of study treatment. 
4 For further details please refer to Section 8.4.4 Electrocardiogram (ECG) 
5 Pre-dose 
6 For further details refer to Section 6.1 Study Treatment. From Cycle 5 onward only canakinumab, pembrolizumab and pemetrexed (for non-squamous subjects only) to 
be administered. 
7 For further details refer to specifying table in Section 8.5.2 Pharmacokinetics (PK), immunogenicity (IG) and pharmacodynamics (PD) assessments 
8 Until study completion and regardless of any new therapies 

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Table 8-3 
Assessment Schedule, Double-blind, randomized, placebo-controlled part 
Period 
Screening 
Induction 
Maintenance 
Follow-up 
Visit Name 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Subsequent 
Cycles 
EOT 
Safety follow-up 
visit (every 26 d for 
130 d after the last 
dose of the study 
treatment) 
End of 
post 
treatment 
follow-up 
Survival 
follow-up 
(every 12 
weeks) 
Days 
-28 to -1 1 
2 
8 
15 1 
2 1 
1 
1 
8 
Day 1 (or as reported) - 
1 
2 
3 
4 
5 
- 
- 
Main informed consent 
X 
  
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
Optional pharmacogenetic 
informed consent 
X 
  
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
IRT Screening (after ICF 
signature) 
X 
  
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
IRT randomization 
  
X 
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
Collection of concomitant 
molecular alteration data 
(EGFR/ALK) 
S 
  
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
Archival or newly obtained 
tumor sample for PD-L1 
testing by Novartis 
designated laboratory (and 
for ALK/EGFR if no local 
testing available) 
X 
  
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
Demography 
X 
  
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion / Exclusion 
criteria 
X 
  
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
Medical history/current 
medical conditions 
X 
  
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
Diagnosis, stage and 
grade of cancer 
X 
  
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
Smoking history 
X 
  
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
Prior/concomitant 
medications 
From 28 days prior to first dose until 130 days after EOT or start of new antineoplastic drugs, whichever is sooner. 
After starting a new antineoplastic drug, only report concomitant medications for AEs/SAEs suspected to be related 
to any study drugs. 
  
  
Non-drug therapies and 
procedures 
From 28 days prior to first dose until 130 days after EOT or start of new antineoplastic drugs, whichever is sooner. 
After starting a new antineoplastic drug, only report non-drug therapies for AEs/SAEs suspected to be related to any 
study drugs. 
  
  

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Period 
Screening 
Induction 
Maintenance 
Follow-up 
Visit Name 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Subsequent 
Cycles 
EOT 
Safety follow-up 
visit (every 26 d for 
130 d after the last 
dose of the study 
treatment) 
End of 
post 
treatment 
follow-up 
Survival 
follow-up 
(every 12 
weeks) 
Days 
-28 to -1 1 
2 
8 
15 1 
2 1 
1 
1 
8 
Day 1 (or as reported) - 
1 
2 
3 
4 
5 
- 
- 
Prior anti-neoplastic 
therapies (medications, 
surgery, radiotherapy) 
X 
  
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
Physical Examination 
S 
S 
  
  
  
S 
  S 
S 
S 
  
S 
S 
S 
  
S 
  
S 
  
  
ECOG performance status X 
X 
  
  
  
X 
  X 
X 
X 
  
X 
X 
X 
  
X 
  
X 
  
  
Body Height 
X 
  
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
Body Weight 
X 
X 
  
  
  
X 
  X 
X 
X 
  
X 
X 
X 
  
X 
  
X 
  
  
Vital Signs 
X 
X 
  
  
  
X 
  X 
X 
X 
  
X 
X 
X 
  
X 
  
X 
  
  
Determination of 
tuberculosis status 
S 
  
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
HIV history (HIV testing 
where locally required) 
S 
  
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
Hematology 
X 
For all subjects: on Day 1 and 15; only for 
subjects on nab-paclitaxel: Day 1, Day 8 
and Day 15 
X 
  
X 
X 
X 
  
X 
  
X 
  
  
Blood Chemistry 
X 
For all subjects: on Day 1 and 15; only for 
subjects on nab-paclitaxel: Day 1, Day 8 
and Day 15 
X 
  
X 
X 
X 
  
X 
  
X 
  
  
Coagulation 
X 
If clinically indicated 
  
  
Total T3, FT4 and TSH 
X 
X 
  
  
  
  
  
X 
  
X 
  
To be repeated every 
other Cycle beginning 
with Cycle 7 
X 
X 
  
  
  
  
  
  
Hepatitis testing 
X 
If clinically indicated 
  
  
  
  
  
  
  
Urinalysis 
X 
X 
  
  
  
X 
  X 
X 
X 
  
X 
X 
X 
  
X 
  
X 
  
  
Serum pregnancy test 
X 
  
  
  
  
  
    
  
  
  
  
X1   
  
  
  
  
  
  
Urine pregnancy test1 
  
S 
  
  
  
S 
  S 
S 
S 
  
S 
  
S 
  
S 
  
S 
  
  

Novartis 
 
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Page 104 of 224 
Amended Protocol Version 06 (Clean) 
 
Protocol No. CACZ885U2301 
 
Period 
Screening 
Induction 
Maintenance 
Follow-up 
Visit Name 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Subsequent 
Cycles 
EOT 
Safety follow-up 
visit (every 26 d for 
130 d after the last 
dose of the study 
treatment) 
End of 
post 
treatment 
follow-up 
Survival 
follow-up 
(every 12 
weeks) 
Days 
-28 to -1 1 
2 
8 
15 1 
2 1 
1 
1 
8 
Day 1 (or as reported) - 
1 
2 
3 
4 
5 
- 
- 
CT or MRI of Chest and 
Abdomen (with 
intravenous contrast 
enhancement)2 
X 
Every 6 weeks (for the first 12 weeks), then every 9 weeks through week 75 and every 12 weeks 
thereafter3 
  
  
Brain CT or MRI2 
X 
If clinically indicated and/or positive at baseline, follow same schedule as CT/MRI of chest and abdomen 
  
  
Whole body bone scan2 
X 
If clinically indicated 
  
  
CT scan or MRI of other 
metastatic sites (e.g., 
neck, pelvis, etc.)2 
If 
clinically 
indicated 
If clinically indicated and/or positive at baseline, follow same schedule as CT/MRI of chest and abdomen 
  
  
Localized bone CT scan, 
MRI or x-ray (for any 
skeletal lesions identified 
on the whole body bone 
scan that are not visible on 
the chest/abdomen and 
pelvis, if applicable, CT or 
MRI)2 
If 
clinically 
indicated 
If clinically indicated and/or positive at baseline, follow same schedule as CT/MRI of chest and abdomen 
  
  
Photography (for any skin 
lesion)2 
If 
clinically 
indicated 
If clinically indicated and/or positive at baseline, follow same schedule as CT/MRI of chest and abdomen 
  
  
Electrocardiogram (ECG)4   
X5 
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
Electronic patient reported 
outcomes (ePRO)6 
  
Day 1 of each cycle; at the End of Treatment (EOT) visit; before tumor assessments during efficacy 
follow-up (See Table 8-4); and 7 and 28 days post progression per RECIST 1.1 as per Investigator. 
  
  
Adverse Events 
Continuous, up to 130 days after last dose of study treatment or start of new post study treatment antineoplastic 
medication (whichever is sooner) 
  
  
Serious Adverse Events 
Continuous, up to 130 days after last dose of study treatment or start of new post study treatment antineoplastic 
medication (whichever is sooner) 
  
SAEs 
related to 
study 
treatment15 
Drug administration7 
  
X 
  
  
  
X 
  X 
X 
X 
  
X 
  
  
  
  
  
  
  
  

Novartis 
 
Confidential 
Page 105 of 224 
Amended Protocol Version 06 (Clean) 
 
Protocol No. CACZ885U2301 
 
Period 
Screening 
Induction 
Maintenance 
Follow-up 
Visit Name 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Subsequent 
Cycles 
EOT 
Safety follow-up 
visit (every 26 d for 
130 d after the last 
dose of the study 
treatment) 
End of 
post 
treatment 
follow-up 
Survival 
follow-up 
(every 12 
weeks) 
Days 
-28 to -1 1 
2 
8 
15 1 
2 1 
1 
1 
8 
Day 1 (or as reported) - 
1 
2 
3 
4 
5 
- 
- 
Nab-paclitaxel Drug 
administration7 
  
Only for subjects on nab-paclitaxel: 
administration on Day 1, Day 8, and Day 
15 at each cycle 
  
  
  
  
  
  
  
  
  
  
  
IRT drug discontinuation 
  
  
  
  
  
  
    
  
  
  
  
X 
  
  
  
  
  
  
  
Optional Newly obtained 
tumor sample on 
treatment8,14 
  
  
  
  
  
  
  Anytime 
between 
C3D1 
and 
C3D15 
  
  
  
  
  
  
  
  
  
  
  
  
Optional Newly obtained 
tumor sample at confirmed 
disease progression8,14 
  
At time of confirmed disease progression and prior to the start of new 
antineoplastic therapy 
  
  
  
  
  
  
  
Blood (serum) for hs-CRP 
testing8,9, 14 
  
X 
  
  
  
X 
  X 
X 
X 
  
C12D1, C16D1 
X 
X10   
X10   
X10   
  
Blood (plasma) for 
cytokine testing8,11, 14 
  
X 
  
  
  
X 
  X 
X 
X 
  
C12D1, C16D1 
X 
X10   
X10   
X10   
  
Optional unscheduled 
blood (plasma) for cytokine 
analysis (and soluble 
circulating markers)11,14 
  
In case of suspected immune-related adverse event observed 
  
Blood (plasma) for 
circulating tumor DNA 
(ctDNA)8,11,14 
  
X 
  
  
  
  
    
  
X 
  
C8D1,  
C12D1  
X 
  
  
  
  
  
  
  
Blood for circulating tumor 
cells (CTC)12, 14 
  
X 
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
Optional Blood for 
pharmacogenetic analysis 
(PG informed consent is 
required) 14 
  
X 
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
Canakinumab PK 
sampling13 
  
X 
X 
X 
X 
X 
  X 
X 
X 
X 
C6D1, C8D1, C12D1, 
C16D1 
X 
X 
  
X 
  
X 
  
  

Novartis 
 
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Page 106 of 224 
Amended Protocol Version 06 (Clean) 
 
Protocol No. CACZ885U2301 
 
Period 
Screening 
Induction 
Maintenance 
Follow-up 
Visit Name 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Subsequent 
Cycles 
EOT 
Safety follow-up 
visit (every 26 d for 
130 d after the last 
dose of the study 
treatment) 
End of 
post 
treatment 
follow-up 
Survival 
follow-up 
(every 12 
weeks) 
Days 
-28 to -1 1 
2 
8 
15 1 
2 1 
1 
1 
8 
Day 1 (or as reported) - 
1 
2 
3 
4 
5 
- 
- 
Canakinumab 
Immunogenicity sampling13 
  
X 
  
  
  
  
    
X 
  
  
C8D1, C12D1, C16D1 X 
X 
  
X 
  
X 
  
  
Canakinumab 
Pharmacodynamic / Total 
IL-1β13 
  
X 
  
  
X 
  
    
  
X 
  
C16D1 
X 
X 
  
X 
  
X 
  
  
Pembrolizumab PK 
sampling13 
  
X 
X 
X 
X 
X 
  X 
X 
X 
  
C6D1, C8D1, C12D1, 
C16D1 
X 
X 
  
  
  
  
  
  
Pembrolizumab 
Immunogenicity sampling13 
  
X 
  
  
  
X 
    
X 
  
  
C8D1, C12D1, C16D1 X 
X 
  
  
  
  
  
  
Pemetrexed PK sampling13   
X 
  
  
  
X 
    
  
  
  
  
  
  
  
  
  
  
  
  
Cisplatin PK sampling13 
  
X 
  
  
  
X 
    
  
  
  
  
  
  
  
  
  
  
  
  
Carboplatin PK sampling13   
X 
  
  
  
X 
    
  
  
  
  
  
  
  
  
  
  
  
  
Paclitaxel PK sampling13 
  
X 
  
  
  
X 
X   
  
  
  
  
  
  
  
  
  
  
  
  
nab-Paclitaxel PK 
sampling13 
  
X 
  
  
  
X 
X   
  
  
  
  
  
  
  
  
  
  
  
  
Antineoplastic therapies 
since discontinuation of 
study treatment 
  
  
  
  
  
  
    
  
  
  
  
  
At every visit (on site or phone call) during 
safety follow up, efficacy follow up and survival 
follow up. 
Disposition Assessment 
X 
  
  
  
  
  
    
  
  
  
  
X 
  
  
  
  
  
X 
  
Survival Follow-up 
  
  
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
X 

Novartis 
 
Confidential 
Page 107 of 224 
Amended Protocol Version 06 (Clean) 
 
Protocol No. CACZ885U2301 
 
Period 
Screening 
Induction 
Maintenance 
Follow-up 
Visit Name 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Subsequent 
Cycles 
EOT 
Safety follow-up 
visit (every 26 d for 
130 d after the last 
dose of the study 
treatment) 
End of 
post 
treatment 
follow-up 
Survival 
follow-up 
(every 12 
weeks) 
Days 
-28 to -1 1 
2 
8 
15 1 
2 1 
1 
1 
8 
Day 1 (or as reported) - 
1 
2 
3 
4 
5 
- 
- 
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 For women with child bearing potential status confirmed only. For further details please refer to Section 8.4.5 
2 For further details please refer to Section 8.3 Efficacy assessments 
3 Tumor assessment at end of treatment (EOT) only for subjects without documented RECIST PD and who do not enter the efficacy follow-up phase provided the last 
scan was not conducted within 30 days prior to the end of study treatment. 
4 For further details please refer to Section 8.4.4 Electrocardiogram (ECG) 
5 Pre-dose 
6 ePRO questionnaires should be completed prior to all other assessments in the Assessment Schedule. For further details please refer to Section 8.5.1 Clinical 
Outcome Assessments (COA). 
7For further details please refer to Section 6.1 Study Treatment. From Cycle 5 onward only canakinumab/matching placebo, pembrolizumab and pemetrexed (for non-
squamous subjects only) to be administered.  
8 Also to be collected as unscheduled, if needed and at time of confirmed disease progression 
9 (5 mL) of whole blood will be collected for hs-CRP. For further details please refer to Section 8.5.3.2 
10 Only collected prior to start of any new antineoplastic therapy 
11 (10 mL) of whole blood will be collected for each of the following: Cytokines, Unscheduled cytokines at AE, and ctDNA 
12 (10 mL) of whole blood will be collected for CTC. Assessment to be performed only on a subset of subjects, as specified in the protocol. 
13 For further details please refer to Section 8.5.2 Pharmacokinetics (PK), immunogenicity (IG) and pharmacodynamics (PD) assessments 
14 For China only: biomarker tests will not be done unless approval has been obtained by all relevant Chinese authorities 
15 Until study completion and regardless of any new therapies 

Novartis 
 
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Page 108 of 224 
Amended Protocol Version 06 (Clean) 
 
Protocol No. CACZ885U2301 
 
Table 8-4 
Assessment Schedule, Open Label Extension Phase 
Period  
Crossover/ 
Transition 
Maintenance (Open Label Extension) 
Follow up 
Visit Name  
Open Label Extension (OLE) Cycles 
EOT 
OLE Safety follow-up visit (every 
26 d for 130 d after the last dose 
of the study treatment) 
End of 
post 
treatment 
follow-up 
Survival 
follow-up 
(every 12 
weeks) 
 Visits 
- 
OLE Cycle 1 Day 1 and subsequent OLE 
cycles 
- 
1 
2 
3 
4 
5 
- 
- 
IRT OLE registration  
X 
 
 
 
 
 
 
 
 
 
Extension Details CRF 
completed  
X 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
Continuously collect during the study until 130 days after EOT or start of new antineoplastic drugs, 
whichever is sooner. After starting a new antineoplastic drug, only report concomitant medications for 
AEs/SAEs suspected to be related to any study drugs. 
 
 
Non-drug therapies and 
procedures 
Continuously collect during the study until 130 days after EOT or start of new antineoplastic drugs, 
whichever is sooner. After starting a new antineoplastic drug, only report non-drug therapies for 
AEs/SAEs suspected to be related to any study drugs. 
 
 
Physical Examination 
 
S 
S 
S 
 
S 
 
S 
 
 
ECOG performance status 
 
X 
X 
X 
 
X 
 
X 
 
 
Body Weight 
 
Only if clinically indicated 
X 
X 
 
X 
 
X 
 
 
Vital Signs 
 
X 
X 
X 
 
X 
 
X 
 
 
Hematology 
 
On OLE C1D1 and every second cycle 
thereafter and as clinically indicated 
Only for subjects on pemetrexed: please 
monitor labs according to local label 
X 
X 
 
X 
 
X 
 
 
Blood Chemistry 
 
On OLE C1D1 and every second cycle 
thereafter and as clinically indicated 
Only for subjects on pemetrexed: please 
monitor labs according to local label 
X 
X 
 
X 
 
X 
 
 
Coagulation 
 
If clinically indicated 
 
 
Total T3, FT4 and TSH 
 
On OLE C1D114 and every fourth cycle 
thereafter and as clinically indicated 
X 
X 
 
 
 
 
 
 
Hepatitis testing 
 
If clinically indicated 
 
 
 
 
 
 
 
Serum pregnancy test 
 
 
X1 
 
 
 
 
 
 
 

Novartis 
 
Confidential 
Page 109 of 224 
Amended Protocol Version 06 (Clean) 
 
Protocol No. CACZ885U2301 
 
Period  
Crossover/ 
Transition 
Maintenance (Open Label Extension) 
Follow up 
Visit Name  
Open Label Extension (OLE) Cycles 
EOT 
OLE Safety follow-up visit (every 
26 d for 130 d after the last dose 
of the study treatment) 
End of 
post 
treatment 
follow-up 
Survival 
follow-up 
(every 12 
weeks) 
 Visits 
- 
OLE Cycle 1 Day 1 and subsequent OLE 
cycles 
- 
1 
2 
3 
4 
5 
- 
- 
Urinalysis 
 
On OLE C1D114 and every fourth cycle 
thereafter and as clinically indicated 
X 
X 
 
X 
 
X 
 
 
Urine pregnancy test1 
 
S 
 
S 
 
S 
 
S 
 
 
CT or MRI of Chest and 
Abdomen (with intravenous 
contrast enhancement)2 
 
Follow the same schedule as in Table 8-2 (Safety Run In part) or Table 8-3 (Randomized 
part), as appropriate, until 159 Weeks (approximately 3 years) after the study C1D1; 
thereafter, every 24 weeks3. 
 
 
Brain CT or MRI2 
 
If clinically indicated and/or positive at study baseline, follow same schedule as CT/MRI of 
chest and abdomen 
 
 
Whole body bone scan2 
 
If clinically indicated 
 
 
CT scan or MRI of other 
metastatic sites (e.g., neck, 
pelvis, etc.)2 
 
If clinically indicated and/or positive at study baseline, follow same schedule as CT/MRI of 
chest and abdomen 
 
 
Localized bone CT scan, MRI 
or x-ray (for any skeletal 
lesions identified on the whole 
body bone scan that are not 
visible on the chest/abdomen 
and pelvis, if applicable, CT or 
MRI)2 
 
If clinically indicated and/or positive at study baseline, follow same schedule as CT/MRI of 
chest and abdomen 
 
 
Photography (for any skin 
lesion) 2 
 
If clinically indicated and/or positive at study baseline, follow same schedule as CT/MRI of 
chest and abdomen 
 
 
Electrocardiogram (ECG)4 
 
If clinically indicated 
 
 
Electronic patient reported 
outcomes (ePRO) 5, 15 
 
Follow the same schedule as for tumor assessments. Also, at the End of Treatment (EOT) 
visit; before tumor assessments during efficacy follow-up (See Table 8-5); and 7 and 28 days 
post progression per RECIST 1.1 as per Investigator 
 
 
Adverse Events 
 
Continuous, up to 130 days after last dose of study treatment or start of new post study 
treatment antineoplastic medication (whichever is sooner) 
 
 

Novartis 
 
Confidential 
Page 110 of 224 
Amended Protocol Version 06 (Clean) 
 
Protocol No. CACZ885U2301 
 
Period  
Crossover/ 
Transition 
Maintenance (Open Label Extension) 
Follow up 
Visit Name  
Open Label Extension (OLE) Cycles 
EOT 
OLE Safety follow-up visit (every 
26 d for 130 d after the last dose 
of the study treatment) 
End of 
post 
treatment 
follow-up 
Survival 
follow-up 
(every 12 
weeks) 
 Visits 
- 
OLE Cycle 1 Day 1 and subsequent OLE 
cycles 
- 
1 
2 
3 
4 
5 
- 
- 
Serious Adverse Events 
 
Continuous, up to 130 days after last dose of study treatment or start of new post study 
treatment antineoplastic medication (whichever is sooner) 
 
SAEs 
related to 
study 
treatment 
12 
Drug administration6 
 
X 
 
 
 
 
 
 
 
 
IRT drug discontinuation 
 
 
X 
 
 
 
 
 
 
 
Optional newly obtained tumor 
sample at confirmed disease 
progression 7,11,15 
 
At time of confirmed disease progression and prior to 
the start of new antineoplastic therapy 
 
 
 
 
 
 
 
Blood (serum) for hs-CRP 
testing 7,8,11, 15 
X13 
OLE Cycle 3 Day 113 
X 
X9 
 
X9 
 
X9 
 
 
Blood (plasma) for cytokine 
testing 7,10,11, 15 
X13 
OLE Cycle 3 Day 113 
X 
X9 
 
X9 
 
X9 
 
 
Optional unscheduled blood 
(plasma) for cytokine analysis 
(and soluble circulating 
markers) 10,11, 15 
 
In case of suspected immune-related adverse event observed 
 
Blood (plasma) for circulating 
tumor DNA (ctDNA) 7,10,11,15 
X13 
 
X 
 
 
 
 
 
 
 
Antineoplastic therapies since 
discontinuation of study 
treatment 
 
 
 
At every visit (on site or phone call) during safety follow up, 
efficacy follow up and survival follow up 
Disposition Assessment 
 
 
X 
 
 
 
 
 
X 
 
Survival Follow-up 
 
 
 
 
 
 
 
 
 
X 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 For women with child bearing potential status confirmed only. For further details please refer to Section 8.4.5 
2 For further details please refer to Section 8.3 Efficacy assessments 

Novartis 
 
Confidential 
Page 111 of 224 
Amended Protocol Version 06 (Clean) 
 
Protocol No. CACZ885U2301 
 
Period  
Crossover/ 
Transition 
Maintenance (Open Label Extension) 
Follow up 
Visit Name  
Open Label Extension (OLE) Cycles 
EOT 
OLE Safety follow-up visit (every 
26 d for 130 d after the last dose 
of the study treatment) 
End of 
post 
treatment 
follow-up 
Survival 
follow-up 
(every 12 
weeks) 
 Visits 
- 
OLE Cycle 1 Day 1 and subsequent OLE 
cycles 
- 
1 
2 
3 
4 
5 
- 
- 
3 Tumor assessment at end of treatment (EOT) only for subjects without documented RECIST PD and who do not enter the efficacy follow-up phase provided the last 
scan was not conducted within 30 days prior to the end of study treatment. 
4 For further details please refer to Section 8.4.4 Electrocardiogram (ECG) 
5 ePRO questionnaires should be completed prior to all other assessments in the Assessment Schedule. For further details, please refer to Section 8.5.1 Clinical 
Outcome Assessments (COA). 
6 For further details please refer to Section 6.1 Study Treatment.  
7 Also to be collected as unscheduled, at time of confirmed disease progression 
8 5 mL of whole blood will be collected for hs-CRP. For further details please refer to Section 8.5.3.2 
9 Only collected prior to start of any new antineoplastic therapy 
10 5 mL of whole blood will be collected for Cytokines and Unscheduled cytokines at AE; 10 mL of whole blood will be collected for ctDNA 
11 For China only: biomarker tests will not be done unless approval has been obtained by all relevant Chinese authorities 
12 Until study completion and regardless of any new therapies 
13 Only for patients crossing over from placebo to canakinumab: prior to crossover to canakinumab and on OLE C3D1 for hsCRP and cytokines; only prior to crossover 
to canakinumab ,for ctDNA 
14 If a test was done at the immediately preceding visit, do not repeat on OLE C1D1.  
15 Not applicable for Safety Run In patients who transition to Open Label Extension phase 

Novartis 
 
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Page 112 of 224 
Amended Protocol Version 06 (Clean) 
 
Protocol No. CACZ885U2301 
 
Table 8-5 
Assessment Schedule, Post implementation of protocol amendment 05 
Period 
Maintenance 
Follow-up 
Visit Name 
Subsequent Cycles 
EOT 
Safety follow-up visit (every 26 d for 130 d after the 
last dose of the study treatment) 
End of 
follow 
up 
Days 
Day 1 
- 
1 
2 
3 
4 
5 
 
Main informed consent 
X 
 
 
 
 
 
 
 
Prior/concomitant medications 
From 28 days prior to first dose until 130 days after EOT  
 
Non-drug therapies and procedures 
From 28 days prior to first dose until 130 days after EOT  
 
Physical Examination 
S 
S 
S 
 
S 
 
S 
 
Body Weight 
X 
X 
X 
 
X 
 
X 
 
Vital Signs 
X 
X 
X 
 
X 
 
X 
 
Hematology 
D1 of every second cycle thereafter and as 
clinically indicated 
For subjects on pemetrexed: monitor labs 
according to local label 
X 
X 
 
X 
 
X 
 
Blood Chemistry 
D1 of every second cycle thereafter and as 
clinically indicated 
For subjects on pemetrexed: monitor labs 
according to local label 
X 
X 
 
X 
 
X 
 
Serum pregnancy test 
  
X1 
 
 
 
 
 
 
Urine pregnancy test1 
S 
  
S 
 
S 
 
S 
 
CT or MRI of Chest and Abdomen 
(with intravenous contrast 
enhancement)2 
S - Every 12 weeks3  
 
 
 
 
 
 
Brain CT or MRI2 
S - If clinically indicated and/or positive at baseline, follow 
same schedule as CT/MRI of chest and abdomen 
 
 
 
 
 
 
Whole body bone scan2 
S - If clinically indicated 
 
 
 
 
 
 
CT scan or MRI of other metastatic 
sites (e.g., neck, pelvis, etc.)2 
S - If clinically indicated and/or positive at baseline, follow 
same schedule as CT/MRI of chest and abdomen 
 
 
 
 
 
 
Localized bone CT scan, MRI or x-ray 
(for any skeletal lesions identified on 
the whole-body bone scan that are not 
visible on the chest/abdomen and 
pelvis, if applicable, CT or MRI)2 
S - If clinically indicated and/or positive at baseline, follow 
same schedule as CT/MRI of chest and abdomen 
 
 
 
 
 
 

Novartis 
 
Confidential 
Page 113 of 224 
Amended Protocol Version 06 (Clean) 
 
Protocol No. CACZ885U2301 
 
Period 
Maintenance 
Follow-up 
Visit Name 
Subsequent Cycles 
EOT 
Safety follow-up visit (every 26 d for 130 d after the 
last dose of the study treatment) 
End of 
follow 
up 
Days 
Day 1 
- 
1 
2 
3 
4 
5 
 
Photography (for any skin lesion)2 
S - If clinically indicated and/or positive at baseline, follow 
same schedule as CT/MRI of chest and abdomen 
 
 
 
 
 
 
Electrocardiogram (ECG)4  
X If clinically indicated  
 
Adverse Events 
Continuous, up to 130 days after last dose of study treatment  
 
Serious Adverse Events5 
Continuous, up to 130 days after last dose of study treatment  
 
Drug administration6 
X 
 
 
 
 
 
 
 
IRT drug discontinuation 
 
X 
 
 
 
 
 
 
Disposition Assessment 
 
X 
 
 
 
 
 
X 
X: Assessment to be recorded in the clinical database or received electronically from a vendor 
S: Assessment to be recorded in the source documentation only 
1 For women with childbearing potential status confirmed only. For further details please refer to Section 8.4.5 Pregnancy and assessments for fertility  
2 For further details please refer to Section 8.3 Efficacy assessments. Post implementation of Protocol amendment 05, only the RECIST 1.1 response assessment will 
be recorded in the clinical database. Other efficacy assessment will be recorded in the source documentation only 
3 Tumor assessment at end of treatment (EOT) only for subjects without documented RECIST PD provided the last scan was not conducted within 30 days prior to the 
end of study treatment 
4 For further details please refer to Section 8.4.4 Electrocardiogram  
5 SAE experienced after the 130-day safety follow-up period should be reported to the Novartis Safety only if the investigator suspects a causal relationship to the study 
treatment. For further details refer to Section 8.4 Safety and Section 10.1.3 SAE reporting 
6 For further details please refer to Section 6.1 Study Treatment 

Novartis 
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Amended Protocol Version 06 (Clean) 
 
Protocol No. CACZ885U2301 
 
8.1 
Screening 
All subjects must provide a signed main ICF prior to performing any study specific procedures. 
Subjects will be evaluated against all study inclusion and exclusion criteria. 
After signing the study ICF, the screening assessments will be done within 28 days prior to 
enrollment/randomization (Table 8-2 and Table 8-3). Laboratory parameters may be retested 
within the 28-day screening period for a subject if such parameters meet an exclusion criterion. 
Laboratory assessments performed as part of the screening evaluations will not be required to 
be repeated prior to dosing (except complete blood count if not done within 7 days prior to the 
first dose of treatment) unless deemed clinically necessary by investigator and/or required as 
per local institutional policies.  
In the safety run-in part of the study, known PD-L1 status is not required. In part 2 subject 
randomization will be stratified based on central determination of PD-L1 status and a tumor 
tissue will be sent to a Novartis designated central laboratory for determination of PD-L1 status 
prior to randomization, immediately after patient has signed the ICF and no later than Day -14 
before randomization.  
In addition, EGFR and ALK status must be determined prior to enrollment/randomization for 
all subjects. Local testing is allowed and results must be documented in the source documents 
prior to randomization. If local EGFR and ALK testing is not possible, the tumor sample will 
be tested by the Novartis designated central laboratory.  
Imaging assessments will be completed at screening during the regular work-up of the subject 
within 28 days prior to start of treatment. Imaging done 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. 
Re-screening is not allowed (subject who was screen-failed cannot sign a new informed consent 
form (ICF), however, laboratory parameters or other screening parameters may be retested 
within 28-day screening period for an individual subject). 
Subjects who are randomized and fail to start treatment, e.g. subjects randomized in error, will 
be considered an early terminator. The reason for early termination should be recorded on the 
appropriate eCRF. 
8.1.1 
Eligibility screening 
When all screening procedures are completed and the subject’s eligibility is confirmed (i.e. all 
inclusion/exclusion criteria have been verified), the key eligibility criteria checklist embedded 
in the IRT system will be completed prior to the first dose of study drug. 
Please refer to Section 6.3.2 and as well as comply with detailed guidelines in the IRT manual. 
8.1.2 
Information to be collected on screening failures 
Subjects who sign an informed consent form and are subsequently found to be ineligible prior 
to enrollment/randomization will be considered screen failures. The reason for screen failure 
should be recorded on the appropriate eCRF. The demographic information, informed consent, 
and inclusion/exclusion eCRF pages must also be completed for screen failure subjects. No 

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other data will be entered into the clinical database for subjects who are screen failures, unless 
the subject experienced a serious adverse event during the screening phase (Section 10.1.2 for 
reporting details). Adverse events that are not SAEs will be followed by the investigator and 
collected only in the source data. If the subject fails to be randomized, the IRT must be notified 
within 2 days. 
8.2 
Subject demographics/other baseline characteristics 
Data to be collected on subject characteristics at screening include: 
• Demographic information (age, gender, race and ethnicity as allowed by local regulations).  
• Other background or relevant medical history (including smoking history) 
• Cancer characteristics including diagnosis, history, extent of cancer, prior anticancer 
treatments (medications, radiation, surgeries), date of progression prior to study entry 
• Other assessments will be completed for the purpose of determining eligibility for inclusion 
in the study as reported in  Table 8-2  and  Table 8-3 (e.g. ECOG Performance Status, 
complete physical examination, vital signs, hematology, blood chemistry, coagulation, 
urinalysis, serum pregnancy test for all female subjects, tumor imaging assessments). Vital 
signs must include at minimum: heart rate, systolic and diastolic blood pressure, respiratory 
rate, and body temperature. 
• Prior and current concomitant medications and surgical and medical procedures. 
• Tumor imaging assessments - Refer to Table 8-6  . 
Data to be collected on Cycle 1 Day 1 pre-dose include: 
• Patient Reported Outcomes (PROs) 
• 12-Lead Electrocardiogram (ECG) 
• Pharmacokinetics (PK), immunogenicity (IG) and pharmacodynamics (PD). 
8.3 
Efficacy assessments 
8.3.1 
Tumor assessments 
Tumor response will be assessed locally by the investigator according to the Novartis guideline 
version 3.2 based on RECIST 1.1 ( Section 16.1 ) and iRECIST ( Section 16.2 ). The imaging 
collection plan is presented in Table 8-6 and is applicable for both study parts (safety run-in 
part and double-blind, randomized, placebo-controlled part). The local investigator's 
assessment will be used for primary endpoint analysis (RECIST 1.1) and for treatment decision 
making based on secondary and exploratory efficacy endpoints (RECIST 1.1 and iRECIST). 
For the randomized part, imaging data will be centrally collected and checked for quality by an 
imaging Contract Research Organization (CRO) designated by Novartis. Central review of the 
imaging data will be performed according to an audit based approach detailed in the Statistical 
Analysis Plan (SAP) ( Section 12.8.1 ). Further details on the central assessment can be found 
in the independent review charter of the imaging CRO. Please refer to the site imaging 
operations manual for additional information on the image acquisition and data collection by 
the imaging CRO. Imaging data for the OLE phase should not be submitted to the imaging CRO 
as there will be no central assessment done, only local assessment will be performed in the OLE.  

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Tumor assessments on study treatment should be scheduled using the C1D1 date as the 
reference date and continued regardless of study treatment interruption, unscheduled 
assessments, or transition to the OLE phase. Additional imaging assessments may be performed 
at any time during the study at the investigator’s discretion to support the efficacy evaluations 
for a subject, as necessary. Clinical suspicion of disease progression at any time requires a 
physical examination and tumor 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. Combined Positron Emission Tomography (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 progressive disease per RECIST 1.1 ( Section 16.1 ) and per 
iRECIST ( Section 16.2 ). 
The coded medical images will be used primarily for analysis as described in this protocol; 
however, the images may also be used for the development and evaluation of new analysis 
methods directly related to the area of research that this study covers. 
Post implementation of protocol amendment 05, only the RECIST 1.1 response assessment will 
be recorded in the appropriate CRF page. Other efficacy assessments will be recorded in the 
source documentation only. Also, the efficacy follow-up will no longer be performed. 
Table 8-6 
Imaging Assessment Collection Plan 
Procedure 
Screening/ 
Baseline 
Post baseline (during Treatment) 
Efficacy follow up (post 
implementation of 
protocol amendment 05: 
not applicable) 
CT or MRI of 
Chest and 
Abdomen (with 
intravenous 
contrast 
enhancement) 
Mandated 
Mandated at week 6 and week 12 starting 
on C1D1, then every 9 weeks (through 
week 75), every 12 weeks thereafter until 
progression of disease (PD) as per 
RECIST 1.1 or transition to OLE. 
Study treatment beyond initial RECIST 
1.1 PD: Follow-up scan 4 to 8 weeks after 
initial iUPD, and then continue tumor 
assessments using the same schedule until 
immune confirmed progression by iRECIST 
(iCPD) or discontinuation of study 
treatment (whichever occurs earlier).  
For subjects who discontinue study 
treatment without iCPD, continuation of 
tumor assessments until iCPD or start of 
new anti-neoplastic therapy is 
recommended 
End of Treatment (EOT): done for all 
subjects without prior documented RECIST 
1.1 PD and who do not enter the efficacy 
follow-up phase provided the last scan was 
not conducted within 30 days prior to the 
end of study treatment  
Efficacy Follow-up for 
progression: continue 
tumor assessments using 
the same schedule until 
RECIST 1.1 PD or death 
(regardless of start of 
new anti-neoplastic 
therapy). 

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Procedure 
Screening/ 
Baseline 
Post baseline (during Treatment) 
Efficacy follow up (post 
implementation of 
protocol amendment 05: 
not applicable) 
OLE phase: Follow the same schedule as 
in Table 8-2 (Safety Run In part) or  
Table 8-3 (Randomized part), as 
appropriate, until 159 weeks 
(approximately 3 years) after the study 
C1D1; thereafter, every 24 weeks. 
Post implementation of protocol 
amendment 05: every 12 weeks until 
protocol defined patient discontinuation or 
sponsor study termination. 
Brain CT or MRI 
Mandated 
If clinically indicated and/or positive at 
baseline, follow same schedule as CT/MRI 
of chest and abdomen 
 If clinically indicated 
and/or positive at 
baseline, follow same 
schedule as CT/MRI of 
chest and abdomen 
Whole body 
bone scan 
Mandated 
If clinically indicated 
 If clinically indicated 
CT scan or MRI 
of other 
metastatic sites 
(e.g., neck, 
pelvis, etc.) 
Only if clinically 
indicated 
If clinically indicated and/or positive at 
baseline, follow same schedule as CT/MRI 
of chest and abdomen 
 If clinically indicated 
and/or positive at 
baseline, follow same 
schedule as CT/MRI of 
chest and abdomen 
Localized bone 
CT scan, MRI or 
x-ray (for any 
skeletal lesions 
identified on the 
whole body 
bone scan that 
are not visible 
on the 
chest/abdomen , 
if applicable, CT 
or MRI) 
Only if clinically 
indicated 
If clinically indicated and/or positive at 
baseline, follow same schedule as CT/MRI 
of chest and abdomen 
 If clinically indicated 
and/or positive at 
baseline, follow same 
schedule as CT/MRI of 
chest and abdomen 
Photography (for 
any skin lesions) 
Only if clinically 
indicated 
If clinically indicated and/or positive at 
baseline, follow same schedule as CT/MRI 
of chest and abdomen 
 If clinically indicated 
and/or positive at 
baseline, follow same 
schedule as CT/MRI of 
chest and abdomen 
8.3.1.1 
Baseline imaging assessments 
Imaging assessments will be performed at screening/baseline within 28 days of start of 
treatment (Day -28 to Day -1 prior to Cycle 1 Day 1). 
Any imaging assessments already completed during the regular work-up of the subject within 
28 days prior to start of treatment, including before signing the main study ICF, can be 
considered the baseline images for this study. Any imaging assessments obtained after 
enrollment (subjects in part 1) or randomization (subjects in part 2) cannot be considered 
baseline images. 

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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. 
8.3.1.2 
Post-baseline imaging assessments 
Post-baseline imaging assessments are imaging assessments completed during the study 
treatment until end of treatment (EOT). 
Imaging assessments for response evaluation will be performed at week 6 and week 12 starting 
on C1D1, then every 9 weeks through week 75, then every 12 weeks thereafter until disease 
progression per RECIST 1.1, death, lost to follow-up, pregnancy, withdrawal of consent or 
transition to the OLE phase. During the OLE phase, imaging assessments should follow the 
same schedule as in the safety run in part (Table 8-2) or the randomized part (Table 8-3), as 
appropriate, until 159 weeks (approximately 3 years) after the study C1D1; thereafter, every 24 
weeks.  
If study treatment is continued beyond disease progression as per RECIST 1.1 (Section 6.1.4.1), 
a follow-up scan after the initial immune unconfirmed RECIST 1.1 progressive disease (iUPD) 
per iRECIST per investigator should be done within 4 to 8 weeks, then tumor assessment will 
continue using the same schedule until immune confirmed PD (iCPD) by iRECIST per 
investigator or until discontinuation study treatment for other reasons (whichever occurs 
earlier).  
For subjects who discontinue study treatment without iCPD, continuation of tumor assessments 
until iCPD or start of new anti-neoplastic therapy is recommended.  
8.3.1.3 
End of treatment imaging assessments 
At end of treatment, imaging assessments will be done for all subjects without prior documented 
RECIST 1.1 PD and who do not enter the efficacy follow-up phase provided the last imaging 
assessments was not conducted within 30 days prior to the end of study treatment.  
8.3.1.4 
Efficacy follow-up imaging assessments 
All subjects who discontinue study treatment without prior documented disease progression 
RECIST 1.1 as per investigator will continue these efficacy imaging assessments, in the efficacy 
follow-up phase, until documented disease progression by RECIST 1.1 as per investigator, 
withdrawal of consent, pregnancy, lost to follow up, or death irrespective of start of new anti-
neoplastic therapy. 
Post implementation of protocol amendment 05, efficacy follow-up will no longer be performed. 
8.3.2 
Appropriateness of efficacy assessments 
Not applicable. 
8.3.3 
Survival assessments 
All subjects will be followed for survival status every 12 weeks regardless of treatment 
discontinuation reason (except if consent is withdrawn or subject is lost to follow-up) until death, 

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lost to follow-up, or withdrawal of consent for survival follow-up. Additional survival 
assessments may be performed outside the 12 weeks follow-up schedules if a survival update 
is required for an interim assessment to meet safety or regulatory needs. Survival information 
can be obtained via phone, and information will be documented in the source documents and 
appropriate eCRFs. 
Information on all subsequent therapies received for NSCLC, if any, after study treatment has 
been completed, will be collected (including start date, stop date, and date of progression if any). 
Post implementation of protocol amendment 05, survival follow-up will no longer be performed. 
8.4 
Safety 
During treatment  
Safety will be monitored by assessing physical examination, Eastern Cooperative Oncology 
Group (ECOG) Performance Status, vital signs, body weight, ECG, Patient Reported Outcomes, 
laboratory assessments, pregnancy tests, as well as collecting adverse events at every visit. For 
details on AE collection and reporting, refer to Section 10. Post implementation of protocol 05, 
performance status will no longer be performed. All safety assessments should be completed as 
per Table 8-2, Table 8-3 Table 8-4 and Table 8-5. 
Post treatment discontinuation  
All safety assessments (including pregnancy test for female subjects of child bearing potential) 
should be completed as per Table 8-2, Table 8-3, Table 8-4 and Table 8-5.  
However, if the subject begins post-treatment antineoplastic medication before the completion 
of the 130-Day safety follow-up visit, only the new SAEs and AEs suspected to be related to 
study treatment will be collected up to the 130-Day safety follow-up visit.  
After the 130-Day safety follow-up visit, only SAEs suspected to be related to study treatment 
will be collected during survival follow-up. Data collected should be added to the appropriate 
eCRF. Post implementation of protocol amendment 05, SAE experienced after the 130-day 
safety follow-up period should be reported to Novartis Safety only if the investigator suspects 
a causal relationship to the study treatment (Section 10.1.3). 
As per Section 4.6, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, regular 
phone or virtual calls can occur as per the assessment schedule (or more frequently if needed) 
for safety monitoring and discussion of the subject´s health status until it is safe for the subject 
to visit the site again. 
8.4.1 
Laboratory evaluations 
Central safety laboratories will be used for the analysis of scheduled hematology, chemistry, 
and other blood specimens ( Table 8-2 ,  Table 8-3 , and Table 8-8 ). The laboratory evaluations 
should be assessed on the actual scheduled day, even if study drug is being withheld. The time 
windows for laboratory evaluations correspond to the visit time windows for each visit 
( Table 8-1 ).  

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During the OLE phase, only local laboratory testing will be performed for safety evaluations 
(Table 8-4 and Table 8-7).  
Post the implementation of protocol amendment 05, only local laboratory testing will be 
performed for safety evaluations aligned to standard of care with their current treatment and 
dosing regimen. (Table 8-5 and Table 8-8).  
More frequent timepoints should be added as deemed necessary per the investigator's judgment 
to make sure toxicity profile is sufficiently characterized (e.g. DLT assessment in the safety 
run-in) and dose modifications performed to safeguard the safety of the subject. Additional 
results from unscheduled laboratory evaluations should be recorded on the appropriate eCRF. 
Laboratory values obtained during the screening phase from the central laboratory will be used 
to assess eligibility. However, the site does not need to wait for the results of centrally-analyzed 
laboratory assessments when an immediate clinical decision needs to be made  
(e.g. confirmation of eligibility, study drug interruption, re-initiation, and/or termination). In 
those cases, local laboratory testing may be performed. The investigator is responsible for 
reviewing all laboratory reports for subjects in the study and evaluating any abnormalities for 
clinical significance. For visits with safety laboratory assessment only, a subject on-site visit 
may not be required, as per the investigator’s discretion, and local laboratory testing may be 
performed. 
Dipstick urinalysis (macroscopic panel) will be performed at the site (unless local institution 
policies dictate otherwise), and in the case of any out of range parameters, a urine sample will 
be sent to central laboratory for further analysis (microscopic panel). 
Details on the collection, sample shipment, and reporting of results by the central laboratory are 
provided in the Central Laboratory Manual and Flowchart. 
If at any time a subject has laboratory parameters obtained from a local laboratory, Novartis 
must be provided with a copy of the certification and a tabulation of the normal ranges and units 
for this laboratory. The results of the local laboratory will be recorded in the eCRF if any the 
following criteria are met: 
• A treatment decision was made based on the local results, or 
• There are no concomitant central results available, or 
• Local lab results document an AE not reported by the central lab, or 
• Local lab results document an AE where the severity is worse than the one reported by the 
central lab. 
As per Section 4.6, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, regular 
phone or virtual calls can occur as per the assessment schedule (or more frequently if needed) 
for safety monitoring and discussion of the subject´s health status until it is safe for the subject 
to visit the site again. 

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Table 8-7 
Clinical laboratory parameters collection plan prior to implementation 
of protocol amendment 05 
Test Category 
Test Name 
Hematology 
Hemoglobin, Platelets, Red blood cells (RBC), White blood cells (WBC) with Differential 
(Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils in percentage or absolute) 
Chemistry 
Albumin, ALT, AST, calciuma (at screening, calcium corrected for albumin will be tested in 
addition to calcium), creatinine, creatinine clearancea, creatine kinase, total bilirubin, direct 
and indirect bilirubin (only if total bilirubin is ≥ grade 2), blood urea nitrogen (BUN) or urea, 
magnesium, potassium, sodium, fasting glucosea, phosphate (inorganic phosphorus), alkaline 
phosphatase, amylase, pancreatic amylase (as needed), lipase, GGT 
Thyroid 
Total T3, FT4 and TSH 
Coagulation 
Pro-thrombin time (PT) and International normalized ratio [INR] or Quick Test 
Hepatitis 
HBV-DNA, HbsAg, HbsAb, HbcAb, HCV RNA-PCR (baseline) 
Infectious 
markers 
Tuberculosis testing (as defined by country guidelines), HIV (where locally required) 
Urinalysis 
Macroscopic panel (Dipstick) (color, bilirubin, blood, glucose, ketones, leukocyte esterase, 
nitrite, pH, protein, specific gravity, urobilinogen) Microscopic panel (RBC, WBC, casts, 
crystals, bacteria, epithelial cells) 
Pregnancy 
At screening visita and EOT, serum pregnancy test 
If local requirements dictate otherwise, local regulations should be followed 
a not applicable for the OLE phase 
Table 8-8 
Clinical laboratory parameters collection plan post implementation of 
protocol amendment 05 
Test Category 
Test Name  
Hematology 
Hemoglobin, Platelets, White blood cells (WBC) with Differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils in percentage or absolute) 
Chemistry 
Albumin, ALT, AST, creatinine, creatinine clearance, creatine kinase, total bilirubin, direct 
and indirect bilirubin (only if total bilirubin is ≥ grade 2) 
Pregnancy 
At EOT, serum pregnancy test  
If local requirements dictate otherwise, local regulations should be followed 
8.4.1.1 
Laboratory testings 
Hematology, chemistry, thyroid function tests, coagulation, urinalysis and infectious disease 
marker tests are to be performed according to the visit schedule (Table 8-2 and Table 8-3). 
Laboratory assessment done ≤ 7 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 laboratory hematology testing may also be performed as medically necessary, 
and for accurate DLT determination in the safety run-in. Additional results from unscheduled 
hematology lab evaluations should be recorded on the appropriate electronic Case Report Form 
(eCRF). 
Estimate of GFR (via estimated creatinine clearance rate) will be done using Cockcroft-Gault 
formula:  

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8.4.2 
Determination of tuberculosis status 
Determination of tuberculosis (active or latent) status will be required before administration of 
study drug and should be performed as defined by country guidelines. If presence of 
tuberculosis (active or latent) is established then treatment for tuberculosis must have been 
completed according to locally approved country guidelines prior to screening for the study. In 
case a subject develops tuberculosis during the study, this event must be followed-up and 
recorded in the eCRF. 
8.4.3 
Performance status 
The performance status will be assessed according to the Eastern Cooperative Oncology Group 
(ECOG) performance status scale as specified in Table 8-9 (Oken et al 1982) following the 
schedule given in Table 8-2 , Table 8-3 and Table 8-4.  
Post implementation of protocol amendment 05, performance status will no longer be 
performed. 
Table 8-9 
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 
8.4.4 
Electrocardiogram (ECG) 
Local single 12-lead ECGs should be recorded prior to the dose administration, after the subject 
has been resting for 5-10 min prior to the timepoints indicated in Table 8-2,Table 8-3,  
Table 8-4 and Table 8-5. 

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An unscheduled ECG may be repeated at the discretion of the investigator at any time during 
the study and as clinically indicated. Interpretation of the tracing must be made by a qualified 
physician and documented in the appropriate eCRF. 
Each ECG tracing should be labeled with the study number, subject initials (where regulations 
permit), subject number, date, and kept in the source documents at the study site. Clinically 
significant ECG abnormalities present at screening should be reported on the appropriate eCRF. 
New or worsened clinically significant findings occurring after informed consent must be 
recorded on the appropriate eCRF. 
8.4.5 
Pregnancy and assessments of fertility 
During screening, a serum pregnancy test will be completed for all female subjects. Only for 
women of child bearing potential on Cycle 1 Day 1 prior to dosing and at subsequent cycles, a 
urine pregnancy test (dipstick) will be performed and a serum pregnancy test will also be 
completed at EOT. The time windows granted for pregnancy testing are identical to the 
corresponding visit time windows for each visit (Table 8-2 and Table 8-3). If local requirements 
dictate otherwise, local regulations should be followed. 
During the OLE phase or post implementation of protocol amendment 05, only urine pregnancy 
test (dipstick) will be performed for women of child bearing potential, as shown on Table 8-4 
and Table 8-5. Except at EOT, there will be a serum pregnancy test.  
Women who are determined not to be of child bearing potential before the study will only 
complete a serum pregnancy test at screening. When non-child bearing potential status is 
determined during the study, further pregnancy testing will not be continued. 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), and 
otherwise not of child bearing potential if they have had surgical bilateral oophorectomy (with 
or without hysterectomy), or bilateral tubal ligation at least 6 weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed by 
follow up hormone level assessment is she considered not of child bearing potential (such 
testing is not covered as part of the study assessments). If local requirements dictate otherwise, 
local regulations should be followed. 
If a positive pregnancy test is obtained in between study visits, the subject must immediately 
notify the investigator. Male subjects must notify the investigator in case their partner becomes 
pregnant during the treatment period (Section 10.1.4). 
As per Section 4.6, during a public health emergency as declared by local or regional authorities' 
i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, if subjects 
cannot visit the site to have serum pregnancy tests, urine pregnancy test kits may be used. 
Relevant subjects can perform the urine pregnancy test at home and report the result to the site. 
It is important that subjects are instructed to perform the urine pregnancy test first and only if 
the test result is negative proceed with the administration of the study treatment. A 
communication process should be established with the subject so that the site is informed and 
can verify the pregnancy test results (e.g. following country specific measures). 

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8.5 
Additional assessments 
8.5.1 
Clinical Outcome Assessments (COAs) 
The European Organization for Research and Treatment of Cancer’s core quality of life 
questionnaire (EORTC-QLQ-C30), the lung cancer specific module (QLQ-LC13), and the 
EuroQoL 5-level instrument (EQ-5D-5L, tablet version) will be used to evaluate patient 
reported outcome (PRO) measures of health-related quality-of-life (QoL), physical functioning, 
disease symptoms, treatment-related side effects, global health status, and utilities 
(Aaronson et al 1993, Bergman et al 1994, Rabin and de Charro 2001). 
All electronic PROs (ePROs) data will only be collected during the double-blind, randomized, 
placebo-controlled part of the study and in the OLE phase using an electronic tablet device 
provided by a CRO designated by Novartis. Subjects enrolled in the safety run-in part of the 
study will not complete ePROs. All ePRO assessments should be administered in the subject’s 
local language according to the assessment schedule in Table 8-3 for the randomized part and 
Table 8-4 for the OLE phase, as applicable, prior to any assessments (including imaging 
assessments), treatments, or receipt of results from any test to avoid biasing the subject’s 
perspective. 
The ePROs will be completed prior to any other assessments on Day 1 of each cycle and at the 
End of Treatment visit (EOT) (Table 8-4), and then: 
• For subjects who discontinue treatment due to RECIST 1.1 progression as per investigator 
and enter the safety follow-up period, ePROs will be collected within 7 days of the reported 
progression, and again at 28 days (-7 / +14 days) post progression. 
• For subjects who discontinue study treatment for any reason other than RECIST 1.1 
progression as per investigator and enter the efficacy follow-up period, ePROs will be 
collected at the same timepoints as the imaging assessments until RECIST 1.1 progression 
(on-site). Following progression, ePROs will then be collected within 7 days of the reported 
progression, and again at 28 days (-7 / +14 days) post progression. 
During the OLE phase, ePROs will be completed following the same schedule as tumor 
assessments as well as at the EOT visit, during the efficacy follow-up and during the safety 
follow-up, as detailed above and in Table 8-4.  
Subjects should be given sufficient space and time to complete all study questionnaires. If 
missing responses are noted, the tablet will alert subjects of any missing responses. Attempts 
should be made to collect complete questionnaires for all subjects.  
The ePROs in this study are self-administered. If a subject is not able to self-administer the 
ePRO (e.g. due to illiteracy or blindness) or refuses to complete the questionnaires, this should 
be documented in the source documents and the questionnaires will not be completed. A 
subject’s inability or refusal to complete study questionnaire(s) are not protocol deviations. 
Please refer to the study ePRO manual for detailed instructions for completion and handling of 
the ePROs. 
Post implementation of protocol amendment 05, the ePRO questionnaires will no longer be 
performed. 

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8.5.2 
Pharmacokinetics (PK), immunogenicity (IG) and pharmacodynamics 
(PD) assessments 
To evaluate canakinumab exposure and immunogenicity in this indication, and also to evaluate 
exposure of the proposed dosing regimen, sample collections for analysis of PK and anti-drug 
antibodies (ADA) are currently planned for canakinumab in the presence of pembrolizumab 
and various chemotherapy agents. 
Blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in 
a forearm vein. Samples are collected from the arm opposite from infusion site. If drug was 
administered via a central venous catheter, sample collection for PK (and IG/PD as 
applicable) should be from a different site. Timepoints of blood sample collection for 
canakinumab, pembrolizumab, and chemotherapy agents are outlined in Table 8-10 .  
For all PK, IG, and PD analytes, the exact date and time of dosing, as well as the exact collection 
date and time of blood sampling must be recorded on the appropriate eCRF. All samples will 
be given a unique sample number and a dose reference ID. 
If subjects experience an AE or SAE leading to a canakinumab dosing interval increase to Q6W 
or Q9W (see Section 6.5.3), do not collect canakinumab PK, PD, and/or IG samples on a visit 
cycle if canakinumab is not administered. Collect PK, PD, and/or IG samples if canakinumab 
is administered on a visit cycle in which samples are already scheduled as stated in protocol 
Table 8-10. 
If subjects experience an AE or SAE leading to discontinuation of the study treatment, an 
unscheduled PK and IG blood sample should be obtained as close as possible to the event 
occurrence. If anaphylactoid reactions occur after injection, two more canakinumab IG samples 
(at the time of the event and 8 weeks later) need to be taken. 
If dose level -1 (DL-1) of canakinumab 200 mg Q6W is explored as an alternative schedule, the 
canakinumab sampling scheme for Q6W regimen (also specified in Table 8-10) will be 
followed. 
On days and time points where blood IG and PD samples are to be drawn, the PK sample must 
be drawn first. 
During the OLE phase, there will be no PK, IG and PD sample collection done.  
Refer to Central Laboratory Flowchart for detailed PK, IG and PD collection. 
Post implementation of protocol amendment 05, the sample collection for analysis of PK, IG 
and PD will no longer be performed.  

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Table 8-10 
Blood collection schedule for canakinumab (PK, IG and PD), 
pembrolizumab (PK and IG) and chemotherapy agents (PK) 
Study Part 
Analyte 
PK/IG/PD 
Scheduled time points for PK sampling* 
Safety run- 
in (all 
subjects) 
Randomized 
(all subjects) 
Canakinumab 
(Q3W) 
PK 
C1D1 pre-dose, C1D2, C1D8, C1D15; C2D1 pre-dose; 
C3D1 pre-dose; C4D1 pre-dose; C5D1 pre-dose, C5D8; 
C6D1 pre-dose; C8D1 pre-dose; C12D1 pre-dose; 
C16D1 pre-dose; EOT; safety follow up 26 days post 
EOT, safety follow up 78 days post EOT; safety follow up 
130 days post EOT; Unscheduled 
IG 
C1D1 pre-dose; C4D1 pre-dose; C8D1 pre-dose; C12D1 
pre-dose; C16D1 pre-dose; EOT; safety follow up 26 
days post EOT, safety follow up 78 days post EOT; safety 
follow up 130 days post EOT; Unscheduled 
PD (Total IL-
1β) 
C1D1 pre-dose, C1D15; C5D1 pre-dose; C16D1 pre-
dose; EOT; safety follow up 26 days post EOT, safety 
follow up 78 days post EOT; safety follow up 130 days 
post EOT; Unscheduled 
Canakinumab 
(Q6W) 
(for dose level -1) 
PK 
C1D1 pre-dose, C1D2, C1D8, C1D15; C2D1; C3D1 pre-
dose; C4D1; C5D1 pre-dose, C5D8; C7D1 pre-dose; 
C11D1 pre-dose; C15D1 pre-dose; EOT; safety follow up 
26 days post EOT, safety follow up 78 days post EOT; 
safety follow up 130 days post EOT; Unscheduled 
IG 
C1D1 pre-dose; C4D1; C7D1 pre-dose; C11D1 pre-dose; 
C15D1 pre-dose; EOT; safety follow up 26 days post 
EOT, safety follow up 78 days post EOT; safety follow up 
130 days post EOT; Unscheduled 
PD (Total IL-
1β) 
C1D1 pre-dose, C1D15; C5D1 pre-dose; C15D1 pre-
dose; EOT; safety follow up 26 days post EOT, safety 
follow up 78 days post EOT; safety follow up 130 days 
post EOT; Unscheduled 
Safety run- 
in (all 
subjects) 
Randomized 
(subset of 60 
subjects) 
Pembrolizumab 
PK 
C1D1: pre-infusion, EOI (within 30 min), C1D2, C1D8, 
C1D15; C2D1 pre-infusion; C3D1 pre-infusion; C4D1 pre-
infusion; C5D1 pre-infusion, EOI (within 30 min); C6D1 
pre-infusion; C8D1 pre-infusion; C12D1 pre-infusion; 
C16D1 pre-infusion; EOT; safety follow up 26 days post 
EOT; Unscheduled 
IG 
C1D1 pre-infusion; C2D1 pre-infusion, C4D1 pre-infusion; 
C8D1 pre-infusion; C12D1 pre-infusion; C16D1 pre-
infusion; EOT; safety follow up 26 days post EOT; 
Unscheduled 
Safety run-in 
(all subjects) 
Pemetrexed 
PK 
C1D1 pre-infusion, EOI (within 5 min), 1 h (±10 min), 4 h 
(±10 min), 8 h (±10 min); C2D1 pre-infusion, EOI (within 5 
min), 1 h (±10 min), 2 h (±10 min),4 h (±10 min), 8 h (±10 
min); Unscheduled 
Randomized 
(subset of 40 
subjects) 
Pemetrexed 
PK 
C1D1 pre-infusion, EOI (within 5 min), 1 h (±10 min), 4 h 
(±10 min); C2D1 pre-infusion, EOI (within 5 min), 1 h (±10 
min), 2 h (±10 min), 4 h (±10 min); Unscheduled 
Safety run-in 
(all subjects) 
Cisplatin 
PK 
C1D1 pre-infusion, EOI (within 5 min), 2 h (±10 min), 4 h 
(±10 min), 8 h (±10 min); C2D1 pre-infusion, EOI (within 5 
min), 1.5 h (±10 min), 2 h (±10 min),4 h (±10 min), 8 h 
(±10 min); Unscheduled 
Randomized 
(subset of 40 
subjects) 
Cisplatin 
PK 
C1D1 pre-infusion, EOI (within 5 min), 2 h (±10 min), 4 h 
(±10 min); C2D1 pre-infusion, EOI (within 5 min), 1.5 h 
(±10 min), 2 h (±10 min), 4 h (±10 min); Unscheduled 

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Study Part 
Analyte 
PK/IG/PD 
Scheduled time points for PK sampling* 
Safety run-in 
(all subjects) 
Carboplatin 
PK 
C1D1 pre-infusion, EOI (within 5 min), 1 h (±10 min), 2 h 
(±10 min), 4 h (±10 min), 8 h (±10 min); C2D1 pre-
infusion, EOI (within 5 min), 1 h (±10 min), 2 h (±10 
min),4 h (±10 min), 8 h (±10 min); Unscheduled 
Randomized 
(subset of 40 
subjects) 
Carboplatin 
PK 
C1D1 pre-infusion, EOI (within 5 min), 1 h (±10 min), 2 h 
(±10 min), 4 h (±10 min)**; C2D1 pre-infusion, EOI (within 
5 min), 1 h (±10 min), 2 h (±10 min),4 h (±10 min)**; 
Unscheduled 
**For paclitaxel + carboplatin regimen only, allow +/- 1 hr 
window for the 4 hour carboplatin collection. 
Safety run-in 
(all subjects) 
Paclitaxel 
PK 
C1D1 pre-infusion, EOI (within 5 min), 4 h (±10 min), 8 h 
(±10 min), 12 h (±10 min); C2D1 pre-infusion, EOI (within 
5 min), 4 h (±10 min), 6 h (±10 min), 8 h (±10 min), 12 h 
(±10 min); Unscheduled 
Randomized 
(subset of 25 
subjects) 
Paclitaxel 
PK 
C1D1 pre-infusion, EOI (within 5 min), 4 h (±10 min); 
C1D2 24 h (±1 h); C2D1 pre-infusion, EOI (within 5 min), 
4 h (±10 min), 6 h (±1 h); C2D2 24 h (±1 h); Unscheduled 
Randomized 
(subset of 25 
subjects) 
Nab-paclitaxel 
PK 
C1D1 pre-infusion, EOI (within 5 min), 4 h (±10 min), 
C1D2 24h (± 1 h); C2D1 pre-infusion, EOI (within 5 min), 
4 h (±10 min), 6 h (±1 h);; C2D2 24 h (± 1 h); 
Unscheduled 
EOI= end of infusion; EOT=end of treatment; 
*The collection time points are relative to s.c. canakinumab injection or beginning of i.v. infusion of respective 
drugs. 
8.5.2.1 
Analytical method 
Bioanalysis for PK, IG and PD assessments will employ the validated assays: 
1. Canakinumab will be quantified in serum using a validated competitive enzyme-linked 
immunosorbent assay (ELISA) method, with an anticipated lower limit of quantification 
(LLOQ) of 100 ng/mL. The detailed method description to assess canakinumab (ACZ885) 
concentration will be described in the bioanalytical raw data of the study and in the 
respective Bioanalytical Data Report (BDR). 
2. The IG against canakinumab will be assessed in serum using a validated Meso Scale 
Discovery (MSD) electrochemiluminescence assay. The detailed method description to 
assess immunogenicity will be described in the bioanalytical raw data of the study and in 
the respective BDR. 
3. An ELISA method will be used for bioanalytical analysis of total IL-1 Beta in serum, with 
an anticipated LLOQ of 0.299 ng/mL. The detailed method description to assess PD 
concentration will be described in the bioanalytical raw data of the study and in the 
respective BDR. 
4. Pembrolizumab will be quantified in serum using a validated Ligand binding assay. Details 
of the method will be provided in the Bioanalytical data report (BDR). 
5. The anti-drug antibodies (ADAs) against pembrolizumab will be assessed in serum using a 
validated immunoassay assay Details of the method will be provided in the bioanalytical 
data report (BDR). 
6. Chemotherapy agents (paclitaxel, nab-paclitaxel, pemetrexed, carboplatin, and cisplatin) 
will be quantified in plasma using validated LC/MS and/or ICP-MS assays. The detailed 

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method will be described in the bioanalytical raw data of the study and in the respective 
BDR. 
8.5.3 
Biomarkers 
The exploratory biomarker analysis will investigate whether the immune status of the tumor 
and its microenvironment are associated with the anti-tumor activity of canakinumab. The 
analysis will be performed in tumor biopsy samples collected at baseline, on treatment and time 
of progression, and using non-invasive samples taken at baseline, on treatment and post-
treatment. 
Blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in 
a forearm vein. Samples are collected from the arm opposite from infusion site. If the study 
treatment was administered via central venous catheter, sample collection for biomarkers 
should be from a different site. Refer to Central Laboratory Flowchart for details of mandatory 
and optional biomarker assessments.  
For China only: biomarker tests will not be done unless approval has been obtained by all 
relevant Chinese authorities. 
Post implementation of protocol amendment 05, the sample collection for analysis of 
biomarkers will no longer be performed. 
8.5.3.1 
Exploratory biomarker assessments in tumor biopsy samples 
collected at baseline, on-treatment and/or at progression  
Mandatory tumor samples are to be collected at screening and may include resection, core, 
excisional and incisional biopsies. Fine needle aspirates are not acceptable sample types. 
Assessments may include but are not limited to immunohistochemistry (IHC) immune markers, 
immunological cells and related markers, gene expression profiling, sequencing of specific 
genes and determination of mutation load. Further, the on-treatment and progressive disease 
biopsies will be compared to baseline tumor to assess how the treatments affect the immune 
response at the level of the tumor. 
8.5.3.2 
Exploratory biomarker assessments performed using non-invasive 
samples 
Assessments in blood samples collected at baseline, on treatment, post-treatment follow-up 
phase and at disease progression will include hs-CRP, hs-IL-6 and other cytokines and soluble 
protein biomarkers. The sequencing of specific gene panels and determination of mutation load 
using circulating DNA (ctDNA) will also be performed. Circulating tumor cells (CTCs) will be 
collected at baseline in a subset of subjects (approximately 60 subjects) to enable assessment of 
correlation between the PD-L1 levels in CTC versus tumor biopsy. Correlation between CTC 
counts and treatment outcome will also be evaluated. 
Biomarker results (including hs-CRP) will be blinded and will not be communicated to the 
investigational sites during study conduct. 

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8.5.3.3 
Additional biomarker assessments 
Pharmacogenetic analysis 
For subjects who sign the Optional Pharmacogenetic Patient Information and Informed Consent 
Form, one whole blood (sample will be collected, and used for assessments to identify 
predictive genetic markers. Additional retrospective pharmacogenetic analysis may be 
performed as well. 
8.5.3.4 
Use of residual biological samples 
Optional additional biomarker studies 
If the subject agrees, the biomarker samples that remain after analysis is completed (tumor, 
blood, plasma, and serum) may be kept for up to 15 years to be used for additional studies 
related to canakinumab or cancer, including research to help develop ways to detect, monitor 
or treat cancer. A decision to perform such exploratory biomarker research studies would be 
based on outcome data from this study or from new scientific findings related to the drug class 
or disease, as well as assay availability. 
9 
Discontinuation of study treatment and participant 
discontinuation/withdrawal 
9.1 
Discontinuation 
9.1.1 
Discontinuation of study treatment 
Discontinuation of study treatment for a subject occurs when study treatment is permanently 
stopped (prior to the planned completion of study treatment administration if any) , and can be 
initiated by either the subject or the investigator. The investigator must discontinue study 
treatment for a given subject if, he/she believes that continuation would negatively impact the 
subject's well-being. 
Discontinuation from study treatment is required under the following circumstances: 
• Subject/guardian decision 
• Pregnancy 
• Any situation in which continued study participation might result in a safety risk  
• Unsatisfactory therapeutic effect 
• Subject’s condition no longer requires study treatment 
• Disease progression per RECIST 1.1 if it occurs when canakinumab/matching placebo is 
administered as a single agent 
• Disease progression per RECIST 1.1 if it occurs when pembrolizumab was previously 
discontinued. 
If discontinuation of study treatment occurs due to participant’s decision, the investigator 
should make a reasonable effort to understand the primary reason for the participant’s 
discontinuation of study treatment and record this information.  

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The investigator must contact the IRT to register the subject’s discontinuation from study 
treatment. If discontinuation occurs because treatment code has been broken, please refer to 
Emergency breaking of assigned treatment code section (Section 6.6.2). 
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent ( Section 9.2.2 ). Where possible, they should return for the assessments 
indicated in the assessment schedule. If they fail to return for these assessments for unknown 
reasons, every effort (e.g. telephone, e-mail, letter) should be made to contact the subject/pre-
designated contact as specified in the lost to follow-up section. This contact should preferably 
be done according to the study visit schedule. 
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule. 
For subjects who discontinue 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 12 weeks until documented disease 
progression (per Investigator), death, lost to follow-up, or discontinuation from study or 
withdrawal of consent/opposition to use data/biological samples. 
In some circumstances, subjects may be allowed to continue to receive study treatment beyond 
disease progression as per RECIST 1.1 criteria (Section 6.1.4.1). These subjects will continue 
assessment as outlined in  Section 8  and will complete the end of treatment (EOT) visit only 
after permanent discontinuation of study treatment. 
All subjects will have an EOT visit once all drugs of the study treatment are permanently 
discontinued (canakinumab, pembrolizumab, platinum-based doublet chemotherapy, and 
pemetrexed as applicable). Subjects should be scheduled for an EOT visit as soon as possible 
following the discontinuation of study treatment, at which time all assessments listed for EOT 
visit will be performed (Table 8-2, Table 8-3, Table 8-4 or Table 8-5). This visit should take 
place ≤ 7 days after the last dose of study treatment, if possible and appropriate eCRF page 
should be completed at this time, giving the date and reason for stopping the study treatment. 
EOT is not considered as end of study. 
After study treatment discontinuation, all enrolled/randomized and/or treated subjects will be 
followed for AEs and SAEs for at least 130 days following the last dose of study treatment at 
the end of the treatment phase. Subjects will complete a total of five safety follow-up visits 
every 26 days until 130 days after the last dose of study treatment (Table 8-2, Table 8-3,  
Table 8-4 and Table 8-5). The information collected is kept in source documentation and in 
eCRF. All SAEs reported during this time period must be reported as described 
in  Section 10.1.3. Documentation of attempts to contact the subject should be recorded in the 
source documentation. 
9.2 
Participant discontinuation from the 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. 

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If the participant agrees, a final evaluation at the time of the participant’s study discontinuation 
should be made as detailed in Section 8 Visit schedule and assessments. 
9.2.1.1 
Replacement policy 
Safety run-in part 
Subjects will not be replaced on study. However, if a subject is considered as non-evaluable for 
the Dose-Determination Set (DDS), a new subject will be enrolled until at least the minimum 
number of 6 evaluable subjects is achieved within each treatment cohort. 
Double-blind, randomized, placebo-controlled part 
Subjects will not be replaced. 
9.2.2 
Withdrawal of informed consent and exercise of participants’ 
data privacy rights 
Withdrawal of consent/opposition to use of data and/or biological samples occurs in countries 
where the legal justification to collect and process the data is consent and when a participant: 
• Explicitly requests to stop use of their data 
and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study-related contacts) 
This request should be as per local regulations (e.g. in writing) and recorded in the source 
documentation. Withdrawal of consent impacts ability to further contact the participant, collect 
follow-up data (e.g. to respond to data queries) and potentially other country-specific 
restrictions. It is therefore very important to ensure accurate recording of withdrawal vs. 
discontinuation based on the protocol definitions of these terms. 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw their consent/exercise 
data privacy rights and record this information. The Investigator shall clearly document if the 
participant has withdrawn his/her consent for the use of data in addition to a study 
discontinuation. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject 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 
Section 8 Visit Schedule and assessments. Further details on withdrawal of consent or the 
exercise of participants' data privacy rights are included in the corresponding informed consent 
form. 

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9.2.3 
Lost to follow-up 
For subjects 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 subjects’ data 
privacy rights), the investigator must show "due diligence" by documenting in the source 
documents steps taken to contact the subject, e.g. dates of telephone calls, registered letters, etc. 
A subject should not be considered as lost to follow-up until due diligence has been completed 
or until the end of the study. 
9.2.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time. Reasons for early termination (but not 
limited to): 
• Unexpected, significant, or unacceptable safety risk to subject s enrolled in the study 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
• Discontinuation of investigational drug development in this indication. 
In taking the decision to terminate, Novartis will always consider the subject welfare and safety. 
Should early termination be necessary, subjects must be seen as soon as possible and treated as 
a subjects who discontinued from study treatment’ ( Section 9.1.1 ). The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate consideration 
is given to the protection of the subject’s interests. The investigator or sponsor depending on 
local regulation will be responsible for informing IRBs/IECs of the early termination of the trial. 
9.3 
Study completion and post-study treatment 
The final PFS analysis and the 1st interim OS analysis in the randomized part will occur when 
approximately 253 PFS events are reached ( Section 12.4 ), expected to occur approximately 
18 months after the first subject randomized. At this time, a primary PFS/OS clinical study 
report (CSR) will be produced in case PFS or OS results are found statistically significant. The 
final analysis of the data from the safety run-in part will also be included in this primary PFS/OS 
CSR (Section 12). 
After the primary PFS/OS CSR (if PFS alone is statistically significant), the study will remain 
open for the next OS analyses. Ongoing subjects will continue to receive study treatment and 
be followed as per the schedule of assessments (Table 8-2 and Table 8-3).  
The primary OS analysis will take place when OS reaches statistical significance at either one 
of the interim or final OS analyses and the primary OS CSR will be produced. At this time the 
investigational sites will be unblinded for treatment allocation and subjects will transition to the 
OLE phase (Section 3). If OS is not statistically significant at final analysis but PFS was 
statistically significant at primary analysis, OLE will be initiated after final OS analysis, 
following the unblinding of investigational sites. 
The study will end when all subjects discontinue the study treatment and complete their safety 
follow up, die, withdraw consent or are lost to follow up, whichever comes first. All available 
data from all subjects up to the final analysis cut-off date will be analyzed and summarized in 

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a final CSR. Also, in the event of an early study termination decision (Section 9.1.4), the end 
of the study is the date of that decision. 
At the end of the study, every effort will be made in alignment with local regulations to continue 
provision of investigational treatment (canakinumab) or any of the other drugs (pembrolizumab 
and chemotherapy drugs as applicable) outside this study through an alternative setting to 
subjects who have not yet progressed per RECIST 1.1 as per investigator or iRECIST for 
subjects who in the opinion of investigator are still deriving clinical benefit. 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any occurrence of unfavorable 
and unintended sign(s) [including abnormal laboratory findings], symptom(s) or disease) in a 
subject or clinical investigation subject after providing written informed consent for 
participation in the study. Therefore, an AE may or may not be temporally or causally associated 
with the use of a medicinal (investigational) product. This includes events reported by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant’s legally 
authorized representative). 
The investigator and any qualified designees  are responsible for managing the safety of 
individual subject and identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments. 
Adverse events must be recorded in the eCRF 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) 
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected’. The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single subject  
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not recovered/not 
resolved must be reported. 

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4. Whether it constitutes a SAE ( Section 10.1.2  for definition of SAE) and which seriousness 
criteria have been met 
5. Action taken regarding with study treatment. All adverse events must be treated 
appropriately. Treatment may include one or more of the following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/withdrawn 
6. Outcome (not recovered/not resolved, recovered/resolved, recovered/resolved with 
sequelae, fatal, unknown) 
If the event worsens the event should be reported a second time in the eCRF noting the start 
date when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement 
to a lower grade is determined a new entry for this event should be reported in the eCRF noting 
the start date when the event improved from having been Grade 3 or Grade 4. 
Adverse events that begin or worsen after informed consent should be recorded in the eCRF. 
Conditions that were already present at the time of informed consent should be recorded in the 
eCRF. Adverse event monitoring should be continued for at least 130 days following the last 
dose of study treatment. Adverse events (including lab abnormalities that constitute AEs) 
should be described using a diagnosis whenever possible, rather than individual underlying 
signs and symptoms. When a clear diagnosis cannot be identified, each sign or symptom should 
be reported as a separate adverse event. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. Continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors), should not be reported as a 
serious adverse event, except if the investigator considers that progression of malignancy is 
related to study treatment.  
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator Brochure (IB). 
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 

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baseline or the previous visit, or values which are considered to be non-typical in subjects with 
the underlying disease. 
10.1.1.1 Adverse events of special interest 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may be 
appropriate. Such events may require further investigation in order to characterize and 
understand them. 
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. 
AESI for canakinumab include: 
• Infections/Opportunistic infections 
• Neutropenia 
• Abnormal Liver Parameters 
• Thrombocytopenia 
• Immunogenicity/allergenicity 
• Autoimmunity reactions 
• Second primary malignancy 
• Interactions with vaccines 
• Interactions with drugs eliminated by CYP450 enzymes 
• Pulmonary complications: pulmonary hypertension and interstitial lung disease 
• Injection site reactions 
Details regarding these adverse events are provided in the [canakinumab Investigator’s 
Brochure]. Potential emergent new AEs will be monitored during the course of the study. 
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 - Note: Life-threatening in the context of a SAE refers to a reaction in 
which the subject was at risk of death at the time of the reaction; it does not refer to a reaction 
that hypothetically might have caused death if it were more severe (please refer to the ICH-
E2D Guidelines). 
• 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.  

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• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• Social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
• Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• Is medically significant, e.g. defined as an event that jeopardizes the subject or may require 
medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse.  
Confirmed COVID-19 infection should be considered as medically significant and should 
therefore be reported as a SAE. 
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 occurred. 
10.1.3 
SAE reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until at least 130 days after the subject has stopped study 
treatment must be reported to Novartis safety immediately, without undue delay, but under no 
circumstances later than within 24 hours of obtaining knowledge of the events (Note: If more 
stringent, local regulations regarding reporting timelines prevail). Detailed instructions 
regarding the submission process and requirements are to be found in the Investigator folder 
provided to each site. Information about all SAEs is collected and recorded on the eSAE with 
paper backup within 24 hours of learning of its occurrence and until: 
• At least 130 days following the last dose of study treatment OR 
• The start of a new post study treatment antineoplastic medication if sooner than the 130 
days mentioned above. 
Note: Any SAEs experienced after the 130-day safety follow-up period and prior to start of new 
post study treatment antineoplastic medication should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Post implementation of 
protocol amendment 05, SAE experienced after the 130-day safety follow-up period should be 

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reported to Novartis Safety only if the investigator suspects a causal relationship to the study 
treatment. Please refer to Section 16.6 for safety follow-up diagram. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site. 
The following SAE reporting timeframes apply: 
1. Screen Failures (e.g. a subject who is screened but is not treated or randomized): SAEs 
occurring after the subject has provided informed consent until the time the subject is 
deemed a Screen Failure must be reported to Novartis. 
2. Randomized OR Treated Subjects: SAEs collected between time subject signs ICF until 130 
days after the subject has discontinued or stopped study treatment 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, but under no circumstances later than within 24 hours of the 
investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a Novartis Safety  department 
associate may urgently require further information from the investigator for Health Authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Clinical Trial 
Regulation (EU-CTR) 536/2014 (if submitted under EU CTR) or EU Guidance 2011/C 172/01 
or as per national regulatory requirements in participating countries. 
10.1.4 
Pregnancy reporting 
If a female subject becomes pregnant, the study treatment should be stopped, and the subject 
must be asked to read and sign the pregnancy consent form to allow the investigator to ask about 
her pregnancy. To ensure subject safety, each pregnancy occurring after signing the informed 
consent must be reported to Novartis within 24 hours of learning of its occurrence. The 
pregnancy should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications.  
Pregnancy should be recorded and reported by the investigator to Novartis Safety . Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 

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possible relationship to the study treatment any pregnancy outcome. Any SAE experienced 
during pregnancy must be reported. 
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
If a pregnancy occurs while on study treatment, the newborn will be followed for up to 12 
months. 
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (European Medicines Agency (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 collected in 
the appropriate eCRF page irrespective of whether or not associated with an adverse event / 
serious adverse event (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 dose 
administration eCRF 
(Yes/No) 
Document in AE eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with an 
AE 
Only if associated with an 
SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
10.2 
Additional Safety Monitoring 
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 be constituted prior to the randomization 
of the first subject in part 2. The DMC will review at defined intervals the safety data as well 
as the efficacy and safety data from the final PFS analysis and interim OS analyses of the 
double-blind, randomized, placebo-controlled part of the study. The DMC meeting will be held 
approximately once per year. Additional DMC reviews may be performed if considered 

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appropriate by DMC. DMC will recommend to the sponsor whether to continue, modify or 
terminate a trial. Additional details on the conduct of final PFS and interim OS analyses can be 
found in  Section 12.7   
Specific details regarding composition, responsibilities, data monitoring and meeting frequency, 
and documentation of DMC reports, minutes, and recommendations will be described in a 
separate DMC charter that is established between the sponsor and the DMC. 
10.2.2 
Steering Committee 
The steering committee (SC) will be established comprising investigators participating in the 
trial, i.e. not being members of the DMC and Novartis/sponsor representatives from the Clinical 
Trial Team. 
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the steering committee will be defined in the steering committee charter. 
11 
Data Collection and Database management 
11.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into the electronic Case 
Report Forms (eCRF). The eCRFs have been built using fully validated secure web-enabled 
software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not be given 
access to the Electronic Data Capture (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 subject data for archiving 
at the investigational site. Data collected by third parties (imaging, safety lab, biomarkers, 
PK/IG/PD and PROs) will be sent electronically to Novartis. All data should be recorded, 
handled and stored in a way that allows its accurate reporting, interpretation and verification. 
11.2 
Data protection 
Subjects will be assigned a unique identifier by Novartis. Any subject records or datasets that 
are transferred to Novartis will contain the identifier only; subject names or any information 
which would make the subject identifiable will not be transferred. 
The subject must be informed that his/her personal study-related data will be used by Novartis 
in accordance with local data protection law. The level of disclosure must also be explained to 
the subject who will be required to give consent for their data to be used as described in the 
informed consent.  

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The subject must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by Novartis, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
Novartis has appropriate processes and policies in place to handle personal data breaches 
according to applicable privacy laws. 
11.3 
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 members 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. 
Randomization codes and data about all study treatment (s) dispensed to the subject and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate (at time of the primary OS analysis), it will be locked and the treatment 
codes will be unblinded and made available for data analysis. Any changes to the database 
after that time can only be made after written agreement by Novartis development management. 
DNA samples: The use of DNA to search for biomarkers of disease and drug action is 
exploratory. Any results from this DNA study will not be placed in the subject’s medical records. 
11.4 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a 
Novartis/delegated CRO 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 compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of subject records, the accuracy 
of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, the 
progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. 
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 

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information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed. 
12 
Data analysis and statistical methods 
Part 1: Safety run-in part 
The primary analysis of part 1 to determine the recommended phase 3 dose regimen (RP3R) 
will be conducted when at least 6 evaluable subjects in each of the 3 treatment cohorts have 
been observed for dose limiting toxicity (DLT) for the first 42 days (2 cycles) at the starting 
dose level to establish the RP3R. The final analysis of study data for Part 1 (safety run-in) will 
be conducted at the time of the primary analysis for Part 2 (randomized part), when 
approximately 253 PFS events are expected to have occurred in part 2. Data for all patients 
from part 1 are included. 
Part 2: Double-blind, randomized, placebo-controlled part 
The final PFS analysis in the double-blind, randomized, placebo-controlled part of the study 
will be performed after observing approximately 253 PFS events, in the full analysis set. The 
final OS analysis will be performed after observing approximately 304 deaths in the full analysis 
set (FAS) or at an earlier timepoint if OS meets statistical significance at one of the planned 
interim analysis. 
Any additional data for ongoing subjects in the randomized part following the primary OS 
analysis and data for subjects in OLE (if initiated) will be further summarized in a final study 
report.  
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
12.1 
Analysis sets 
12.1.1 
Full Analysis Set 
Part 1: Safety run-in part 
The full analysis set (FAS) and safety set are defined in the same way and comprise all subjects 
to whom study treatment has been assigned and who received at least one dose of the study 
treatment (i.e. at least one dose of any component of the study treatment that is canakinumab or 

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pembrolizumab or platinum-based doublet chemotherapy (including incomplete infusion) or 
pemetrexed). Subjects will be analyzed according to the dose regimen they have been assigned 
to. 
Part 2: Double-blind, randomized, placebo-controlled part 
The FAS comprises of all subjects to whom study treatment has been assigned by randomization. 
According to the intent to treat principle, subjects will be analyzed according to the treatment 
and strata which they have been assigned during the randomization procedure. 
12.1.2 
Safety set 
Part 1: Safety run-in part 
See definition of FAS. 
Part 2: Double-blind, randomized, placebo-controlled part 
The safety set includes all subjects who received at least one dose of any component of the 
study treatment. Subjects will be analyzed according to the study treatment they received, either 
canakinumab plus pembrolizumab plus platinum-based doublet chemotherapy or canakinumab 
matching-placebo plus pembrolizumab plus platinum-based doublet chemotherapy. The 
treatment received is defined as the randomized treatment if the subject took at least one dose 
of that treatment (i.e. at least one dose of canakinumab or canakinumab matching-placebo) or 
the first treatment received if the randomized treatment was never received. 
12.1.3 
Dose-determining set 
Part 1: Safety run-in part 
The Dose-Determining Set (DDS) includes all subjects from the safety set who meet the 
minimum exposure criterion and have sufficient safety evaluations, or experienced a dose 
limiting toxicity (DLT) during the first 42 days (6 weeks) of dosing (definition of DLT refer 
to  Section 6.5.2 ). 
A subject meets the minimum exposure criterion if the subject received:  
• At least 2 doses of canakinumab (for Q3W dosing regimen cohort) or at least 1 dose of 
canakinumab (for Q6W dosing regimen cohort in case the canakinumab dose is de-escalated 
to Q6W) and 2 infusions of pembrolizumab (full dose)  
• Takes at least 75% of planned doses of the overall platinum-based doublet chemotherapy 
within the first 42 days (6 weeks) of study treatment 
If the subject didn't receive these planned number of doses due to DLT, the subject will be 
considered meeting the minimum exposure criterion.  
Subjects who do not experience a DLT during the first 42 days (6 weeks) are considered to have 
sufficient safety evaluations if they have been observed for ≥ 42 days (6 weeks) following the 
first dose, and are considered by the dose level review team (DLRT) to have sufficient safety 
data to conclude that a DLT did not occur. 

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Part 2: Double-blind, randomized, placebo-controlled part 
Not applicable. 
12.1.4 
Pharmacokinetic set 
Part 1: Safety run-in part 
The Pharmacokinetic Analysis Set (PAS) consists of all subjects who received at least one dose 
of study drug and have at least one evaluable pharmacokinetic (PK) sample. The definition of 
an evaluable PK blood sample will be further specified in the statistical analysis plan (SAP). 
PAS will be defined for canakinumab, pembrolizumab, carboplatin, cisplatin, paclitaxel, and 
pemetrexed separately. 
Part 2: Double-blind, randomized, placebo-controlled part 
The PAS consists of all subjects who received at least one dose of study drug and have at least 
one evaluable PK sample. The definition of an evaluable PK blood sample will be further 
specified in the SAP. PAS will be defined for canakinumab, pembrolizumab, carboplatin, 
cisplatin, paclitaxel, nab-paclitaxel, and pemetrexed separately. 
12.2 
Subject demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by canakinumab dose regimen and cohort for the FAS in the safety 
run-in part and by treatment group using the FAS and safety set for the double-blind randomized 
part. 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 for 
the FAS by system organ class and preferred term, by canakinumab dose regimen and cohort 
in the safety run-in part and by treatment group for the FAS in the double-blind randomized 
part.  
12.3 
Treatments 
The safety set will be used for the analyses below. The exposure related analyses will be 
presented by canakinumab dose regimen and treatment cohort for the safety run-in part and by 
treatment group for the double-blind randomized part. 
The duration of exposure for study treatment and for each study drug (canakinumab, 
pembrolizumab, platinum-based doublet chemotherapy drugs and pemetrexed) will be 
presented. The dose intensity and the relative dose intensity will be summarized for each study 
drug component by descriptive statistics. The number of administrations (or treatment cycles) 
of each study drug component of the study treatment will be summarized by frequencies and 
descriptive statistics. 
The number of subjects with dose adjustments (reductions, dosing interval increase, interruption, 
or permanent discontinuation) and the reasons will be summarized for each study drug. All 
dosing data will be listed. 

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Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system. 
12.4 
Analysis of the primary endpoint(s) 
Part 1: Safety run-in part 
The primary objective is to determine the recommended phase 3 dose regimen (RP3R) of 
canakinumab in combination with pembrolizumab, pemetrexed and carboplatin (cohort A) in 
non-squamous NSCLC cohort, canakinumab in combination with pembrolizumab, pemetrexed 
and cisplatin (cohort B) in non-squamous NSCLC cohort and canakinumab in combination with 
pembrolizumab, carboplatin and paclitaxel in squamous or non-squamous NSCLC cohort 
(cohort C). 
Part 2: Double-blind, randomized, placebo-controlled part 
The primary objectives of the study are to compare progression-free survival (PFS) by local 
investigator assessment as per RECIST1.1 and overall survival (OS) between the two study 
treatment arms. 
12.4.1 
Definition of primary endpoint(s) 
Part 1: Safety run-in part 
The primary endpoint is the incidence of dose limiting toxicities (DLT) in the first 42 days (6 
weeks) of the study treatment. Refer to Section 6.5.2 for definition of DLTs.  
Part 2: Double-blind, randomized, placebo-controlled part 
The primary endpoints are PFS and OS endpoints: 
• PFS is defined as the time from the date of randomization to the date of the first documented 
disease progression based on local investigator assessment as per RECIST 1.1 or death due 
to any cause 
• OS is defined as the time from the date of randomization to the date of death due to any 
cause 
Censoring conventions for PFS and OS are provided below in Section 12.4.3. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
12.4.2.1 Safety run-in part (part 1) 
Identification of recommended regimen 
Determination of the RP3R will be based upon the estimation of the probability of DLT for the 
first 42 days (6 weeks) following the first dose for subjects in the dose-determining set 
(DDS). A lower recommended regimen may be identified based on other safety and PK data 
from the current study ( Section 6.5.1.2 ). 

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Bayesian adaptive approach 
The determination of RP3R will be guided by a Bayesian analysis of DLT data for each cohort 
for the first 42 days (6 weeks) during which subjects receive the combination of canakinumab, 
pembrolizumab and platinum-based doublet chemotherapy. The relationship between dose and 
the probability of DLT is modeled using logistic regression. Details of the Bayesian logistic 
regression model (BLRM) are given in  Section 16.3 . 
The dose limiting toxicity (DLT) relationship of canakinumab in combination with 
pembrolizumab and platinum-based doublet chemotherapy is modeled by a BLRM for each 
dose regimen that comprises single agent toxicity parts and interaction part. Single agent 
toxicity is modeled using logistic regression for the probability of a subject experiencing a DLT 
against log-dose. The odds of a DLT for each dose regimen are then calculated under no 
interaction for the single agent toxicities, and interaction is accounted for by adjusting these 
odds with additional model parameter (odds multipliers). 
Starting dose 
The starting dosing regimen are the following (Section 6.5.1.1 ): 
• Cohort A: canakinumab 200 mg Q3W in combination with pembrolizumab 200 mg, 
carboplatin AUC 5 mg/mL*min and pemetrexed 500 mg/m2 Q3W 
• Cohort B: canakinumab 200 mg Q3W in combination with pembrolizumab 200 mg, 
cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 Q3W 
• Cohort C: canakinumab 200 mg Q3W in combination with pembrolizumab 200 mg, 
carboplatin AUC 6 mg/mL*min and paclitaxel 200 mg/m2 Q3W. 
For this starting dose level of canakinumab (i.e. 200 mg Q3W), the prior risk of excessive 
toxicity (i.e. risk of DLT within [33%-100%]) is 15%, 10% and 22% for cohorts A, B and C, 
respectively, which satisfies the EWOC criterion. 
Dose recommendation 
Dose recommendations will be based on summaries of the posterior distribution of DLT rates 
for each dose level of the respective combination therapy. After each cohort of subjects, the 
posterior distribution for the risk of DLT for new subjects at combination doses of interest will 
be evaluated. The posterior distributions will be summarized to provide the posterior probability 
that the risk of DLT for each dose regimen lies within the following intervals: 
• Under-dosing: [0, 16%] 
• Targeted toxicity: [16%, 33%] 
• Excessive toxicity: [33%, 100%] 
Dosing regimen decisions are guided by the escalation with overdose control (EWOC) principle 
(Rogatko et al 2007). A dosing regimen may only be used for newly enrolled subjects if the risk 
of excessive toxicity at that dosing regimen is less than 25%. 

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Listing of DLTs 
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. 
12.4.2.2 Double-blind, randomized, placebo-controlled part (Part 2) 
12.4.2.2.1 
Gate-keeping procedure 
In order to conserve the overall type-1 error (one-sided level of significance α=0.025) in testing 
the primary endpoints of PFS and OS, an alpha split with a graphical gate-keeping approach 
will be implemented as shown in the figure below (Bretz et al 2009, Bretz et al 2011). 
Figure 12-1 
Graphical gate-keeping procedure to test primary endpoints in order 
to control overall type 1 error 
 
12.4.2.2.2 
Progression free survival (PFS) 
Assuming a proportional hazards model for PFS, the null hypothesis will be tested at one-sided 
1% level of significance. If OS is statistically significant at either interim or final analysis, then 
the 1.5 % alpha assigned to OS will be transferred to PFS and PFS will be tested at one-sided 
2.5% level of significance. 
H01 (null hypothesis): Θ1≥ 0 vs. Ha1 (alternative hypothesis): Θ1 < 0 
Where Θ1 is the log hazard ratio of PFS in the investigational arm vs. control arm. 
In the primary analysis, PFS will be tested using the log-rank test stratified by randomization 
stratification factors when approximately 253 PFS events are observed. The statistical basis for 
a claim of efficacy will be the statistical significance (at the 1% one-sided level of significance 
if OS is not statistically significant at interim and final analysis or 2.5% one-sided level of 
significance if OS is statistically significant at either interim or final analysis) for PFS in favor 
of the canakinumab arm. 
The distribution of PFS will be estimated using the Kaplan-Meier method. The median PFS and 
PFS rate at different timepoints along with 95% confidence intervals (CIs) will be presented by 
treatment arms. A Cox regression model stratified by randomization stratification factors will 
be used to estimate the hazard ratio (HR) of PFS, along with 95% CI based on the Wald test. 
12.4.2.2.3 
Overall survival (OS) 
Assuming a proportional hazards model for OS, the null hypothesis will be tested at one-sided 
1.5% level of significance. If PFS by investigator assessment per RECIST1.1 is statistically 
significant at 1% level of significance, then the 1 % alpha assigned to PFS will be transferred 
to OS and OS will be tested at one-sided 2.5% level of significance. 

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H02 (null hypothesis): Θ2≥ 0 vs. Ha2 (alternative hypothesis): Θ2 < 0 
Where Θ2 is the log hazard ratio of OS in the investigational arm vs. control arm. 
In the primary analysis, OS will be tested using the log-rank test stratified by randomization 
stratification factors. The statistical basis for a claim of efficacy will be the statistical 
significance (at the 1.5% one-sided level of significance if PFS is not statistically significant at 
1% one-sided level of significance or 2.5% one-sided level of significance if PFS is statistically 
significant at 1% one-sided level of significance) for OS in favor of the canakinumab arm. 
The distribution of OS will be estimated using the Kaplan-Meier method. The median OS and 
OS rate at different timepoints along with 95% confidence intervals (CIs) will be presented by 
treatment arms. A Cox regression model stratified by randomization stratification factors will 
be used to estimate the hazard ratio (HR) of OS, along with 95% CI based on the Wald test. 
12.4.3 
Handling of missing values/censoring/discontinuations 
Part 1: Safety run-in part 
Subjects who are ineligible for the DDS will be excluded from the primary analysis (assessment 
of RP3R using incidence of DLT during first 42 days of treatment with canakinumab either in 
combination with pembrolizumab, carboplatin and pemetrexed or in combination with 
pembrolizumab, cisplatin and pemetrexed or in combination with pembrolizumab, carboplatin 
and paclitaxel), 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: Double-blind, randomized, placebo-controlled part  
A subject 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. 
Censoring rules for PFS follow the RECIST 1.1 guidelines and will be further detailed in the 
SAP.  
A subject who has not died by the date of the analysis cut-off date will have their OS censored 
at the last known date the subject is alive. 
12.4.4 
Sensitivity and Supportive analyses 
Part 1: Safety run-in part 
Not applicable 
Part 2: Double-blind, randomized, placebo-controlled part 
Censoring summaries 
The number of subjects censored for PFS and OS analysis and reasons for censoring will be 
summarized by treatment group. 

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PFS by BIRC assessment  
As a supportive analysis of the primary endpoint of PFS by local investigator assessment, PFS 
by blinded review independent committee (BIRC) assessment will be analyzed using the same 
analytical conventions as the primary analysis. PFS assessed by BIRC will serve as supportive 
evidence of the primary endpoint. A sample based BIRC audit strategy will be used to assess 
PFS by BIRC based on the data from FAS. 
Two methods that will be used to summarize the data from the sample-based BIRC assessment 
include: 
• The NCI (National Cancer Institute) method (Dodd et al 2011) uses an auxiliary variable 
estimator of the log-hazard ratio that combines information from subject-level investigator 
assessment from all subjects and the BIRC assessment of these subjects randomly selected 
for central review. This estimate and its one-sided 95% CI will be provided. The NCI 
method will be used for audit sample size determination and summary of treatment effect 
(HR, 95% confidence intervals) based on the supportive BIRC assessment. 
• The data from the BIRC assessment generated following the sampling scheme as above 
will also be summarized using the method proposed by Amit et al (2011), referred to as 
the PhRMA (Pharmaceutical Research and Manufacturers in America) method. The 
differential discordance (DD) of the early discrepancy rate (EDR) and late discrepancy 
rate (LDR) between the treatment arms will be estimated using this approach. The EDR 
and LDR results will also be summarized by treatment arm. 
Details of the audit sample size calculation for the BIRC assessment are provided 
in  Section 12.8 . 
Subgroup analyses for PFS and OS 
If the primary endpoint analyses for PFS and/or OS are statistically significant, subgroup 
analyses to assess the homogeneity of the treatment effect across demographic and baseline 
disease characteristics will be performed for the subgroups as shown below.  
The subgroups are: 
• Gender (male vs. female) 
• Age (<65 vs. ≥65 years) 
• ECOG performance status (0 vs. 1) 
• Smoking history (Former/Current vs. Never) 
• PD-L1 baseline expression level (<1% vs. ≥1%, <50% vs. ≥50%, <1% vs. 1-49% 
vs. ≥50%, in case of non-evaluable PD-L1 status the subjects will be excluded from the 
subgroup analyses) 
• Histology (squamous vs. non-squamous) 
• Geographic region (East Asia vs. Western Europe and North America vs. Rest of the 
world) 
• Chemotherapy regimen (pemetrexed+cisplatin vs. pemetrexed+carboplatin vs. 
carboplatin+paclitaxel vs. carboplatin+nab-paclitaxel) 

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• Tumor mutation burden (TMB) status at baseline (<10 mutations/megabase vs. ≥10 
mutations/megabase, <16 mutations/megabase vs. ≥16 mutations/megabase) 
• hs-CRP at baseline (<2mg/L vs. ≥2mg/L, <10mg/L vs. ≥10mg/L, <50 mg/L vs. ≥50 mg/L) 
Additional subgroup analyses with different thresholds or variables (e.g. hs-CRP on treatment) 
may be conducted for PFS and OS. Details will be specified in the SAP .Sensitivity 
analyses will also be performed for OS and PFS in the FAS. Hazard ratio and 95% confidence 
interval for OS and PFS will be obtained from: 
• an unstratified and covariate unadjusted Cox model. 
• a stratified and covariate adjusted Cox model including covariates such as gender, age and 
smoking history. 
The final list of covariates to be included in the model will be provided in the SAP. Additional 
sensitivity analyses will be detailed in the SAP. 
12.5 
Analysis of secondary endpoints 
12.5.1 
Efficacy endpoints 
Part 1: Safety run-in part 
In order to assess preliminary anti-tumor activity, overall response rate (ORR), disease control 
rate (DCR), and duration of response (DOR) will be summarized in FAS by dose regimen and 
cohort, using the local investigator assessment per RECIST1.1. For definitions of these 
endpoints, refer to Part 2 in Section 12.5.1  . 
Part 2: Double-blind, randomized, placebo-controlled part 
The secondary efficacy endpoints will be assessed using the FAS. The following analyses will 
be performed based on local investigator assessment: 
ORR is defined as the proportion of subjects with best overall response (BOR) of complete 
response (CR) or partial response (PR), as per local review. ORR will be evaluated according 
to RECIST 1.1 (Section 16.1). CR and PR must be confirmed by repeat assessments that should 
be performed not less than 4 weeks after the criteria for response are first met. ORR will be 
estimated and the exact binomial 95% CI will be reported by treatment arm. 
BOR for each subject is determined from the sequence of overall (lesion) responses according 
to the following rules: 
• CR = at least two determinations of CR at least 4 weeks apart before 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 randomization (and not 
qualifying for CR or PR). 
• PD = progression ≤ 13 weeks after randomization (and not qualifying for CR, PR or SD). 
Disease control rate (DCR) is defined as the proportion of subjects with BOR of CR, PR, or 
stable disease (SD). DCR will be analyzed using the same analytical conventions as ORR. 

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Duration of response (DOR) is defined as the duration of time between the date of first 
documented response (CR or PR) and the date of first documented progression or death due to 
any cause. If a subject has not had an event, DOR is censored at the date of last adequate tumor 
assessment. Subjects 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. The 
median DOR along with 95% CIs will be presented by treatment arm. 
Time to response (TTR) is defined as the time from the date of randomization to the date of first 
documented response (CR or PR, which must be confirmed subsequently). Subjects who did 
not achieve a confirmed CR or PR will be censored at the last adequate tumor assessment date 
when they did not have a PFS event or at maximum follow-up (i.e. FPFV to LPLV used for the 
analysis) when they did have a PFS event. The distribution function of TTR will be estimated 
using the Kaplan-Meier method. The median TTR along with 95% CIs will be presented by 
treatment arm. 
ORR, DCR, DOR and TTR will be analyzed based on the data from FAS per RECIST1.1 based 
on local investigator assessment. 
12.5.2 
Safety endpoints 
For the safety run-in part (Part 1), summary tables and listings will be presented by 
canakinumab dose regimen and cohort using the safety set. For the double-blind, randomized, 
placebo-controlled (Part 2), all listings and tables will be presented by treatment group 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 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). 
The overall observation period will be divided into three mutually exclusive segments: 
1. Pre-treatment period: from day of subject’s informed consent to the day before first dose 
of any component of the study treatment 
2. On-treatment period: from day of first dose of any component of the study treatment to 
130 days after last dose of any component of the study treatment 
3. Post-treatment period: starting at day 131 after last dose of any component of the study 
treatment. 
12.5.2.1 Adverse events 
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 v5.0) and 
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Serious adverse events, non-serious adverse events and adverse events of special interest 
(AESI) during the on-treatment period will be tabulated. AESIs will be defined based on the 
case retrieval strategy (CRS) available at the time of the analysis.  
All deaths (on-treatment and post-treatment) will be summarized overall and separately. 
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. 
12.5.2.2 Clinical laboratory evaluations 
Grading of laboratory values will be assigned programmatically as per CTCAE v5.0. The 
calculation of CTCAE grades will be based on the observed laboratory values only, clinical 
assessments will not be taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used. 
For laboratory tests where grades are not defined by CTCAE v5.0, results will be categorized 
as low/normal/high based on laboratory normal ranges. 
The following summaries/listings will be generated separately for hematology, and 
biochemistry tests: 
• Listing of all laboratory data with values flagged to show the corresponding CTCAE v5.0 
grades if applicable and the classifications relative to the laboratory normal ranges 
For laboratory tests where grades are defined by CTCAE v5.0 
• Worst post-baseline CTCAE grade (regardless of the baseline status). Each subject will be 
counted only once for the worst grade observed post-baseline. 
• Shift tables using CTCAE v5.0 grades to compare baseline to the worst on-treatment value 
For laboratory tests where grades are not defined by CTCAE v5.0, 
• Shift tables using the low/normal/high/ (low and high) classification to compare baseline to 
the worst on-treatment value. 
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots may be 
specified in the analysis plan. 
12.5.2.3 Other safety evaluations 
Vital signs 
Data on vital signs will be tabulated and listed by treatment group, visit/cycle, notable values 
will be flagged. Summary statistics will be provided by treatment group. 
Immunogenicity 
Immunogenicity of canakinumab and pembrolizumab will be characterized descriptively by 
tabulating anti-drug antibodies (ADA) prevalence at baseline and ADA incidence on-treatment. 

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The impact of immunogenicity on PK, safety and efficacy may be explored and further details 
will be specified in the SAP. 
12.5.3 
Pharmacokinetics 
The Pharmacokinetic Analysis Set (PAS) will be used in the pharmacokinetic data analysis in 
both safety run-in and randomized parts of the study. Descriptive statistics (n, m (number of 
non-zero concentrations), mean, coefficient of variation CV%, SD, median, geometric mean, 
geometric CV%, minimum and maximum) for canakinumab, pembrolizumab and 
chemotherapy agents separately will be presented at each scheduled timepoint for both safety 
run-in and double-blind, randomized, placebo-controlled parts of the study. 
All concentration data for canakinumab, pembrolizumab and chemotherapy agents vs. time 
profiles will be displayed graphically.  
The descriptive statistics (n, mean, CV%, standard deviation (SD), median, geometric mean, 
geometric CV%, minimum and maximum) will be presented for PK parameters as well, except 
Tmax, where only n, median, minimum and maximum will be presented for canakinumab, 
pembrolizumab and chemotherapy agents, when applicable. PK parameters (e.g. AUC, Cmin, 
Cmax, Tmax, T1/2) will be estimated and reported at appropriate timepoints, when derivation 
of selective PK parameters is feasible. 
12.5.3.1 Population pharmacokinetic analysis 
If there is adequate amount of data, a mixed-effects model may be applied to the serum 
canakinumab concentration-time data from this study along with other studies to generate post-
hoc estimates of pharmacokinetic parameters using NONMEM to characterize canakinumab 
exposure and to determine the effects of intrinsic (i.e. demographic factors) and extrinsic 
covariates (e.g. combination partners) on canakinumab exposure. If there is sufficient data for 
analysis, the details of the population pharmacokinetic analyses may be provided in a separate 
reporting and analysis plan, and the results may be reported in a separate population 
pharmacokinetic report. Similarly, population PK analysis may also be applied to 
pembrolizumab and chemotherapy agents to determine the effects of canakinumab on these 
agents. 
12.5.3.2 Data handling principle 
12.5.4 
Patient reported outcomes 
Three patient-reported outcomes (PRO) questionnaires will be assessed in the study part 2 only 
(double-blind, randomized, placebo-controlled part): EORTC QLQ-C30 with the lung cancer 
module QLQ-LC13 and the EQ-5D-5L. 
QLQ-C30 and QLQ-LC13 will be considered as the primary scale. 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 subject questionnaire (Fayers 2001, 
VanReenen 2017). No imputation procedures will be applied for missing items or missing 
assessments.  

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The FAS will be used for analyzing PRO data. Analyses will include comparison of time to 
definitive 10-point deterioration between the 2 treatment arms using the EORTC QLQ-C30 
with its lung cancer module QLQ-LC13. Time to definitive 10-point deterioration symptom 
scores for chest pain, cough and dyspnea per QLQ-LC13 questionnaire are the three primary 
PRO variables of interest. Utilities derived from EQ-5D-5L together with time to definitive 
deterioration in global health status/QoL, shortness of breath and pain per QLQ-C30 are the 
secondary PRO variables of interest. The time to definitive 10-point deterioration is defined as 
the time from the date of randomization to the date of event, which is defined as at least 10 
points absolute increase from baseline (worsening) of the corresponding scale score, with no 
later change below this threshold (i.e. <10 points was observed or if this increase was observed 
at the last assessment for the subject) or death due to any cause. If a subject has not had an event, 
time to definitive deterioration will be censored at the date of the last adequate assessment. It 
will be summarized using Kaplan-Meier curves. Summary statistics from Kaplan-Meier 
distributions will be determined, including the median time to definitive 10-point deterioration 
along with two-sided 95% confidence interval. Additionally, time to definitive deterioration 
with different cut-offs definition for deterioration may be specified in the SAP as deemed 
appropriate. A stratified Cox regression will be used to estimate the hazard ratio (HR), along 
with two-sided 95% confidence interval.  
Descriptive statistics will be used to summarize the original scores, as well as change from 
baseline, of the QLQ-C30/QLQ-LC13 and EQ-5D-5L at each scheduled assessment timepoint 
for each treatment group. Additionally, change from baseline in the scale and subscale values 
at the time of each assessment will be summarized. Subjects 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 number of subjects completing each questionnaire and the number of missing or incomplete 
assessments will be summarized by treatment group for each scheduled assessment timepoint. 
No formal statistical tests will be performed for PRO data and hence no multiplicity adjustment 
will be applied.  
In addition, a repeated measurement analysis model for longitudinal data will be used to 
estimate differences in EORTC QLQ-C30/QLQ-LC13 domains as well as the VAS and utility 
scores of the EQ-5D-5L between treatment arms. The differences in least square means between 
the treatment arms and corresponding 95% confidence interval at selected timepoints will be 
presented. Details, including handling of missing data, will be specified in the SAP. 
12.6 
Analysis of exploratory endpoints 
12.6.1 
Exploratory efficacy endpoints 
Analysis of exploratory efficacy endpoints of iPFS, iORR, and iDCR based on local investigator 
assessment per iRECIST and PFS2 will also be performed. Analysis of all exploratory efficacy 
endpoints will be performed by treatment arm using the FAS and only on the double-blind, 
randomized, placebo-controlled part of the study. 
Immune related progression-free survival (iPFS) is defined as the time from the date of 
randomization to the date of progression or death due to any cause. A progression event is 
defined as confirmed progression (iCPD), where the date of progression will be the date of first 

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iUPD assessment that was confirmed. In the absence of a confirmed progression, an 
unconfirmed progression (iUPD) with no further adequate tumor assessments will also be 
regarded as a progression event. If a subject has not had an event, progression-free survival will 
be censored at the date of last adequate tumor assessment. The iPFS distribution will be 
estimated using the Kaplan-Meier method, and the Kaplan-Meier curves, medians and 95% 
confidence intervals of the medians will be presented for each treatment group. The hazard ratio 
for iPFS will be calculated, along with its 95% confidence interval, using a stratified Cox model. 
Immune related overall response rate (iORR) is defined as the proportion of subjects with a 
best overall response of iCR or iPR. iORR and its 95% confidence interval will be presented by 
treatment group. 
Immune related disease control rate (iDCR) is defined as the proportion of subjects with best 
overall response of iCR or iPR or iSD. iDCR and its 95% confidence interval will be presented 
by treatment group. 
PFS2: PFS2 is defined as time from date of randomization to the first documented progression 
on 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 will be performed using data from FAS.  
12.6.2 
Pharmacokinetics and pharmacodynamics (PK/PD) relationships 
Descriptive statistics (n, m (number of non-zero concentrations), mean, CV%, SD, median, 
geometric mean, geometric CV%, minimum and maximum) for total IL-1β concentrations for 
valid PK samples will be presented at each scheduled timepoint. Concentration of total IL-1β 
vs. time profiles will be displayed graphically. A valid PK sample will be defined in the SAP.  
The relationship between canakinumab PK, PD (inflammatory biomarkers such as hs-CRP and 
hs-IL-6), safety and efficacy (PFS, OS) may be explored and further details will be specified in 
the SAP. 
12.6.3 
Biomarkers 
The statistical goals of exploratory biomarker analyses should be considered as promoting the 
generation of new scientific hypotheses and are exploratory in nature. 
12.6.3.1 Outline of the data analysis 
12.6.3.2 Data analysis principle 
12.6.3.2.1 
Analysis sets 
FAS will be used for biomarker related analyses unless otherwise specified. 
12.6.3.2.2 
Basic tables, figures and listings 
Depending on the endpoint of interest, graphical displays such as box plots or strip plots may 
be used to assess the relationship of different biomarkers with clinical benefit by treatment. 

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These may be separated by treatment arm and include either baseline or change from baseline 
values, where applicable. 
For hs-CRP and hs-IL-6, baseline and change from baseline (absolute change, percent change 
and fold change) at each timepoint will be summarized in tables that include sample size, mean, 
standard deviation, %CV, median, minimum and maximum. For fold change from baseline, 
geometric mean and geometric %CV will also be included. 
For categorical markers such as mutation status, 2x2 contingency tables may be used to assess 
the relationship with clinical benefit and/or Kaplan – Meier curves may be generated given the 
number of events warrant such an assessment. 
If additional analyses are needed to be performed after the completion of the end-of-study 
clinical study report (CSR), they will be documented in separate reports. The data analysis will 
be described in an addendum of the statistical analysis plan (SAP) or in a stand-alone analysis 
plan document, as appropriate. 
12.7 
Interim analyses 
Part 1: safety run-in part 
The decision RP3R in the safety run-in will be based on analyses performed after each cohort 
in each chemotherapy regimen. More precisely, after each cohort of subjects the next dose will 
be chosen depending on the observed data (based on safety, PK, tolerability data, guided by the 
recommendations from the BLRM of DLT using EWOC, and recommendations from 
participating investigators). Details of this procedure and the process for communication with 
investigators are provided in  Section 6.5.1.2 . 
Part 2: Double-blind, randomized, placebo-controlled part 
There is no interim analysis (IA) for PFS. The final PFS analysis, is planned after approximately 
253 PFS events have been observed. This is expected to occur approximately 18 months after 
the date of first subject randomized in part 2. The 1st IA for OS will be performed at the same 
time of final PFS analysis when approximately 120 over the 304 targeted OS events (39%) 
deaths are expected to be observed. The intent of this analysis is to assess superior efficacy with 
either PFS and/or OS results. There is no intent to assess futility at the time of the 1st interim 
OS analysis. 
A maximum of three analyses will be performed for OS. The type I error probability will be 
controlled 
by 
using 
a 
Lan-DeMets 
(O’Brien-Fleming) 
alpha 
spending 
function 
(Lan and DeMets 1983) at the 1.5% (if PFS was not statistically significant) or 2.5% (if PFS 
was statistically significant) overall level of significance.  
Based on the choice of alpha-spending function described above and if the first interim OS 
analysis is performed exactly at 120 OS events, the efficacy boundary expressed on the p-value 
scale (or the Z-statistic scale) at the interim is calculated as: 
• p < 0.0001082(or Z =3.699) if OS is tested at one-sided 1.5% alpha level 
• p< 0.0003604(or Z=3.382) if OS is tested at one-sided 2.5% alpha level 

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The observed (i.e., nominal) p-value has to be less than the p-value scale efficacy boundary 
defined above (or equivalently the observed z-statistic has to be > Z-statistic scale boundary) to 
declare statistical significance at 1.5% one-sided alpha level or 2.5% one-sided alpha level. 
If the study continues to the 2nd IA for OS, it will be performed when approximately 243 OS 
events have been documented. If exactly 120 OS events are observed at the 1st IA for OS, the 
study continued and exactly 243 events are obtained at the 2nd IA for OS, the observed p-value 
will have to be less than 0.006 (or equivalently Z-statistic has to be >2.485) to declare statistical 
significance at 1.5% one-sided alpha level, or will have to be less than 0.012 (or equivalently 
Z-statistic has to be >2.255) to declare statistical significance at 2.5% one-sided alpha level. 
The 2nd interim OS analysis is anticipated to take place approximately 30 months after the first 
subject is randomized. 
Since the observed number of events at the interim analyses may not be exactly equal to the 
planned 120 OS events at first interim OS analysis (or 243 OS events at 2nd interim analysis), 
the efficacy boundaries will need to be re-calculated using the pre-specified α-spending 
functions and based on the actual number of observed events at the corresponding interim and 
the total number of targeted events to calculate the exact information fraction. The observed p-
value (or Z-test statistic or HR estimate) at each interim analysis will then be compared against 
the re-calculated efficacy boundaries. 
If the study continues to the final OS analysis, the final OS analysis will be performed when 
approximately 304 OS events have been documented. In practice, the final analysis will be 
based on the actual number of OS events documented at the cut-off date for the final OS analysis 
and the alpha already spent at the interim analyses. The boundary for the final analysis will be 
derived accordingly from the pre-specified α-spending function such that the overall 
significance level across all analyses is maintained at 0.015 or 0.025 (if PFS results are found 
statistically significant at 1% level). The final OS analysis is expected to occur approximately 
38 months after the first subject is randomized. 
The statistical properties of the group sequential design are summarized in  Table 12-1  below. 
Table 12-1 
Simulated probabilities to stop for overall survival efficacy at final PFS 
analysis, interim or final OS analyses 
Scenario 
Look 
# deaths 
Simulated cumulative 
probabilities 
Simulated incremental 
probabilities 
Stop for efficacy 
Stop for efficacy 
If OS is tested at one-sided alpha=0.015 
Under H0 (HR=1) 
Final PFS (1st 
interim OS) 
120 
0.02% 
0.02% 
  
2nd interim OS 
243 
0.65% 
0.63% 
  
Final OS 
304 
1.44% 
0.80% 
Under Ha 
(HR=0.69) 
Final PFS (1st 
interim OS) 
120 
4.5% 
4.5% 
  
2nd interim OS 
243 
65.0% 
60.5% 
  
Final OS 
304 
84.6% 
19.6% 
If OS is tested at one-sided alpha=0.025 
Under H0 (HR=1) 
Final PFS (1st 
interim OS) 
120 
0.04% 
0.04% 

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Scenario 
Look 
# deaths 
Simulated cumulative 
probabilities 
Simulated incremental 
probabilities 
Stop for efficacy 
Stop for efficacy 
  
2nd interim OS 
243 
1.25% 
1.21% 
  
Final OS 
304 
2.40% 
1.15% 
Under Ha 
(HR=0.69) 
Final PFS (1st 
interim OS) 
120 
8.6% 
8.6% 
  
2nd interim OS 
243 
72.9% 
64.3% 
  
Final OS 
304 
89.0% 
16.1% 
Note: Simulation is performed in East 6.4 with number of simulations=30, 000 and simulation 
seed = 1234. Any unblinding than can occur following final PFS and interim OS analyses, is 
described in  Section 6.4.  
12.8 
Sample size calculation 
12.8.1 
Primary endpoint(s) 
Part 1: Safety run-in part 
No formal statistical power calculations to determine sample size were performed for this part 
of the study. In the case that the starting dose (canakinumab 200 mg s.c. Q3W) with the fixed 
dose combination of pembrolizumab plus cohort specific platinum-based doublet chemotherapy 
is confirmed to be safe and tolerated, the safety run-in part is expected to enroll approximately 
9 subjects in each treatment cohort in order to have at least 6 evaluable subjects , so 
approximately 27 subjects enrolled in total. Otherwise, additional subjects are foreseen to be 
enrolled to assess additional cohorts at canakinumab dose level-1 Q6W. 
Part 2: Double-blind, randomized, placebo-controlled part 
The sample size of the study is based on the 2 primary endpoints PFS and OS. The hypotheses 
to be tested and details of the testing strategy are described in  Section 12.4.2 . 
Progression-free survival (PFS) 
Based on KEYNOTE-189 study (Gandhi et al 2018), the median PFS for pembrolizumab in 
combination with platinum-based doublet chemotherapy followed by pembrolizumab 
maintenance treatment (control arm) in subjects with non-squamous NSCLC is approximately 
9 months. Based on KEYNOTE-407 (Paz-Ares 2018), the median PFS for pembrolizumab in 
combination with taxane-based chemotherapy followed by pembrolizumab maintenance 
treatment (control arm) in subjects with squamous NSCLC is 6.4 months. Based on the 
assumption that 30% subjects in this current study (CACZ885U2301) will have squamous 
histology (Rittmeyer et al 2017, Hellmann et al 2018), the median PFS in the control arm for 
this study is expected to be approximately 8 months based on simulation. Under the assumption 
that the median PFS in the control arm is 8 months, it is expected that addition of canakinumab 
will result in a 37.5% reduction in the PFS hazard rate (corresponding to an increase in median 
PFS from 8 months to 12.8 months under the exponential model assumption). If the true 
HR=0.625 (under the alternative hypothesis), a total of approximately 253 PFS events are 
required to have 92% power at a one-sided 1% level of significance if OS is not significant or 

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96.2% power at 2.5% level of significance if OS is significant to reject the null hypothesis 
(HR=1) using a log-rank test. If the final PFS analysis is performed when the targeted 
253 PFS events are observed, the observed hazard ratio will have to be <0.746 or <0.782 to 
declare statistical significance at a one-sided 1% alpha level or 2.5% alpha level, 
respectively. Assuming a recruitment period of approximately 15 months from the start of the 
double-blind, randomized, placebo-controlled part with an accrual rate of 10 subjects/months 
for first 2 months, 20 subjects/months from 2 to 4 months, 40 subjects/months from 4 to 6 
months and 50 subjects/month thereafter, along with an assumed 10% dropout rate/year for PFS, 
approximately 600 subjects will need to be randomized to the two treatment arms in a 1:1 ratio. 
Given the above assumptions it is estimated that the events for the final PFS analysis will occur 
at approximately 18 months from the date of first subject randomized in the study. 
Overall survival  
Based on KEYNOTE-189 (Gandhi et al 2018) , the 12-month OS rate for the subjects with non-
squamous NSCLC randomized in pembrolizumab in combination with platinum-based doublet 
chemotherapy followed by pembrolizumab maintenance treatment (control arm) is 69.2%. 
Assuming an exponential distribution, median OS is derived to be approximately 23 months. 
Based on KEYNOTE-407 (Paz-Ares 2018), the median OS for pembrolizumab in combination 
with taxane-based chemotherapy followed by pembrolizumab maintenance treatment (control 
arm) in subjects with squamous NSCLC at the time of the 2nd IA is 15.9 months (95% CI: 13.2, 
NE). This median estimate may be immature given the high censoring rate and only ~30% of 
subjects had events. Therefore, the 9-month OS rate of 73% estimated graphically from the 
Kaplan-Meier curve was used to derive the median OS for the control arm in squamous NSCLC, 
which is calculated to be approximately 20 months assuming an exponential distribution. Based 
on the assumption that 30% subjects in the current study (CACZ885U2301) will have squamous 
histology, the median OS in the control arm for this study is expected to be approximately 22 
months based on simulation. Under the assumption that the median OS in the control arm is 22 
months, it is assumed that addition of canakinumab will result in a 31% reduction in the OS 
hazard rate (corresponding to an increase in median OS from 22 months to 31.9 months under 
the exponential model assumption). If the true HR=0.69 (under the alternative hypothesis), a 
total of approximately 304 deaths are required to have 85% power at a one-sided 1.5% level of 
significance if PFS is not significant or 89.3% power at 2.5% level of significance if PFS is 
significant to reject the null hypothesis (HR=1) using a log-rank test. If the final OS analysis is 
performed when the targeted 304 OS events are observed after exactly 120 OS events and 
243 OS events have been observed at 1st and 2nd interim analysis respectively, the observed 
hazard ratio will have to be <0.775 or <0.793 to declare statistical significance at one-sided 
1.5% alpha level or 2.5% alpha level respectively. A 5% dropout rate/year for OS is assumed. 
The interim analyses for OS are planned at the time of final PFS analysis and when 
approximately 80% of deaths are observed (expected at approximately 30 months from the date 
of first subject randomized). Events required for the final OS analysis are expected at 
approximately 38 months from the date of first subject randomized in the study. 
These calculations were performed using EAST 6.4. 

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Audit size for BIRC assessed PFS 
The audit size of the sample-based BIRC assessment will be 40% of all randomized subjects 
based on the audit size calculation approach proposed by Dodd et al 2011, assuming 
investigator and BIRC assessments are similar and the estimated log of investigator-based HR is 
-0.47 (i.e. HR=0.625). The audit size of 40% will ensure that the upper bound of a one-sided 
95% CI for BIRC-based log-hazard ratio has 91 % probability of being below 0 (i.e. HR<1) if 
the correlation between investigator assessment and BIRC assessment is 0.8 (the estimated 
correlation approximated based on data from the Novartis [CLDK378A2303] and 
[CLDK378A2301] studies in NSCLC) 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (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.). 
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 

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Operating Procedures (SOPs) as well as applicable global/local GCP regulations and ICH 
Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be implemented. 
14.1 
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for subject safety may be implemented immediately 
provided the Health Authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis must 
be notified of this action and the IRB/IEC at the study site must 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 Guideline 
Document status: 
Version 3.2: February 11, 2016 
Version 3.1: November 29, 2011 
Version 3: October 19, 2009 Version 2: January 18, 
2007 Version 1: December 13, 2002 
Release date: 
11-Feb-2016  
 
Authors (Version 3.2): 
 
 
Authors (Version 3.1): 
 
Authors (Version 3): 
 
Authors (Version 2): 
 
 
Authors (Version 1): 
 
Glossary 
CR 
Complete response 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CT 
Computed tomography 
DFS 
Disease-free survival 
eCRF 
Electronic Case Report Form 
FPFV 
First patient first visit 
GBM 
Glioblastoma multiforme 
MRI 
Magnetic resonance imaging 
LPLV 
Last patient last visit 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PR 
Partial response 
RAP 
Reporting and Analysis Plan 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SD 
Stable disease 
SOD 
Sum of Diameter 
TTF 
Time to treatment failure 
TTP 
Time to progression 
UNK 
Unknown 
PPD
PPD
PPD
PPD
PPD

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16.1.1 
Introduction 
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This document 
is based on the RECIST criteria for tumor responses (Therasse 2000) and the revised RECIST 
1.1 guidelines (Eisenhauer 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 by (Therasse 2000) and revised RECIST 
guidelines (version 1.1) by (Eisenhauer 2009). 
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 subjects without measurable disease, even if not expected as per eligibility criteria in this 
protocol, see Section 16.1.3.2.9  
Measurable lesions (both nodal and non-nodal) 
• Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5 mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm. 
• Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft tissue 
component meets the definition of measurability. 
• Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes >=15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring >=10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at baseline, 
regardless of the slice thickness, are normal and not considered indicative of disease. 
• Cystic lesions:  

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• Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no septations, 
and low CT density [water-like] content) should not be considered as malignant lesions 
(neither measurable nor non-measurable) since they are, by definition, simple cysts. 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
noncystic lesions are present in the same subject, 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 subject 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 subjects be excluded from trials where the main focus is on the Overall 
Response Rate (ORR). Guidance on how subjects with just non-measurable disease at baseline 
(even if not expected as per eligibility criteria of this protocol) will be evaluated for response 
and also handled in the statistical analyses is given in Section 16.1.3.2.9. 
16.1.2.2 Methods of tumor measurement - general guidelines 
In this document, the term “contrast” refers to intravenous (i.v.) contrast. 
The following considerations are to be made when evaluating the tumor: 
• All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the treatment. 
• Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment. 
• For optimal evaluation of subjects, 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 subject 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 

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

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• 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 
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 on-
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 

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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 
Non-nodal lesions 
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are subject to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance of 
the cut from the longest diameter; such lesions may appear to have responded or progressed on 
subsequent examinations, when, in fact, they remain the same size). 
If the lesion has completely disappeared, the lesion size should be reported as 0 mm. 
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement. This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval. 
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated. 
Nodal lesions 
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are not 
expected to disappear completely, so a “non-zero size” will always persist. 
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval. 

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16.1.2.4.2 
Determination of target lesion response 
Table 16-1 
Response criteria for target lesions 
Response Criteria 
Evaluation of target lesions 
Complete Response (CR): 
Disappearance of all non-nodal target lesions. In addition, any pathological 
lymph nodes assigned as target lesions must have a reduction in short axis to < 
10 mm 1 
Partial Response (PR): 
At least a 30% decrease in the sum of diameter of all target lesions, taking as 
reference the baseline sum of diameters. 
Progressive Disease (PD): 
At least a 20% increase in the sum of diameter of all measured target lesions, 
taking as reference the smallest sum of diameter of all target lesions recorded at 
or after baseline. In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm 2. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions 
which would qualify for PD. 
Unknown (UNK) 
Progression has not been documented and one or more target lesions have not 
been assessed or have been assessed using a different method than baseline.3 
1. 
SOD for CR may not be zero when nodal lesions are part of target lesions 
2. 
Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present and all 
nodal lesions are <10 mm in size. In this case, the target lesion response is CR 
3. 
In exceptional circumstances an UNK response due to change in method could be over-ruled by the 
investigator or central reviewer using expert judgment based on the available information (see Notes on 
target lesion response and methodology change in Section 16.1.2.2). 
Notes on target lesion response 
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance (i.e., 
the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually present 
and/or not visualized for technical reasons in this previous assessment. If it is not possible to 
change the 0 value, then the investigator/radiologist has to decide between the following 
possibilities: 
• The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease 
• The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the 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 all measured target 
lesions, taking as reference the smallest sum of diameters of all target lesions recorded at or 
after baseline with at least 5 mm increase in the absolute sum of the diameters). Proper 
documentation should be available to support this decision. This applies to subjects who 
have not achieved target response of CR. For subjects who have achieved CR, please refer 
to last bullet in this section. 
• For those subjects who have only one target lesion at baseline, the reappearance of the target 
lesion which disappeared previously, even if still small, is considered a PD. 
• Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
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is 140 mm (with data for 2 other lesions missing) then a PD should be assigned. However, 
in other cases where a PD cannot definitely be attributed, the target lesion response would 
be UNK. 
• Nodal lesion decrease to normal size: When nodal disease is included in the sum of target 
lesions and the nodes decrease to “normal” size they should still have a measurement 
recorded on scans. This measurement should be reported even when the nodes are normal 
in order not to overstate progression should it be based on increase in the size of nodes. 
• Lesions split: In some circumstances, disease that is measurable as a target lesion at 
baseline and appears to be one mass can split to become two or more smaller sub-lesions. 
When this occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) of 
the two split lesions should be added together and the sum recorded in the diameter field on 
the case report form under the original lesion number. This value will be included in the 
sum of diameters when deriving target lesion response. The individual split lesions will not 
be considered as new lesions, and will not automatically trigger a PD designation. 
• Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis - 
nodal lesions) of the “merged lesion” should be used when calculating the sum of diameters 
for target lesions. On the case report form, the diameter of the “merged lesion” should be 
recorded for the size of one of the original lesions while a size of “0”mm should be entered 
for the remaining lesion numbers which have coalesced. 
• The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications. 
• Since lesions less than 10 mm are considered normal, a CR for target lesion response should 
be assigned when all nodal target lesions shrink to less than 10 mm and all non- nodal target 
lesions have disappeared. 
• Once a CR target lesion response has been assigned a CR will continue to be appropriate 
(in the absence of missing data) until progression of target lesions. 
• Following a CR, a PD can subsequently only be assigned for target lesion response if either 
a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 mm and 
there is at least 20% increase in sum of the diameters of all nodal target lesions relative to 
nadir with at least 5 mm increase in the absolute sum of the diameters. 
• A change in method for the evaluation of one or more lesions will usually lead to an UNK 
target lesion response unless there is progression indicated by the remaining lesions which 
have been evaluated by the same method. In exceptional circumstances an investigator or 
central reviewer might over-rule this assignment to put a non-UNK response using expert 
judgment based on the available information. E.g. a change to a more sensitive method 
might indicate some tumor shrinkage of target lesions and definitely rule out progression in 
which case the investigator might assign an SD target lesion response; however, this should 
be done with caution and conservatively as the response categories have well defined 
criteria. 

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

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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 
subject in which case the response should be UNK, as for any of this subject's assessment 
(Section 16.1.2.5). 
• A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to >= 10 mm for the first time in the study plus 5 
mm absolute increase.  
FDG-PET: can complement CT scans in assessing progression (particularly possible for ‘new’ 
disease). See Section 16.1.2.2. 
16.1.2.5 Evaluation of overall lesion response 
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response and presence of new lesions as shown below in  
Table 16-3. 
Table 16-3 
Overall lesion response at each assessment 
Target lesions 
Non-target lesions 
New Lesions 
Overall lesion response 
CR 
CR 
No 
CR1 
CR 
Non-CR/Non-PD3 
No 
PR 
CR, PR, SD 
UNK 
No 
UNK 
PR 
Non-PD and not UNK 
No 
PR1 
SD 
Non-PD and not UNK 
No 
SD1, 2 
UNK 
Non-PD or UNK 
No 
UNK1 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1This overall lesion response also applies when there are no non-target lesions identified at baseline. 
2Once confirmed PR was achieved, all these assessments are considered PR. 
3As 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. 

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16.1.3 
Efficacy definitions 
The following definitions primarily relate to subjects who have measurable disease at 
baseline. Section 16.1.3.2.9 outlines the special considerations that need to be given to subjects 
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 subject'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 130 days after the last dose 
of study treatment will not be included in the best overall response derivation. If any alternative 
cancer therapy is taken while on study any subsequent assessments would ordinarily be 
excluded from the best overall response determination. If response assessments taken after 
withdrawal from study treatment and/or alternative therapy are to be included in the main 
endpoint determination, then this should be described and justified in the protocol. 
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met. 
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed. 
• For non-randomized trials where response is the primary endpoint, confirmation is needed. 
• For trials intended to support accelerated approval, confirmation is needed 
• For all other trials, confirmation of response may be considered optional. 
The best overall response for each subject is determined from the sequence of overall (lesion) 
responses according to the following rules: 
• CR = at least two determinations of CR at least 4 weeks apart before 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) > 5 weeks after randomization/start of treatment 
(and not qualifying for CR or PR). 
• PD = progression <=13 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD). 

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• UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 5 weeks or early progression within the first 13 weeks) 
The time durations specified in the SD/PD/UNK definitions above are based on a 6 week tumor 
assessment frequency taking 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 subject 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 subject has a single PR (>=30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not >=20% increase from previous smallest sum), the objective 
status at that assessment should be SD. Once a confirmed PR was seen, the overall lesion 
response should be considered PR (or UNK) until progression is documented or the lesions 
totally disappear in which case a CR assignment is applicable. In studies where confirmation of 
response is not required after a single PR the overall lesion response should still be considered 
PR (or UNK) until progression is documented or the lesion totally disappears in which case a 
CR assignment is applicable. 
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the subsequent 
visits. Assuming that non-target lesions did not progress, the overall lesion response would be 
PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the PR for this subject. 
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 subject 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 subject 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 
overall lesion responses. 

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Based on the subjects’ best overall response during the study, the following rates are then 
calculated: 
Overall response rate (ORR) is the proportion of subjects 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 subjects with a best overall response of CR or 
PR or SD. The objective of this endpoint is to summarize subjects 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 subjects 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 subjects with progressive disease within 7 
weeks of the start of treatment. 
The protocol should define populations for which these will be calculated. The timepoint for 
EPR is study specific. EPR is used for the multinomial designs of Dent and Zee (2001) and 
counts all subjects who at the specified assessment do not have an overall lesion response of 
SD, PR or CR. subjects 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, subjects with a best overall response assessment of unknown 
(UNK) will not be regarded as “responders” but may be included in the denominator for ORR 
and DCR calculation depending on the analysis population (e.g. populations based on an ITT 
approach). 
16.1.3.2 Time to event variables 
16.1.3.2.1 
Progression-free survival 
Usually in all Oncology studies, subjects 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 
subject 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. 

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16.1.3.2.2 
Overall survival 
All subjects should be followed until death or until subject has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date the 
subject was last seen alive / last known date subject 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 subject is not known to have died, survival will be censored 
at the date of last known date subject alive. 
16.1.3.2.3 
Time to progression 
Some studies might consider only death related to underlying cancer as an event which indicates 
progression. In this case the variable “Time to progression” might be used. TTP is defined as 
PFS except for death unrelated to underlying cancer. 
Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
a subject has not had an event, time to progression is censored at the date of last adequate tumor 
assessment. 
16.1.3.2.4 
PFS2 
A recent EMA guidance 2012 recommends a substitute end point intermediate to PFS and OS 
called PFS2, a surrogate for OS when OS cannot be measured reliably, which assesses the 
impact of the experimental therapy on next-line treatment. The main purpose of this endpoint 
is to assess long term maintenance strategies, particularly of resensitizing agents and where it 
is necessary to examine the overall “field of influence”. 
PFS2, which could be termed PFS deferred, PFS delayed, tandem PFS, or PFS version 2.0, is 
the time from date of randomization/start of treatment to the date of event defined as the first 
documented progression on next-line treatment or death from any cause. The censoring rules 
for this endpoint will incorporate the same principles as those considered for PFS in this 
document, and in addition may involve other considerations which will need to be detailed in 
the protocol. 
Please note that data collection for the PFS2 is limited to the date of progression and not specific 
read of the tumor assessments. 
It is strongly recommended that the teams consult regulatory agencies for scientific advice given 
the limited experience with the use of this endpoint in regulatory setting in light of 
methodological issues w.r.t. censoring foreseen. 
16.1.3.2.5 
Time to treatment failure 
This endpoint is often appropriate in studies of advanced disease where early discontinuation is 
typically related to intolerance of the study drug. In some protocols, time to treatment failure 
may be considered as a sensitivity analysis for time to progression. The list of discontinuation 
reasons to be considered or not as treatment failure may be adapted according to the specificities 
of the study or the disease. 

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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 subjects who did not experience treatment failure will be censored at last adequate 
tumor assessment. 
16.1.3.2.6 
Duration of response 
The analysis of the following variables should be performed with much caution when restricted 
to responders since treatment bias could have been introduced. There have been reports where 
a treatment with a significantly higher response rate had a significantly shorter duration of 
response but where this probably primarily reflected selection bias which is explained as 
follows: It is postulated that there are two groups of subjects: a good risk group and a poor risk 
group. Good risk subjects tend to get into response readily (and relatively quickly) and tend to 
remain in response after they have a response. Poor risk subjects 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 subjects. Less potent agents 
induce a response mainly in good risk subjects only. This is described in more detail by  
(Morgan 1988). 
It is recommended that an analysis of all subjects (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 
subjects (i.e. not restricting to “responders” only) using appropriate statistical methods such as 
the techniques described in Ellis 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-subject analysis of these endpoints are not appropriate since the status of 
subjects throughout the study is usually taken into account in the analysis). 
Duration of overall response (CR or PR): For subjects with a CR or PR (which may have to 
be confirmed) the start date is the date of first documented response (CR or PR) and the end 
date and censoring is defined the same as that for time to progression. 
The following two durations might be calculated in addition for a large Phase III study in which 
a reasonable number of responders is seen. 
Duration of overall complete response (CR): For subjects 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 subjects 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. 

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16.1.3.2.7 
Time to response 
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be confirmed 
depending on the type of study and its importance. Where the response needs to be confirmed 
then time to response is the time to the first CR or PR observed. 
Although an analysis on the full population is preferred a descriptive analysis may be performed 
on the “responders” subset only, in which case the results should be interpreted with caution 
and in the context of the overall response rates, since the same kind of selection bias may be 
introduced as described for duration of response in Section 16.1.3.2.6. It is recommended that 
an analysis of all subjects (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 subjects should definitely be included in the analysis to ensure the statistical 
test is valid. For analysis including all subjects, subjects who did not achieve a response (which 
may have to be a confirmed response) will be censored using one of the following options. 
• at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for subjects 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 subject 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 subjects have not yet 
progressed so they theoretically still have a chance of responding 
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint. 
16.1.3.2.8 
Definition of start and end dates for time to event variables 
Assessment date 
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest of 
all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that assessment is 
CR/PR/SD/UNK. Otherwise, if overall lesion response is progression - the assessment date is 
calculated as the earliest date of all measurement dates at that evaluation number. 
In the calculation of the assessment date for time to event variables, any unscheduled 
assessment should be treated similarly to other evaluations. 
Start dates 
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date. 
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• 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 16.1.3.2.8). 
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months. 
• Date of discontinuation is the date of the end of treatment visit. 
• Date of last contact is defined as the last date the subject 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 subject alive from the survival follow-up page is used. 
If no survival follow-up is available, the date of discontinuation is used as last contact date. 
• Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery. 
16.1.3.2.9 
Handling of patients with non-measurable disease only at baseline 
It is possible that subjects with only non-measurable disease present at baseline are entered into 
the study, because of a protocol violation. 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 subjects 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 
subjects with measurable disease at baseline, subjects without measurable disease should also 
be incorporated in an appropriate manner. The overall response for subjects with non- 
measurable disease is derived slightly differently according to Table 16-4. 

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Table 16-4 
Overall lesion response at each assessment: subjects 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 subjects is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response subjects 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 subjects 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 subjects with only 
non-measurable disease at baseline, handling subjects with a best response of CR as “responders” 
with respect to ORR and all other subjects as “non-responders”. 
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
subjects with only non-measurable disease at baseline, with possible sensitivity analyses which 
exclude these particular subjects. Endpoints such as PFS which are reliant on the determination 
and/or timing of progression can incorporate data from subjects with only non- measurable 
disease. 
16.1.3.2.10 Sensitivity analysis 
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 subject being lost to follow-up? It is important that the protocol and RAP specify the 
primary analysis in detail with respect to the definition of event and censoring dates and also 
include a description of one or more sensitivity analyses to be performed. 
Based on definitions outlined in Section 16.1.3.2.8, and using the FDA guideline on endpoints 
(FDA Guidelines 2007) 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 

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Situation 
Options for end-date (progression or censoring)1 
(1) = default unless specified differently in the 
protocol or RAP 
Outcome 
C1 
Progression or death after 
exactly one missing 
assessment 
(1) Date of progression (or death) 
(2) Date of next scheduled assessment2 
Progressed 
Progressed 
C2 
Progression or death after 
two or more missing 
assessments 
(1) Date of last adequate assessment2 
(2) Date of next scheduled assessment2 
(3) Date of progression (or death) 
Censored 
Progressed 
Progressed 
D 
No progression 
(1) Date of last adequate assessment 
Censored 
E 
Treatment discontinuation 
due to ‘Disease 
progression’ without 
documented progression, 
i.e. clinical progression 
based on investigator claim 
(1) Ignore clinical progression and follow situations 
above 
(2) Date of discontinuation (visit date at which clinical 
progression was determined) 
As per above 
situations 
Progressed 
F 
New anticancer therapy 
given 
(1) Ignore the new anticancer therapy and follow 
situations above (ITT approach) 
(2) Date of last adequate assessment prior to new 
anticancer therapy 
(3) Date of secondary anti-cancer therapy 
(4) Date of secondary anti-cancer therapy 
As per above 
situations 
Censored 
Censored 
Event 
G 
Deaths due to reason other 
than deterioration of ‘Study 
indication’ 
(1) Date of last adequate assessment 
Censored 
(only TTP and 
duration of 
response) 
1 =Definitions can be found in Section 16.1.3.2.8. 
2 =After the last adequate tumor assessment. “Date of next scheduled assessment” is defined 
in Section 16.1.3.2.8. 
3 =The rare exception to this is if the subject 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 subjects 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 

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of tumor assessment by e.g. CT-scan, option (2) may be used for indications with high early 
progression rate or difficulties to assess the tumor due to clinical deterioration. 
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1) (ITT) is the recommended approach; events 
documented after the initiation of new cancer therapy will be considered for the primary 
analysis i.e. progressions and deaths documented after the initiation of new cancer therapy 
would be included as events. This will require continued follow-up for progression after the 
start of the new cancer therapy. In such cases, it is recommended that an additional sensitivity 
analysis be performed by censoring at last adequate assessment prior to initiation of new cancer 
therapy. 
Option (2), i.e. censoring at last adequate assessment may be used as a sensitivity analysis. If a 
high censoring rate due to start of new cancer therapy is expected, a window of approximately 
8 weeks performed after the start of new cancer therapy can be used to calculate the date of the 
event or censoring. This should be clearly specified in the analysis plan. 
In some specific settings, local treatments (e.g. radiation/surgery) may not be considered as 
cancer therapies for assessment of event/censoring in PFS/TTP/DoR analysis. For example, 
palliative radiotherapy given in the trial for analgesic purposes or for lytic lesions at risk of 
fracture will not be considered as cancer therapy for the assessment of BOR and PFS analyses. 
The protocol should clearly state the local treatments which are not considered as antineoplastic 
therapies in the PFS/TTP/DoR analysis. 
The protocol should state that tumor assessments will be performed every x weeks until 
radiological progression irrespective of initiation of new antineoplastic therapy. It is strongly 
recommended that a tumor assessment is performed before the subject is switched to a new 
cancer therapy. 
Additional suggestions for sensitivity analyses 
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for censoring and 
events only at scheduled visit dates. The latter could be handled by replacing in Table 16-5 the 
“Date of last adequate assessment” by the “Date of previous scheduled assessment (from 
baseline)”, with the following definition: 
• Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly 
followed from baseline, immediately before or on the date of the last adequate tumor 
assessment. 
 In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on the 
individual requirements for the specific study and disease area and have to be specified in the 
protocol or RAP documentation. 
16.1.4 
Data handling and programming rules 
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates). 

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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 
Subjects 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 subjects 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 subject, 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. 
Subjects may discontinue study treatment for any of the following reasons: 
• Adverse event(s) 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 
• Subject/guardian decision 
• Progressive disease 
• Study terminated by the sponsor 
• Non-compliant with study treatment 
• No longer requires treatment 
• Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given) 
Death is a reason which “must” lead to discontinuation of subject 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. 
Subjects may provide study phase completion information for one of the following reasons: 
• Adverse event 
• Lost to follow-up 
• Physician decision 

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

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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 16.1.3.2.8). If all measurement dates have 
no day recorded, the 1st of the month is used. 
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation. 
16.1.4.5.3 
Incomplete dates for last known date patient alive or death 
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact. 
16.1.4.5.4 
Non-target lesion response 
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’. 
16.1.4.5.5 
Study / project specific programming 
The standard analysis programs need to be adapted for each study/project. 
16.1.4.5.6 
Censoring reason 
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page. 
For survival the following censoring reasons are possible: 
• Alive 
• Lost to follow-up 
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible: 
• Ongoing without event 
• Lost to follow-up 
• Withdrew consent 
• Adequate assessment no longer available* 
• Event documented after two or more missing tumor assessments (optional, see Table 16-5) 
• Death due to reason other than underlying cancer (only used for TTP and duration of 
response) 
• Initiation of new anti-cancer therapy 

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* Adequate assessment is defined in Section 16.1.3.2.8. This reason is applicable when 
adequate evaluations are missing for a specified period prior to data cut-off (or prior to any 
other censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason should 
also be noted: 
• This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Sponsor decision” on study evaluation completion page), when subjects 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. 
16.1.5 
References (available upon request) 
Dent S, Zee B, Dancey J, et al (2001) application of a new multinomial phase II stopping rule 
using response and early progression. J Clin Oncol: 19:785-91. 
Eisenhauer EA, Therasse P, BogaertsJ, et al (2009) New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Euro JCancer; 45:228-47. 
Ellis S, Carroll KJ, Pemberton K, et al (2008) Analysis of duration of response in oncology 
trials. Contemp Clin Trials; 29:456-65. 
EMA Guidance: 2012 Guideline on the evaluation of anticancer medicinal products in man 
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007 
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18 
Therasse P, Arbuck SG, Eisenhauer EA, et al (2000) New Guidelines to Evaluate the 
Response to Treatment in Solid Tumors. J Natl Cancer Inst ;, 92; 205-16 

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16.2 
Appendix 2: Guidelines for iRECIST 
Changes from iRECIST Version 1.0: 
The main purpose of the amendment is to incorporate the additional clarifications provided by 
iRECIST EORTC working group. Below are the key changes: 
Clarified the conditions under which the overall response can be reset following unconfirmed 
progression (iUPD) in Section 16.2.2.4.4 
• The target and non-target lesion response tables (Table 16-6 and Table 16-7) were 
simplified based on the reset of response criteria provided in Section 16.2.2.4.4 
• The new lesion-target and new lesion-non-target response Section 16.2.2.4.3.1 and  
Section 16.2.2.4.3.2 were added to provide guidance on assessment of response based on 
new lesion- target and new lesion- non-target lesions. It is important to follow the existing 
new lesions as it can remain as iUPD due to no change in size, result in confirmation of 
progression (iCPD), disappear completely resulting in iCR or shrink in size resulting in a 
response of iSD 
• Overall lesion response table (Table 16-10) was updated taking into account the new 
lesion-target and new lesion-non-target response 
• Example scenarios in Section 16.2.5 were updated to include the target response, non-
target response, new lesion-target response and new lesion-non-target response rows 
• Scenario 4 was updated based on clarifications provided by iRECIST EORTC working 
group on confirmation of progression (iCPD) following missing assessments after iUPD 
16.2.1 
Introduction 
This guideline provides the general principles and application of iRECIST (modified RECIST 
1.1 for immune-based therapeutics) to assess tumor response and to derive efficacy endpoints 
in Novartis oncology immunotherapy clinical trials. This guideline is based on the publication: 
“iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics in solid 
tumors” by Seymour et al 2017. 
This guideline will also refer to Novartis RECIST 1.1 (v3.2) for sections and derivations which 
are unchanged from RECIST 1.1. 
This document is organized as follows: 
•  Section 16.2.2  describes the efficacy assessments: disease measurability, methods of 
tumor assessments, baseline documentation of target/non-target lesions, follow-up of 
target, non- target and new target/non-target lesions and evaluation of overall lesion 
response 
•  Section 16.2.3  provides the definitions and derivations of immune related best overall 
response and time to event endpoints 
•  Section 16.2.4  lists references used in the text 
•  Section 16.2.5  provides the example scenarios 

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16.2.2 
Efficacy assessments 
Tumor evaluations are done based on iRECIST criteria (Seymour et al 2017) and RECIST 1.1 
guidelines (Eisenhauer et al 2009). 
16.2.2.1 Disease measurability 
The definition of disease measurability, classification of baseline lesions into target and non- 
target lesions, measurement and management of nodal disease, and calculation of sum of 
diameters (SOD) remains the same as RECIST 1.1. Please refer to Novartis RECIST 1.1 (v3.2) 
Section 16.1 for details. 
While there is no requirement to measure new lesions in RECIST 1.1, the new lesions identified 
at follow-up evaluations will be assessed and categorized as target or non-target in iRECIST 
using the same criteria of measurability as in RECIST 1.1. For additional details on handling of 
new lesions in iRECIST refer to Section 16.2.2.3.3. 
16.2.2.2 Methods of tumor measurement 
The methods used to measure tumors remain the same as RECIST 1.1. Please refer to Novartis 
RECIST v3.2 Section 16.1 for details. 
16.2.2.3 Target, non-target and new lesions 
The methods used to classify lesions at baseline remains the same as RECIST 1.1. Please refer 
to Novartis RECIST 1.1 (v3.2) Section 16.1 for details. 
16.2.2.3.1 
Target lesions 
The selection of target lesions at baseline and their follow-up with the calculation of 
baseline/follow-up sum of diameters (SOD) should be performed as per RECIST 1.1. 
16.2.2.3.2 
Non-target lesions 
The selection of non-target lesions at baseline and their follow-up with the assessment of lesion 
status should be performed as per RECIST 1.1 with the exception of the follow-up evaluations 
following unconfirmed progression based on these non-target lesions. Please refer to 
Section 16.2.2.4.2 for further details. 
16.2.2.3.3 
New lesions 
A lesion not present at baseline and appearing at any follow-up evaluation time-point (TP) is 
considered a New Lesion. A new lesion will be considered as ‘Newly appeared’ at a follow- up 
evaluation TP if it appeared for the first time at that TP and did not exist prior to that TP. For 
all subsequent TP, this new lesion will be not considered as ‘Newly appeared’ and will be 
followed as a “Pre-existing” new lesion. 
New lesions appearing at a follow-up evaluation TP will be classified either as New Lesion 
Target (NLT) or New Lesion Non-Target (NLNT) based on the TP when they were first 
identified using the same measurability criteria mentioned in RECIST 1.1. Once a new lesion 
is classified as NLT or NLNT, it should be followed as NLT and NLNT respectively at each 
subsequent TP regardless of change in size. New lesions do not have to resolve for subsequent 

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overall response assessment of iSD or iPR provided the next assessment did not confirm 
progression (see Section 16.2.2.4.3). 
New Lesions Target 
All new measurable lesions up to a maximum of 5 new lesions (nodal + non-nodal) in total (and 
a maximum of 2 lesions per organ), representative of all involved organs should be identified 
as New Lesions Target (NLT). Each NLT should be uniquely and sequentially numbered, 
measured and recorded in the eCRF corresponding to “New Lesions Target”. A sum of 
diameters (iSOD; long axis for non-nodal lesions, short axis for nodal) for all NLT will be 
calculated at each follow-up evaluation TP from the first appearance of a NLT. NLTs should 
not be included in the sum of diameter of the original target lesions identified at baseline. 
 New Lesions Non-target 
All other new lesions which are not considered as new lesions-target at the corresponding 
evaluation TP will be considered as New Lesions Non-Target (NLNT). Multiple NLNTs 
involved in the same organ can be recorded as a single NLNT (i.e. multiple liver metastases). 
Each NLNT should be uniquely numbered in the appropriate eCRF. The lesion status of the 
NLNT at each follow-up evaluation compared to the “previous assessment” should be recorded 
at each follow-up evaluation TP. 
16.2.2.4 Response evaluation 
Response will be assessed using iRECIST based on Seymour et al 2017. Response assigned 
using iRECIST will have a prefix of an ‘i’ (i.e. immune) (e.g. iCR for complete response) to 
differentiate them from RECIST 1.1 response. 
The principles used to establish objective tumor response are largely unchanged from RECIST 
1.1. The major change in iRECIST is the concept of unconfirmed disease progression (iUPD) 
and confirmed disease progression (iCPD). The response evaluation will remain the same for 
RECIST 1.1 and iRECIST up to the first iUPD timepoint. 
Following are the key differences in response evaluation based on iRECIST compared to 
RECIST 1.1: 
• Confirmation of disease progression is required per iRECIST. This leads to two separate 
response categories for overall response corresponding to progressive disease: 
unconfirmed progressive disease (iUPD) and confirmed progressive disease (iCPD); the 
rules for confirmation of disease progression are provided in Section 16.2.2.4.4. 
• New lesions are to be separately followed and measured at subsequent evaluation TPs in 
iRECIST for response assessment. 
• An iUPD can be followed by a complete (iCR) or partial response (iPR) or stable disease 
(iSD) or Non-iCR/Non-iUPD (for subjects with only non-measurable disease at baseline, 
even if not expected as per eligibility criteria of this protocol) as overall response. If this 
happens, the bar (i.e. overall response) is “reset” and iUPD needs to re-occur per RECIST 
1.1 followed by iCPD in order for the progression to be confirmed. 

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16.2.2.4.1 
Target lesion response 
The target lesion response will be assessed based on the criteria shown in Table 16-6. 
Table 16-6 
Determination of target lesion response by iRECIST 
Time point (TP) 
response criteria 
Applicable to Evaluation 
Time-points 
Evaluation criteria 
Immune Complete 
Response (iCR) 
Any post-baseline evaluation TP 
prior to confirmation of 
progression (i.e. 
determination of overall lesion 
response of iCPD) 
Same as CR criteria for target lesions by 
RECIST 1.1. 
iCR will be target lesion response at the next 
assessment if CR criteria per RECIST 1.1 is met 
and the overall response is reset after the 
previous assessment of overall response of 
iUPD*. 
Immune Partial 
Response (iPR) 
Any post-baseline evaluation TP 
prior to confirmation of 
progression (i.e. 
determination of overall lesion 
response of iCPD) 
Same as PR criteria for target lesions by 
RECIST 1.1 (i.e. reduction in target lesion 
SOD>=30% from baseline). 
iPR will be target lesion response at the next 
assessment if PR criteria per RECIST 1.1 is met 
and the overall response is reset after the 
previous assessment of overall response of 
iUPD*. 
Immune Stable 
Disease (iSD) 
Any post-baseline evaluation TP 
prior to confirmation of 
progression (i.e. 
determination of overall lesion 
response of iCPD) 
Same as SD criteria for target lesions by 
RECIST 1.1 (i.e. neither sufficient shrinkage to 
qualify for PR nor sufficient increase to qualify 
for PD) 
iSD will be target lesion response at the next 
assessment if SD criteria per RECIST 1.1 is met 
and the overall response is reset after the 
previous assessment of overall response of 
iUPD*. 
Immune unconfirmed 
progressive disease 
(iUPD) 
A post-baseline TP prior to iCPD 
where the previous adequate 
evaluation TP overall response 
was not iUPD 
Same as PD criteria for target lesions by 
RECIST 1.1 (i.e. increase in target lesion SOD 
≥20% from nadir with an absolute increase of ≥5 
mm). 
For iUPD after iCR, follow RECIST 1.1. 
A post-baseline TP prior to iCPD 
where the previous adequate 
evaluation TP overall response 
was iUPD 
iUPD will remain iUPD provided the overall 
response is not reset and there is no 
confirmation of iUPD*. 
• 
 
Not Evaluable (NE) 
Any post-baseline evaluation TP 
Same as UNK (Unknown)/NE (Not evaluable) 
criteria for target lesions by RECIST 1.1 
*For details on confirmation of progression (iCPD) and the reset of overall response after prior 
iUPD refer to Section 16.2.2.4.4. 
For additional notes on target lesion response (e.g. reappearance of lesions, lesion 
split/coalesced etc.) refer to Novartis RECIST 1.1 (v3.2). 
16.2.2.4.2 
Non-target lesion response 
The non-target lesion response will be assessed based on the criteria shown in  Table 16-7 . 

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Table 16-7 
Determination of non-target lesion response by iRECIST 
Time point (TP) 
response criteria 
Applicable to Evaluation 
Time-points 
Evaluation criteria 
Immune Complete 
Response (iCR) 
Any post-baseline evaluation 
TP prior to confirmation of 
progression (i.e. 
determination of overall lesion 
response of iCPD) 
Same as CR criteria for non-target lesions by 
RECIST 1.1 
iCR will be non-target lesion response at the next 
assessment if CR criteria per RECIST1.1 is met and 
the overall response is reset after the previous 
assessment of overall response of iUPD*. 
Immune Non- 
CR/non-UPD (Non- 
iCR/Non-iUPD) 
Any post-baseline evaluation 
TP prior to confirmation of 
progression (i.e. 
determination of overall lesion 
response of iCPD) 
Same as NON-CR/NON-PD criteria for non- target 
lesions by RECIST 1.1 
Non-iCR/Non-iUPD will be non-target lesion 
response at the next assessment if the overall 
response is reset after the previous assessment of 
overall response of iUPD*. 
Immune unconfirmed 
progressive disease 
(iUPD) 
A post-baseline TP prior to 
iCPD where the previous 
adequate evaluation TP 
overall response was not iUPD 
Same as PD criteria for non-target lesions by 
RECIST 1.1 (i.e. unequivocal progression of non-
target lesions). 
For iUPD after iCR follow RECIST 1.1. 
A post-baseline TP prior to 
iCPD where the previous 
adequate evaluation TP 
overall response was iUPD 
iUPD will remain iUPD provided the overall 
response is not reset and there is no confirmation of 
iUPD*. 
Not Evaluable (NE) 
Any post-baseline evaluation 
TP 
Same as UNK (Unknown)/NE (Not evaluable) 
criteria for non-target lesions by RECIST 1.1 
*For details on confirmation of progression (iCPD) and the reset of overall response after prior iUPD refer 
to Section 16.2.2.4.4 
For additional notes on non-target lesion response (e.g. unequivocal progression etc.) refer to 
Novartis RECIST 1.1 (v3.2). 
16.2.2.4.3 
New lesion consideration in response 
As mentioned in Section 16.2.2.3.3, the new lesions are classified as New Lesions Target (NLT) 
and New Lesions Non-Target (NLNT). Both NLT and NLNT will contribute to the overall 
response determination; however, will not be added to the SOD for baseline target lesions. 
• A NLT or NLNT appearing for the first time at any post-baseline evaluation TP will result 
in an overall lesion response of iUPD unless it confirms disease progression which 
occurred at the previous TP. If it confirms disease progression which occurred at the 
previous TP, then overall lesion response will be iCPD. 
• Recurrence of iUPD after return to iSD or better response following previous iUPD will 
be based on RECIST 1.1 principles. The new lesions would result in a new iUPD if:  
• New lesion appeared at that TP. 
• The pre-existing NLT met RECIST 1.1 criteria for PD i.e. 20% or more increase in 
iSOD from nadir with an absolute increase of ≥ 5 mm. Nadir iSOD is obtained based 
on all previous TP assessments of NLT. 
• The pre-existing NLNT showed unequivocal worsening. 
• New lesions do not have to resolve for a subsequent overall lesions response of iSD or iPR 
if there is a reset of overall response 

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16.2.2.4.3.1 New lesion-target (NLT) response 
The new target lesion response will be applicable only from the time point of appearance of 
new target lesion(s) until the disappearance of the new target lesion(s). The new target lesion 
response will be assessed based on the criteria shown in Table 16-8.  
Table 16-8 
Determination of new lesion-target response by iRECIST 
Time point (TP) 
response criteria 
Applicable to Evaluation 
Time-points 
Evaluation criteria  
Immune unconfirmed 
progressive disease 
(iUPD) 
A post-baseline TP from the 
appearance of new-target lesion 
and prior to iCPD, where the 
previous adequate evaluation 
TP overall response was not 
iUPD 
A new target lesion appears at the current TP 
or pre-existing NLT met RECIST 1.1 PD 
criteria based on iSOD from new target lesions 
(At least 20% increase in iSOD relative to nadir 
or baseline with at least 5 mm absolute 
increase) 
A post-baseline TP from the 
appearance of new-target lesion 
and prior to iCPD, where the 
previous adequate evaluation 
TP overall response was iUPD 
iUPD will remain iUPD provided there is no 
change in size of new target lesions and the 
overall response is not reset and there is no 
confirmation of iUPD* 
Immune Stable Disease 
(iSD) 
A post-baseline evaluation TP 
after the appearance of a new 
target lesion prior to iCPD 
iSD will be new target lesion response at the 
next assessment following iUPD if there is 
change in size of new target lesions and the 
previous TP overall response of iUPD will be 
reset to iSD or better* 
Immune Partial 
Response (iPR) 
NA 
Immune Complete 
Response (iCR) 
A post-baseline evaluation TP 
after the appearance of a new 
target lesion prior to iCPD 
Disappearance of all new target lesions 
Not Evaluable (NE) 
A post-baseline evaluation TP 
after the appearance of a new 
target lesion 
Same as UNK (Unknown)/NE (Not evaluable) 
criteria per RECIST 1.1 
*For details on confirmation of progression (iCPD) and the reset of overall response after prior iUPD refer to 
Section 16.2.2.4.4. 
16.2.2.4.3.2 New lesion-non-target response 
The new non-target lesion response will be applicable only from the time point of appearance 
of new non-target lesion(s) until the disappearance of the new non-target lesion(s). The new 
non-target lesion response will be assessed based on the criteria shown in Table 16-9. 
Table 16-9 
Determination of new lesion-non-target response by iRECIST 
Time point (TP) 
response criteria 
Applicable to Evaluation Time-points 
Evaluation criteria  
Immune unconfirmed 
progressive disease 
(iUPD) 
A post-baseline TP from the 
appearance of new non-target lesion 
and prior to iCPD. where the previous 
adequate evaluation TP overall 
response was not iUPD 
A new non-target lesion appears at the 
current TP or pre-existing NLNT showed 
unequivocal worsening 

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Time point (TP) 
response criteria 
Applicable to Evaluation Time-points 
Evaluation criteria  
A post-baseline TP from the 
appearance of new non-target lesion 
and prior to iCPD, where the previous 
adequate evaluation TP overall 
response was iUPD 
iUPD will remain iUPD provided there is 
no change in new non-target lesions and 
the overall response is not reset and 
there is no confirmation of iUPD* 
Immune Non-CR/non-
UPD (NON-iCR/NON-
iUPD) 
A post-baseline evaluation TP after the 
appearance of a new non-target lesion 
prior to iCPD 
NON-iCR/NON-iUPD will be the new non-
target lesion response if there is change 
in new non-target lesions and the 
previous overall response of iUPD will be 
reset to iSD or better* 
Immune Complete 
Response (iCR) 
A post-baseline evaluation TP after the 
appearance of a new non-target lesion 
prior to iCPD 
Disappearance of all new non-target 
lesions 
Not Evaluable (NE) 
A post-baseline evaluation TP after 
appearance of a new non-target lesion 
Same as UNK (Unknown)/NE (Not 
evaluable) criteria for non-target lesions 
by RECIST 1.1 
*For details on confirmation of progression (iCPD) and the reset of overall response after prior iUPD refer to 
Section 16.2.2.4.4. 
16.2.2.4.4 Confirmation of disease progression and reset of overall lesion response 
Unlike RECIST 1.1, iRECIST requires confirmation of progression. A confirmatory scan 
should be performed at least 4 weeks after initial iUPD and no longer than 8 weeks after iUPD, 
provided the subject is clinically stable and does not require change of treatment. If progression 
is confirmed at the confirmatory scan, the overall lesion response will be iCPD. If the next 
assessment after iUPD is not evaluable (NE), then the next adequate tumor assessment will be 
considered for the determination of iCPD. 
Confirmation of progression requires either 
• further worsening in the lesion category (i.e. target, non-target, new lesion) with existing 
iUPD 
or 
• a lesion category without prior iUPD met RECIST 1.1 criteria for progression. 
Overall lesion response will be assessed as iCPD based on the following criteria if there is a 
further continued increase in tumor burden compared to the previous TP response of iUPD: 
• If initial iUPD was due to Target lesions: further increase in target lesions of at least 5 
mm* in the absolute value of SOD compared to the iUPD from previous TP. 
• If initial iUPD was due to Non-Target lesions: Any increase in non-target lesions 
compared to the iUPD from previous TP. 
• If initial iUPD was due to New lesions: Further increase in size of new lesion(s) (an 
increase of at least 5 mm* in iSOD of NLT or any increase in NLNT) compared to the 
iUPD from previous TP or appearance of additional new lesions at current TP. 
• RECIST 1.1 criteria for PD was met in lesion categories (target or non-target or 
appearance of additional new lesions), where iUPD was not previously identified. 
*Note: Sequential increases are additive; Thus a 4 mm increase at one assessment, followed at 
the next assessment by a further 2 mm increase meets the criteria for iCPD. 

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If progression (iUPD) was not confirmed at the next evaluation TP (i.e. no iCPD), then ; there 
are two scenarios for overall lesion response at the next evaluation TP as defined below: 
• The overall lesion response is reset with response of iSD or better if it meets RECIST 1.1 
criteria even if the new lesions do not resolve 
• iUPD will remain at the next evaluation TP if there is no change in tumor burden or it 
meets PD per RECIST 1.1 criteria  
• No change in tumor burden is defined as <5mm change in SOD/iSOD based on 
target/new-target lesions and no change in the status of non-target/new non-target 
lesions. 
The overall lesion response is reset with a TP response of iSD or better if it meets RECIST 1.1 
criteria (even if the new lesions do not resolve), after the previous evaluation TP response of 
iUPD, if it meets one of the below criteria compared to the TP, where prior iUPD was observed: 
• Decrease of at least 5 mm in SOD based on target lesions 
• Shrinkage in non-target lesions resulting in reduction of tumor burden 
• Decrease of at least 5 mm in iSOD based on new target lesions 
• Shrinkage in new non-target lesions resulting in reduction of tumor burden 
After the overall lesion response is reset following iUPD, the target, non-target, new lesion 
target and new lesion non-target response evaluation will follow the criteria specified in  
Table 16-6, Table 16-7, Table 16-8 and Table 16-9. 
Note: Even if the overall lesion response is reset, all assessments including those assessments 
done prior to reset of response should be considered for determination of nadir, which will be 
used to determine the next occurrence of iUPD. 
16.2.2.4.5 
Overall lesion response 
The overall lesion response for a post-baseline TP will be assessed as shown in Table 16-10. 
Table 16-10 
Overall lesion response for a time-point based on consideration of 
target lesions, non-target lesions and new lesions 
Row # 
Target 
lesion 
response* 
Non-target 
lesion 
response* 
New lesion response* 
Overall TP response 
Target† 
Non-target†† 
No prior 
iUPD** 
Prior iUPD**; 
*** 
1 
iCR 
iCR 
iCR 
iCR 
iCR 
iCR 
2 
iCR 
NON-iCR/NON-
iUPD 
iCR, iSD 
iCR, NON-
iCR/NON-iUPD 
iPR 
iPR 
3 
iPR 
iCR, NON-
iCR/NON-iUPD 
iCR, iSD 
iCR, NON-
iCR/NON-iUPD 
iPR 
iPR as long as 
there is no iCPD 
4 
iSD 
iCR, NON-
iCR/NON-iUPD 
iCR, iSD 
iCR, NON-
iCR/NON-iUPD 
iSD 
iSD as long as 
there is no iCPD 
5 
iUPD with no 
change or 
decrease 
from last TP 
iUPD with no 
change or 
decrease from 
last TP 
No iCPD due 
to new-target 
lesions 
No iCPD due to 
new non-target 
lesions 
NA 
iUPD remains 
unless iCPD 
confirmed 
6 
iSD, iPR, 
iCR 
iUPD 
iUPD, iCR 
iUPD, iCR 
iUPD 
Remains iUPD 
unless iCPD 
confirmed 

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Row # 
Target 
lesion 
response* 
Non-target 
lesion 
response* 
New lesion response* 
Overall TP response 
Target† 
Non-target†† 
No prior 
iUPD** 
Prior iUPD**; 
*** 
7 
iUPD 
NON-iCR/NON-
iUPD or iCR 
iUPD, iCR 
iUPD, iCR 
iUPD 
Remains iUPD 
unless iCPD 
confirmed 
8 
iUPD 
iUPD 
iUPD, iCR 
iUPD, iCR 
iUPD 
Remains iUPD 
unless iCPD 
confirmed 
9 
Non-iUPD 
Non-iUPD 
iUPD 
iUPD, NON-
iCR/NON-iUPD, 
iCR 
iUPD 
Remains iUPD 
unless iCPD 
confirmed 
10 
Non-iUPD 
Non-iUPD 
iUPD, iSD, 
iCR 
iUPD 
iUPD 
Remains iUPD 
unless iCPD 
confirmed 
* Using RECIST 1.1 principles. 
If no RECIST PD occurs, RECIST 1.1 and iRECIST categories for CR, PR and SD will be the same. 
** in any lesion category. 
*** previously identified in assessment immediately prior to this TP. If this is not the case then refer to column 
‘No prior iUPD’. 
† Only applicable on/after the time point a new lesion-target appeared. If there are no new lesions-target 
consider new lesion-target response as if it is iCR. 
†† Only applicable on/after the time point a new lesion-non-target appeared. If there are no new lesions-non-
target consider new lesion-non-target response as if it is iCR. 
If there are no baseline scans available, then the overall response at each assessment will be Not 
Evaluable (NE). 
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 iCR. 
For subjects with only non-measurable disease at baseline (even if not expected as per eligibility 
criteria of this protocol), the overall response will be obtained based on Non-target response 
(refer to Table 16-7) and new lesions (Table 16-8, Table 16-9). Table 16-10 can be used for 
obtaining the overall response without considering the target lesion requirement in this situation. 
16.2.2.5 Treatment continuation beyond RECIST 1.1 PD 
Differentiating transient pseudo-progression from true progression, potentially requiring a 
change in therapy, can be challenging. Although early discontinuation of an effective drug is 
not desirable, continued long-term treatment with a non-effective drug past true progression 
might delay the initiation of potentially effective salvage therapy. 
All decisions regarding continuation or discontinuation of therapy should be made by the 
investigator in conjunction with the subject. It is recommended that clinical trials, which permit 
treatment beyond initial RECIST 1.1 defined progression (i.e., iUPD) should only allow 
subjects who are clinically stable to continue on treatment until the next assessment (≥4 weeks 
later) and is still deriving benefit as per investigator assessment. The next imaging assessment 
after RECIST 1.1 PD should ideally be no longer than 8 weeks later, to ensure that subjects 
remain fit for salvage therapies. A longer timeframe before the next assessment may be 

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reasonable if pseudo-progression is well described in the tumor type, especially if no effective 
salvage therapies are available and this should be justified in the trial protocol. 
The imaging findings and the recommendation to continue treatment despite iUPD should be 
discussed with the subject before a decision is made about whether or not to continue therapy. 
subjects who have iUPD and are not clinically stable should be designated as not clinically 
stable in the case report form and it is recommended that the treatment should be withdrawn. 
The determination of clinical stability/benefit which would allow continuation of therapy will 
need to be made at the initial progression based on RECIST1.1 PD (iUPD by iRECIST) and at 
each subsequent assessment of iUPD. 
16.2.2.5.1 
Guidance on assignment of clinical stability 
An assignment of clinical stability generally requires that no worsening of performance status 
has occurred, that no clinically relevant increases in disease-related symptoms such as pain or 
dyspnea occur that are thought to be associated with disease progression (these symptoms are 
generally understood to mean a requirement for increased palliative intervention), and that no 
requirement for intensified management of disease-related symptoms exists, including 
increased analgesia, radiotherapy, or other palliative care. 
16.2.3 
Efficacy definitions 
16.2.3.1 Best overall response 
For best overall response (BOR), the requirement for confirmation of progression needs to be 
taken into account for the derivation but otherwise the same principles as described in the 
Novartis RECIST 1.1 (v3.2).  Section 16.1.3.1  will apply unless stated otherwise below or in 
the study protocol. 
The best overall response for each subject is determined from the sequence of overall responses 
recorded while on treatment or till start of new antineoplastic therapy according to the following 
rules: 
• iCR = at least two determinations of iCR at least 4 weeks apart. Note that there should not 
be any tumor assessment with an overall response of iUPD in between. 
• iPR = at least two determinations of iPR or better at least 4 weeks apart (and not qualifying 
for iCR). Note that there should not be any intervening tumor assessment with an overall 
response of iUPD in between. 
• iSD = at least one iSD assessment (or better) > 5 weeks after randomization/start of 
treatment (and not qualifying for iCR or iPR). 
• iCPD = iCPD with initial iUPD assessment of the progression ≤ 13 weeks after 
randomization/ start of treatment (and not qualifying for iCR, iPR or iSD) For example  
• If overall response for TP1= iUPD; TP2 = iUPD; TP3 = iUPD and TP4 = iCPD then 
iBOR = iCPD. 
• If overall response for TP1= NE; TP2 = iUPD; TP3 = iUPD and TP4 = iCPD then iBOR 
= iCPD. 
• iUPD = iUPD with no further adequate tumor assessments ≤ 13 weeks after randomization/ 
start of treatment (and not qualifying for iCR, iPR, iSD or iCPD) 

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• NE = all other cases (i.e. not qualifying for confirmed iCR or iPR and without iSD after 
more than 5 weeks or early progression within the first 13 weeks) 
The primary analysis of the best overall response will be based on the sequence of investigator 
(investigator overall lesion responses). 
Additional Notes 
• If the subject has a confirmed progression (iCPD) 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. 
• Overall lesion responses of iCR (which may have to be a confirmed iCR depending on the 
study) must stay the same until an iUPD assessment, with the exception of an NE status. A 
subject who had a iCR, and confirmed (if required), cannot subsequently have a lower status 
other than an iUPD (or iCPD), e.g. iPR or iSD, as this would imply a progression based on 
one or more lesions reappearing, in which case the status would become an iUPD. 
• Similarly, once an overall lesion response of iPR is observed (which may have to be a 
confirmed iPR depending on the study) this assignment must stay the same or improve over 
time until an iUPD assessment, with the exception of a NE status. 
For subjects with only non-measurable disease at baseline (even if not allowed in this protocol) 
no confirmation is required for Non-iCR/Non-iUPD. For the BOR, the same definition as above 
applies for iCR, iPD and NE. For BOR of Non-iCR/Non-iUPD the definition for iSD will be 
used. 
16.2.3.2 Definition of endpoints 
16.2.3.2.1 
Frequency-based endpoints 
Immune related overall response rate (iORR) is defined as the proportion of subjects with a 
best overall response of iCR or iPR. This is also referred to as ‘immune-related objective 
response rate’ in some protocols or publications. 
Immune related complete response rate (iCRR) is defined as the proportion of subjects with 
a best overall response of iCR. (For studies with a reasonable number of responders expected) 
Immune related disease control rate (iDCR) is defined as the proportion of subjects with a 
best overall response of iCR or iPR or iSD. Subjects with a BOR of iNCRNPD will also be 
included in iDCR if subjects with non-measurable disease at baseline are in the analysis set. 
Immune related clinical benefit rate (iCBR) is defined as the proportion of subjects with a 
best overall response of iCR or iPR or overall lesion response of iSD or Non-iCR/Non-iPD 
lasting for at least 24 weeks. 
16.2.3.2.2 
Time to event endpoints 
For the following time to event endpoints, a progression event will be defined as:- 
• A confirmed progression (iCPD), where the date of progression will be the date of first 
iUPD assessment that was confirmed. 

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For example, if the sequence of overall lesion response at different TPs is as shown below: 
Post-
baseline TP 
1 
2 
3 
4 
5 
6 
Overall 
response 
iSD 
iUPD 
iPR 
iUPD 
iUPD 
iCPD 
The date of progression for analysis will be the date of TP4. 
• In the absence of a confirmed progression, an unconfirmed progression (iUPD) with no 
further adequate tumor assessments will also be regarded as a progression event. In this case, 
the progression date will be the date of the first iUPD assessment with no intervening iSD 
or better overall response. 
For example, if the sequence of overall lesion response at different TPs is as shown below: 
Post-
baseline TP 
1 
2 
3 
4 
5 
6 
Overall 
response 
iSD 
iUPD 
iPR 
iUPD 
iUPD 
NE 
The date of progression will be the date of TP4. TP2 is not considered since there is an 
intervening iPR at TP3. 
Any unconfirmed progression assessments (iUPD) which are subsequently followed by at least 
one further adequate tumor assessment will be ignored in the derivation of these endpoints. An 
adequate tumor assessment is a tumor assessment with overall response other than NE. If the 
sequence of overall lesion response at different TPs is as shown below: 
Post-
baseline TP 
1 
2 
3 
4 
5 
6 
7 
Overall 
response 
iSD 
iUPD 
iPR 
iUPD 
iUPD 
iSD 
NE 
The above is not a progression event and it will be censored in the time to event analysis with 
the date of censoring at TP6. 
1. Immune related progression-free survival (iPFS) 
iPFS is defined as the time from date of randomization/start of treatment to the date of 
progression or death due to any cause. If a subject has not had an event, progression-free 
survival will be censored at the date of last adequate tumor assessment. iUPD without further 
adequate tumor assessments will be considered as an event. An adequate tumor assessment is a 
tumor assessment with overall response other than NE. Refer to Novartis RECIST 1.1 (v3.2) 
for additional details on censoring rules. 
2.  Immune related time to progression (iTTP) 
iTTP is defined as the time from date of randomization/start of treatment to the date of 
progression or death due to underlying cancer. If a subject has not had an event, time to 
progression will be censored at the date of last adequate tumor assessment. iUPD without 
further adequate tumor assessments will be considered as an event. An adequate tumor 
assessment is a tumor assessment with overall response other than NE. Refer to Novartis 
RECIST 1.1 (v3.2) for additional details on censoring rules. 

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3.  Immune related time to response (iTTR) 
iTTR is defined as the time between date of randomization/start of treatment until first 
documented response (confirmed iCR or iPR). Time to response will be censored for subjects 
without confirmed iCR or iPR as described in the Novartis RECIST 1.1 (v3.2). 
4.  Immune related duration of response 
Immune related duration of overall response (iDOR): For subjects with a confirmed iCR or 
iPR the start date will be the date of first documented confirmed response and the end date and 
censoring will be defined the same as that for time to progression (iTTP). 
The following two durations may be calculated in addition for a large Phase III study in which 
a reasonable number of responders are observed. 
Immune related duration of overall complete response: For subjects with a confirmed iCR 
the start date will be the date of first documented confirmed iCR and the end date and censoring 
will be defined the same as that for time to progression (iTTP). 
Immune related duration of stable disease: For subjects with BOR of iCR (confirmed) or 
iPR (confirmed) or iSD the start and end date as well as censoring will be defined the same as 
that for time to progression (iTTP). 
16.2.4 
References 
Eisenhauer EA, Therasse P, et al (2009) New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1), European Journal of Cancer; 45, p228-247. 
Seymour L, Bogaerts J, Perrone A, et al (2017) iRECIST: guidelines for response criteria for 
use in trials testing immunotherpeutics, Lancet Oncol, 18, e143-52. 
16.2.5 
Supplement 1: Example Scenarios 
Below are some example scenarios which are included for clarity on how the criteria can be 
used in specific situations. 
16.2.5.1 Scenario 1: Cross category PD 
 
Baseline 
TP1 
TP2 
TP3 
TL (SOD mm) 
100 
125 
125 
125 
NTL 
Present 
UC 
UC 
Unequi. ↑ 
NLT (# of NLT/ 
iSOD mm) 
- 
- 
- 
- 
NLNT 
- 
- 
- 
- 
TP response 
(RECIST) 
- 
PD 
PD 
PD 
TL response 
(iRECIST)  
 
iUPD  
iUPD  
iCPD  
NTL response 
(iRECIST)  
-  
NiCR/NiUPD  
NiCR/NiUPD  
iUPD  
NLT response 
(iRECIST)  
-  
-  
-  
-  
NLNT response 
(iRECIST)  
-  
-  
-  
-  

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TP response 
(iRECIST) 
- 
iUPD 
iUPD 
iCPD 
TL = Target Lesions; NTL = Non-target Lesions; NLT = New Lesions Target; NLNT = New Lesions Non- 
Target; TP = Time-point; UC = Unchanged 
• RECIST/iRECIST PD/iUPD at TP1 based on Target lesions 
• iRECIST iUPD at TP2 due to no change in lesions. 
• iRECIST Confirmed PD at TP3 due to non-target unequivocal progression which confirms 
the initial TP1 iUPD observed based on target lesions. 
• iBOR will be iCPD. TP1 will be used as event date for iPFS/iTTP/iDOR. 
16.2.5.2 Scenario 2: iPR after initial iUPD 
 
Baseline 
TP1 
TP2 
TP3 
TP4 
TP5 
TL (SOD 
mm) 
100 
125 
50 
52 
52 
60 
NTL 
Present 
UC 
UC 
UC 
UC 
UC 
NLT (# of 
NLT/ 
iSOD mm) 
- 
- 
- 
- 
+/11 
+/11 
NLNT 
- 
+ 
UC 
UC 
+ 
UC 
TP response 
(RECIST) 
- 
PD 
PD 
PD 
PD 
PD 
TL response 
(iRECIST)  
-  
iUPD  
iPR  
iPR  
iPR  
iUPD  
NTL 
response 
(iRECIST)  
-  
NiCR/NiUPD  
NiCR/NiUPD  
NiCR/NiUPD  
NiCR/NiUPD  
NiCR/NiUPD  
NLT 
response 
(iRECIST)  
-  
-  
-  
-  
iUPD  
iUPD  
NLNT 
response 
(iRECIST)  
-  
iUPD  
NiCR/NiUPD  
NiCR/NiUPD  
NiCR/NiUPD  
NiCR/NiUPD  
TP response 
(iRECIST) 
- 
iUPD 
iPR 
iPR 
iUPD 
iCPD 
TL = Target Lesions; NTL = Non-target Lesions; NLT = New Lesions Target; NLNT = New Lesions Non- 
Target; TP = Time-point; UC = Unchanged; 
+ denotes appearance of one new lesion 
• RECIST/iRECIST PD/iUPD at TP1 due to target lesions and new lesion 
• iPR at TP2 as iUPD was not confirmed and target lesions met PR criteria per RECIST 1.1 
even though NLNT remained unchanged. The status is reset with this iPR. Previous iUPD 
will no longer be considered. 
• iPR at TP3 as target lesions met PR criteria per RECIST 1.1 even though NLNT remained 
unchanged. 
• Recurrence of iUPD at TP4 based on another NLT. 
• iCPD at TP5 because target lesions met PD criteria per RECIST 1.1 . 
• iBOR will be iPR. TP4 will be used as event date for iPFS/iTTP/iDOR 

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16.2.5.3 Scenario 3: iPR before and after iUPD 
 
Baseline 
TP1 
TP2 
TP3 
TP4 
TP5 
TP6 
TL (SOD 
mm) 
100 
60 
70 
70 
65 
55 
55 
NTL 
Present 
UC 
UC 
UC 
UC 
UC 
UC 
NLT (# of 
NLT/ 
iSOD mm) 
- 
- 
- 
+/ 10 
+/ 12 
+/ 12 
+/ 18 
NLNT 
- 
- 
- 
- 
- 
- 
 
TP 
response 
(RECIST) 
- 
PR 
PR 
PD 
PD 
PD 
PD 
TL 
response 
(iRECIST)  
-  
iPR  
iPR  
iPR  
iPR  
iPR  
iPR  
NTL 
response 
(iRECIST)  
-  
NiCR/NiUP
D  
NiCR/NiUP
D  
NiCR/NiUP
D  
NiCR/NiUP
D  
NiCR/NiUP
D  
NiCR/NiUP
D  
NLT 
response 
(iRECIST)  
-  
-  
-  
iUPD  
iSD  
iSD  
iUPD  
NLNT 
response 
(iRECIST)  
-  
-  
-  
-  
-  
-  
-  
TP 
response 
(iRECIST) 
- 
iPR 
iPR 
iUPD 
iPR 
iPR 
iUPD 
TL = Target Lesions; NTL = Non-target Lesions; NLT = New Lesions Target; NLNT = New Lesions Non- 
Target; TP = Time-point; UC = Unchanged; 
+ denotes appearance of one new lesion 
• RECIST/iRECIST PR/iPR at TP1 and TP2 due to >=30% decrease in target lesion SOD 
compared to baseline. 
• RECIST/iRECIST PD/iUPD at TP3 due to a NLT of 10 mm. 
• iRECIST iPR at TP4 as iUPD was not confirmed and PR was met based on RECIST 1.1 
and there is improvement in target lesion compared to TP3 iUPD. NLT increased slightly 
but did not meet iCPD criteria. The status is reset with this iPR. Previous iUPD will no 
longer be considered. 
• iRECIST iPR at TP5. 
• iUPD at TP6 as the NLT met the RECIST 1.1 criteria for PD with ≥20% increase in iSOD 
and ≥ 5 mm increase from nadir. 
• iBOR will be iPR. TP6 will be used as event date for iPFS/iTTP/iDOR. 

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16.2.5.4 Scenario 4: Confirmation of progression (iCPD) following missing 
assessments after iUPD 
 
Baseline 
TP1 
TP2 
TP3 
TP4 
TP5 
TL (SOD 
mm) 
100 
50 
50 
55 
55 
60 
NTL 
Present 
UC 
UC 
UC 
UC 
NE 
NLT (# of 
NLT/ 
iSOD mm) 
- 
- 
- 
- 
- 
- 
NLNT 
- 
- 
+ 
UC 
NE 
UC 
TP response 
(RECIST) 
- 
PR 
PD 
PD 
PD 
PD 
TL response 
(iRECIST) 
- 
iPR 
iPR 
iPR 
iPR 
iUPD 
NTL 
response 
(iRECIST) 
- 
NiCR/NiUPD 
NiCR/NiUPD 
NiCR/NiUPD 
NiCR/NiUPD 
NE 
NLT 
response 
(iRECIST) 
- 
- 
- 
- 
- 
- 
NLNT 
response 
(iRECIST) 
- 
- 
iUPD 
iUPD 
NE 
iUPD 
TP response 
(iRECIST) 
- 
iPR 
iUPD 
iUPD 
NE 
iCPD 
TL = Target Lesions; NTL = Non-target Lesions; NLT = New Lesions Target; NLNT = New Lesions 
Non- Target; TP = Time-point; NE = Not evaluated/evaluable; UC = Unchanged; 
+ denotes appearance of one new lesion 
• RECIST/iRECIST PR/iPR at TP1 due to due to ≥30% decrease in target lesion SOD 
compared to baseline. 
• RECIST/iRECIST PD/iUPD at TP2 due to appearance of a NLNT. 
• iRECIST iUPD at TP3 as there is no iCPD and no reset of response. 
• NE at TP4 due to NLNT was not evaluated and iCPD was not observed based on 
target/non-target lesions. 
• iCPD at TP5 as progression in target lesions based on RECIST 1.1. 
• iBOR will be iSD. TP2 will be used as event date for iPFS/iTTP/iDOR. 
16.2.5.5 Scenario 5: iSD after prior iUPD and subsequent recurrence of iUPD 
 
Baseline 
TP1 
TP2 
TP3 
TP4 
TP5 
TP6 
TP7 
TL (SOD 
mm) 
100 
80 
80 
75 
64 
68 
68 
80 
NTL 
Present 
UC 
UC 
UC 
UC 
UC 
UC 
UC 
NLT (# of 
NLT/ iSOD 
mm) 
- 
+/10 
+/10 
+/10 
+/12 
+/15 
+/15 
+/15 
NLNT 
- 
- 
- 
- 
- 
- 
- 
+ 
TP 
- 
PD 
PD 
PD 
PD 
PD 
PD 
PD 

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Baseline 
TP1 
TP2 
TP3 
TP4 
TP5 
TP6 
TP7 
response 
(RECIST) 
TL 
response 
(iRECIST) 
-  
iSD  
iSD  
iSD  
iPR  
iPR  
iPR  
iUPD  
NTL 
response 
(iRECIST) 
-  
NiCR/N
iUPD  
NiCR/Ni
UPD  
NiCR/NiU
PD  
NiCR/NiU
PD  
NiCR/NiU
PD  
NiCR/NiU
PD  
NiCR/NiU
PD  
NLT 
response 
(iRECIST) 
-  
iUPD  
iUPD  
iSD  
iSD  
iUPD  
iUPD  
iUPD  
NLNT 
response 
(iRECIST) 
-  
-  
-  
-  
-  
-  
-  
iUPD  
TP 
response 
(iRECIST) 
- 
iUPD 
iUPD 
iSD 
iPR 
iUPD 
iUPD 
iCPD 
TL = Target Lesions; NTL = Non-target Lesions; NLT = New Lesions Target; NLNT = New Lesions 
Non- Target; TP = Time-point; UC = Unchanged; 
+ denotes appearance of one new lesion 
• RECIST/iRECIST PD/iUPD at TP1 due to NLT 
• iUPD at TP2 as there is no change in lesions from TP1 
• iSD at TP3 based on RECIST 1.1 as iUPD was not confirmed and target lesions met SD 
criteria per RECIST 1.1 even though NLT remained unchanged. The status is reset with 
this iSD. Previous iUPD will no longer be considered. 
• iPR at TP4 as target lesions met PR criteria per RECIST 1.1 even though NLT changed 
but did not meet the criteria for iUPD (≥ 20% increase in iSOD and ≥ 5 mm increase from 
nadir). 
• Recurrence of iUPD at TP5 as the NLT met the RECIST 1.1 criteria for PD (≥20% 
increase in iSOD and ≥ 5 mm increase from nadir). 
• iUPD remained at TP6 as there was no change in lesions compared to TP5. 
• iCPD at TP7 due to appearance of NLNT confirming TP6 iUPD. 
• iBOR will be iSD as iPR was not confirmed. TP5 will be used as event date for 
iPFS/iTTP/iDOR. 
16.2.5.6 Scenario 6: iCPD due to further worsening of target lesions 
 
Baseline 
TP1 
TP2 
TP3 
TP4 
TL (SOD mm) 
100 
120 
122 
124 
126 
NTL 
Present 
UC 
UC 
UC 
UC 
NLT (# of NLT/ 
iSOD 
mm) 
- 
- 
- 
- 
- 
NLNT 
- 
- 
- 
- 
- 
TP response 
(RECIST) 
- 
PD 
PD 
PD 
PD 
TL response 
(iRECIST)  
-  
iUPD  
iUPD  
iUPD  
iCPD  

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NTL response 
(iRECIST)  
-  
NiCR/NiUPD  
NiCR/NiUPD  
NiCR/NiUPD  
NiCR/NiUPD  
NLT response 
(iRECIST)  
-  
-  
-  
-  
-  
NLNT response 
(iRECIST)  
-  
-  
-  
-  
-  
TP response 
(iRECIST) 
- 
iUPD 
iUPD 
iUPD 
iCPD 
TL = Target Lesions; NTL = Non-target Lesions; NLT = New Lesions Target; NLNT = New Lesions Non- 
Target; TP = Time-point; UC = Unchanged; 
• RECIST/iRECIST PD/iUPD at TP1 as PD was met per RECIST 1.1 
• iRECIST iUPD at TP2 and TP3 as iUPD was not confirmed and PD criteria was still met 
per RECIST 1.1 
• iCPD at TP4 due to ≥ 5 mm increase from TP1 where iUPD was first observed. 
• iBOR will be iCPD. TP1 will be used as event date for iPFS/iTTP/iDOR. 
16.2.5.7 Scenario 7: Resolution of some new lesions 
 
Baseline 
TP1 
TP2 
TP3 
TP4 
TP5 
TL (SOD 
mm) 
100 
70 
72 
72 
75 
75 
NTL 
Present 
UC 
UC 
UC 
UC 
UC 
NLT (# of 
NLT/ 
iSOD mm) 
- 
++/ 37 
+*/ 25 
NE 
+*/25 
+*/30 
NLNT 
- 
- 
- 
- 
+ 
UC 
TP response 
(RECIST) 
- 
PD 
PD 
PD 
PD 
PD 
TL response 
(iRECIST)  
-  
iPR  
iSD  
iSD  
iSD  
iSD  
NTL 
response 
(iRECIST)  
-  
NiCR/NiUPD  
NiCR/NiUPD  
NiCR/NiUPD  
NiCR/NiUPD  
NiCR/NiUPD  
NLT 
response 
(iRECIST)  
-  
iUPD  
iSD  
NE  
iSD  
iCPD  
NLNT 
response 
(iRECIST)  
-  
-  
-  
-  
iUPD  
iUPD  
TP response 
(iRECIST) 
- 
iUPD 
iSD 
NE 
iUPD 
iCPD 
TL = Target Lesions; NTL = Non-target Lesions; NLT = New Lesions Target; NLNT = New Lesions Non-Target; 
TP = Time-point; NE = Not evaluated/evaluable; UC = Unchanged; 
+ denotes appearance of one new lesion; * the new lesion resolved 
• RECIST/iRECIST PD/iUPD at TP1 due to first appearance of NLTs. 
• iRECIST iSD at TP2 as TL met SD criteria per RECIST 1.1 with a decrease of > 5 mm in 
iSOD even though one of the NLT remained and one of them resolved. The status is reset 
with this iSD. Previous iUPD will no longer be considered. 
• NE at TP3 as NLTs were not evaluated and iUPD not observed in evaluated categories. 
• Recurrence of iUPD at TP4 due to appearance of NLNT. 

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• iCPD at TP5 due to NLT iSOD further increase of ≥ 5 mm from TP4, where iUPD was 
observed. 
• iBOR will be iSD. TP4 will be used as event date for iPFS/iTTP/iDOR. 
16.2.5.8 Scenario 8: iUPD continues due to no change in target lesions 
 
Baseline 
TP1 
TP2 
TP3 
TP4 
TL (SOD mm) 
100 
72 
72 
69 
66 
NTL 
Present 
UC 
UC 
UC 
UC 
NLT (# of NLT/ 
iSOD 
mm) 
- 
- 
- 
- 
- 
NLNT 
- 
+ 
UC 
UC 
UC 
TP response 
(RECIST) 
- 
PD 
PD 
PD 
PD 
TL response 
(iRECIST) 
- 
iSD 
iSD 
iPR 
iPR 
NTL response 
(iRECIST) 
- 
NiCR/NiUPD 
NiCR/NiUPD 
NiCR/NiUPD 
NiCR/NiUPD 
NLT response 
(iRECIST) 
- 
- 
- 
- 
- 
NLNT response 
(iRECIST) 
- 
iUPD 
iUPD 
iUPD 
NiCR/NiUPD 
TP response 
(iRECIST) 
- 
iUPD 
iUPD 
iUPD 
iPR 
TL = Target Lesions; NTL = Non-target Lesions; NLT = New Lesions Target; NLNT = New Lesions Non-Target; 
TP = Time-point; NE = Not evaluated/evaluable; UC = Unchanged; 
+ denotes appearance of one new lesion 
• RECIST/iRECIST PD/iUPD at TP1 due to NLNT. 
• iUPD at TP2 as there was no change in lesions from TP1. 
• iUPD at TP3 as there was no change in TL (< 5 mm change in SOD from TP2) and there 
was no change in NTL and NLNT. 
• iPR at TP4 as PR criteria per RECIST 1.1 was met with a change > 5 mm in SOD even 
though NLNT remained unchanged. The status is reset with this iPR. Previous iUPD will 
no longer be considered. 
• iBOR will be iSD. TP4 will be used as censoring date for iPFS/iTTP/iDOR. 

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16.3 
Appendix 3: Statistical Details for Safety Run-in Part: Bayesian 
logistic regression model (BLRM): prior and design properties 
for hypothetical data scenarios 
This appendix provides details of the statistical model, the derivation of prior distributions from 
historical and pre-clinical data and respective dosing decisions for some hypothetical data 
scenarios. 
16.3.1 
Statistical Models 
For each of the cohort (cohort A: pemetrexed+carboplatin, cohort B: pemetrexed+cisplatin, 
cohort C: carboplatin+paclitaxel), a separate statistical model will comprise of single-agent 
toxicity parts and interaction parts to describe two-way drug safety interactions. Of note 
pembrolizumab in combination with the platinum-based doublet chemotherapy will be 
considered as a single agent in each of the model. The dose de-escalation part of this study will 
be guided by a Bayesian analysis of dose limiting toxicity (DLT) data. The Bayesian analysis 
will be based on a model with 3 parts, representing: 
• Single agent canakinumab toxicity 
• Pembrolizumab in combination with platinum-based doublet chemotherapy toxicity 
• Interaction between canakinumab and pembrolizumab combined with platinum-based 
doublet chemotherapy 
16.3.1.1 Single agent part 
Let π1(d1) be the risk of DLT for Canakinumab given as a single agent Q3W at dose d1; 
π2k(d2k) be the risk of DLT for platinum-based doublet chemotherapy given as a combined 
therapy with pembrolizumab at dose d2k. 
These single agent dose-DLT models are logistic: 
Canakinumab: logit(π1(d1))=log(α1)+β1log(d1/d1*) 
Pembrolizumab+platinum-based doublet chemotherapy: 
logit(π2k(d2k))=log(α2k)+β2klog(d2k/d2k*) 
where k corresponds to the kth model (k=1, 2, 3), d1*= 200 mg Q3W and 
- for cohort A (1st model), d21* (reference dose of each drug) = 200 mg for pembrolizumab, 
500 mg/m2 for pemetrexed and carboplatin AUC 5 mg/mL*min  
- for cohort B (2nd model), d22* (reference dose of each drug) = 200 mg for pembrolizumab, 
500 mg/m2 for pemetrexed and cisplatin 75 mg/m2 
- for cohort C (3rd model), d23* (reference dose of each drug) = 200 mg for pembrolizumab, 
AUC 6 mg/mL*min for carboplatin and 200 mg/m2 for paclitaxel 
are used to scale the doses of canakinumab, pembrolizumab in combination with platinum-
based doublet chemotherapy, respectively. Hence, α1 and α2k (>0) are the single-agent odds of 
a DLT at 200mg Q3W and at the corresponding fixed doses of pembrolizumab with each 
platinum-based doublet chemotherapy as described above, respectively; β1 and β2k (>0) are the 
increase in the log-odds of a DLT by a unit increase in log-dose. 

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16.3.1.2 Interaction 
Under no interaction, the risk of a DLT at dose d1 of canakinumab and dose d2k of platinum-
based doublet chemotherapy in combination with pembrolizumab is: 
π012k(d1, d2k) = 1- ( 1 - π1 (d1))(1-π2k (d2k)) 
To allow for interaction between canakinumab and pembrolizumab in combination with 
platinum-based doublet chemotherapy, an odds multiplier is introduced. The risk of DLT for 
combination dose (d1, d2k ) is then given by: 
odds(π12k (d1, d2k ))=exp(η12k×d1⁄(d1* )×d2k⁄(d2k* ))×odds(π12k0 (d1, d2k )) 
where odds (π) =π⁄((1-π) ); and η12k is the log-odds ratio between the interaction and no 
interaction model k at reference doses. Here η12k=0 corresponds to no interaction, with η12k>0 
and η12k<0 representing synergistic and antagonistic toxicity respectively. 
16.3.1.3 Prior specifications 
The Bayesian approach requires the specification of prior distributions for all models 
parameters, which include the single agent parameters log(α1 ), log(β1) for canakinumab, and 
log(α2k), log(β2k) for pembrolizumab plus the platinum-based doublet chemotherapy, and the 
interaction parameter η12k, A meta-analytic-predictive (MAP) approach was used to derive the 
prior distribution for the single-agent model parameters for canakinumab. A weakly informative 
prior is derived for the single-agent model parameters for pembrolizumab plus the platinum-
based doublet chemotherapy. 
Prior distribution for the logistic parameters 
A MAP approach was used to incorporate the dose-DLT data from canakinumab. To make the 
prior more robust, an additional mixture component corresponding to high toxicity was 
introduced. 
Description of the meta-analytic-predictive (MAP) approach 
The aim of the MAP approach is to derive a prior distribution for the logistic parameters 
(log(α* ),log(β* )) of the new trial using DLT data from historical studies. 
Let rds and nds be the number of patients with a DLT, and the total number of patients at dose d 
in historical trial s (s=1,…,S). The corresponding probability of a DLT is πds. The model 
specifications for the derivation of the MAP prior are as follows: 
rds|πds ~ Bin (πds,nds ) 
logit (πds )=log(αs ) + βs log(d/d* ) 
(log(αs ),log(βs ))| μ,ψ ~ BVN(μ,ψ), s=1,…,S 
(log(α* ),log(β* )) | μ,ψ ~ BVN(μ,ψ) 
The parameters μ =(μ1,μ2) and ψ are the mean and between-trial covariance matrix for the 
logistic parameters, the latter with standard deviations τ1, τ2, and correlation ρ. The parameters 
τ1 and τ2 quantify the degree of between trial heterogeneity. The following priors will be used 
for these parameters: 

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• normal priors for μ1 and μ2, 
• log-normal priors for τ1 and τ2, and 
• a uniform prior for ρ 
The MAP prior for single-agent model parameters in the new trial, (log(α*),log(β*)), is the 
predictive distribution 
(log(α* ), log(β* )) | (rds, nds ∶ s=1,…,S) 
Since the predictive distribution is not available analytically, Markov chain Monte Carlo 
(MCMC) is used to simulate values from this distribution. This is implemented using JAGS 
version 3.12. The sample from this distribution is then approximated by a mixture of bivariate 
normal (BVN) distributions. BVN mixtures with increasing numbers of mixture components 
are fitted to the sample using the expectation-maximization (EM) algorithm (Dempster 1977). 
The optimal number of components of the mixture is then identified using the Akaike 
information criterion (AIC) (Akaike 1974). 
Single agent canakinumab 
For canakinumab, this study uses a mixture prior consisting of four components. Component 1, 
2 and 3 are derived based on dose-DLT data from canakinumab oncology study 
[CACZ885I2202] by MAP approach. The assigned total weight for Component 1, 2 and 3 is 
90%. Component 4 allows for a higher toxicity case. The assigned weight for Component 4 is 
10%. 
• Component 1, 2 and 3 
For the MAP model for canakinumab, reference dose d2*=200 mg Q3W is used, and data from 
S=1 historical study is available. 
Canakinumab dose levels in Q3W and Q6W dosing schedule are converted to Q4W by finding 
out the dose level in Q4W which provides equivalent area under the curve (AUC 0-6weeks) for 
dose levels in Q3W and Q6W. The simulated PK profiles of canakinumab at 200 mg Q3W and 
300 mg Q4W are comparable PK for Canakinumab. Hence, 200 mg on Q3W regimen is 
equivalent to 300 mg on Q4W regimen and 200 mg on Q6W is equivalent to 150 mg on Q4W 
regimen. 
After the dose conversion is performed as described above, canakinumab single agent data is 
then used to derive MAP prior. Firstly, weakly informative priors are assumed for μ1 and μ2, 
with means corresponding to a risk of DLT at the reference dose of 10%, and a doubling in dose 
leading to a doubling in the odds of the risk of a DLT, respectively. Priors for τ1 and τ2 are 
assigned such that (1) their medians correspond to moderate between trial heterogeneity, and 
(2) their uncertainty (95% prior interval) cover plausible between-trial standard deviations 
(Neuenschwander 2014). Canakinumab data was then used to update the prior described above. 
The prior distributions for the model used for deriving the MAP priors are specified in  
Table 16-11. 

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Table 16-11 
Prior distributions for the parameters of the MAP model used to derive 
the prior for the single-agent canakinumab model parameters 
Parameter 
Prior distribution 
μ1  
N(mean = logit(0.10), sd = 2) 
μ2 
N(mean = 0, sd=1) 
τ1 
log-normal(mean = 0.250, sd = log(2)/1.96) 
τ2 
log-normal(mean = 0.125, sd = log(2)/1.96) 
ρ 
uniform(-1,1) 
Historical data is presented in Table 16-12. 
Table 16-12 
Historical data from [CACZ885I2202] for canakinumab single agent 
Canakinumab 
Q4W dose level 
(mg) 
Converted to 
dose level in 
Q8W (mg) 
Number of 
patients 
completed 4 
months 
Number of patients with 
AEs leading to permanent 
treatment discontinuation 
in first 4 months 
Number of 
patients in total 
5 
10 
87 
0 
87 
15 
30 
93 
1 
94 
50 
100 
84 
0 
84 
150 
300 
90 
1 
91 
• Component 4: 
This weakly informative bivariate normal prior allows for a case with higher toxicity. 
- For the intercept parameter log(α1), the prior mean of -1.099 is derived based on the a-priori 
median of an assumed 25% DLT rate at the reference dose d1*= 200 mg Q3W. By setting the 
standard deviation =2, the respective 95% a-priori interval for probability of DLT at dose 200 
mg Q3W is wide (0.7%, 94.4%), which represents weak prior information. 
- For the log-slope parameter log(β1), the prior mean of 0 and prior standard deviation of 1 allow 
for very flat to very steep slopes. Therefore, it is a weakly informative prior. The interpretation 
is as follows: when tripling the dose, the odds of having a DLT are multiplied by a factor of 3β1. 
- The Component 4 is set to be (-1.099, 0, 2, 1, 0) 
Single agent: Pembrolizumab in combination with platinum-based doublet 
chemotherapy 
Doses for each of the drugs are fixed at: 
-200 mg Q3W for pembrolizumab, 500mg/m2 for pemetrexed and AUC 5 for carboplatin for 
first model (k=1) 
-200 mg Q3W for pembrolizumab, 500 mg/m2 for pemetrexed and 75 mg/m2 for cisplatin for 
second model (k=2) 
-200 mg Q3W for pembrolizumab, AUC 6 carboplatin and 200 mg/m2 for paclitaxel for third 
model (k=3) 
A weakly prior will be assumed according to a DLT rate of 15% for k=1st model, 10% for k=2nd 
model and 20% for k=3rd model. The median for the prior distribution of log(β2k) is set to 0, to 
correspond to a doubling of dose leading to a doubling of the odds of DLT. The standard 

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deviation for log(α2k) is derived assuming that there is 90% probability, 95% probability, 80% 
probability that the DLT rate is lower than 25% for the 1st model, 2nd and 3rd model, respectively. 
The standard deviation for log(β2k) is 1. The correlation between the two standard deviations is 
ρ=0. 
Interaction parameter: weakly prior distribution  
Based on the available information, the interaction is centered at a 0% increase in odds of DLT 
platinum-based doublet chemotherapy in all 3 models (k=1, 2, 3) and under each canakinumab 
dosing regimen. However, in all cases, considerable uncertainty remains as to the true 
interaction, and normal priors are used that allow for both synergistic and antagonistic toxicity. 
The following assumptions will be used for interaction parameters for the 3 models: 
• η12k is normally distributed and centered at 0, i.e. 0% increase in odds of DLT over 
independence at the combination starting dose 
• 97.5th percentile is log(2.5), i.e. 2.5-fold increase in odds of DLT over independence at 
the combination starting dose 
16.3.2 
Summary of prior distributions 
The prior distributions of the model parameters are summarized in Table 16-13. 
The prior summaries for DLT rates are summarized in Table 16-14. 
Table 16-13 
Prior distribution for the 3 models parameters 
Parameter 
Mean 
Standard 
deviations 
correlation 
weight 
Single agent Canakinumab prior applied for the 3 models 
BVN Mixture 
(log(α1, β1)) 
  
  
  
  
Component 1 (MAP 
prior) 
(-3.847 , -0.475) 
(0.651, 0.493) 
0.176 
0.427 
Component 2 (MAP 
prior) 
(-3.128 , 0.018) 
(0.732, 0.425) 
0.463 
0.246 
Component 3 (MAP 
prior) 
(-4.736 , -1.105) 
(0.737, 0.696) 
0.004 
0.227 
Component 4 (high 
toxicity) 
(-1.099 , 0) 
(2, 1) 
0 
0.100 
  
  
  
  
  
1st model 
  
  
  
  
Single agent Pembrolizumab in combination with pemetrexed plus carboplatin chemotherapy  
BVN Mixture (log(α21, β21)) 
Weakly informative 
prior  
(-1.735 , 0) 
(0.496, 1.000) 
0 
1.000 
Interaction parameter  
  
Normal 
0 
0.468 
N/A 
N/A 
η121 
  
  
  
  
  
  
  
  
  
2nd model 
  
  
  
  

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Single agent Pembrolizumab in combination with pemetrexed plus cisplatin 
chemotherapy  
  
BVN Mixture 
(log(α22, β22)) 
  
  
  
  
Weakly informative 
prior  
(-2.197 , 0) 
(0.668, 1.000) 
0 
1.000 
Interaction 
parameter  
  
  
  
  
Normal 
  
  
  
  
η122 
0 
0.468 
N/A 
N/A 
  
  
  
  
  
3rd model  
Single agent Pembrolizumab in combination with carboplatin plus paclitaxel chemotherapy  
BVN Mixture 
(log(α23, β23)) 
  
  
  
  
Weakly informative 
prior  
(-1.386 , 0) 
(0.342, 1.000) 
0 
1.000 
Interaction 
parameter  
  
  
  
  
Normal 
  
  
  
  
η123 
0 
0.468 
N/A 
N/A 
  
Table 16-14 
Summary of prior distribution of DLT rates 
Pembrolizumab 
(Q3W) in 
combination with : 
Prior probabilities that 
P(DLT) is in the interval : 
Mean 
SD 
Quantiles 
  
[0, 
0.16) 
[0.16, 
0.33) 
[0.33,1] 
  
  
2.5% 
50% 
97.5% 
  
In combination with Canakinumab 200 mg Q6W 
1st model : 
Pemetrexed+carb
oplatin 
0.449 
0.477 
0.074 
0.192 
0.111 
0.068 
0.169 
0.471 
2nd model : 
Pemetrexed + 
cisplatin 
0.685 
0.262 
0.053 
0.149 
0.115 
0.038 
0.120 
0.453 
3rd model : 
Carboplatin + 
paclitaxel 
0.180 
0.714 
0.106 
0.236 
0.104 
0.111 
0.218 
0.487 
  
In combination with Canakinumab 200 mg Q3W 
1st model : 
Pemetrexed + 
carboplatin 
0.405 
0.449 
0.145 
0.218 
0.144 
0.057 
0.184 
0.634 
2nd model : 
Pemetrexed 
+cisplatin 
0.598 
0.302 
0.100 
0.175 
0.145 
0.034 
0.135 
0.616 
3rd model : 
carboplatin + 
paclitaxel 
0.220 
0.563 
0.217 
0.260 
0.141 
0.087 
0.232 
0.654 
Note : the P(DLT) on the excessive toxicity interval is highlighted in bold. 

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16.3.3 
Hypothetical on-study scenarios 
To illustrate the performance of the Bayesian models used to guide dose de-escalation, 
hypothetical DLT observed scenarios following the provisional dose levels as defined 
previously are shown for each chemotherapy regiment (pemetrexed plus carboplatin, 
pemetrexed plus cisplatin and carboplatin plus paclitaxel regimen) in Table 16-15, Table 16-16 
and Table 16-17. In each table, the dose that can be used in the next cohort of patients is shown. 
This dose is determined using the model based assessment of the risk of DLT in future patients 
and the dose de-escalation rules 
Note that the next dose combination is selected in concordance with the provisional dose levels 
specified in the protocol wherever it is allowed, to mimic possible on-study de-escalation steps. 
Table 16-15 
Dose decisions recommended by BLRM for pemetrexed plus 
carboplatin chemotherapy regimen under EWOC 
Scenario 
Canakinumab 
regimen with 
Pembrolizumab 
in combination 
with 
pemetrexed+car
boplatin 
chemotherapy  
Number of 
Next dose level 
patients 
DLTs 
Canakinumab 
regimen with 
Pembrolizumab 
in combination 
with 
pemetrexed+ca
rboplatin 
chemotherapy  
P(Target 
toxicity) 
P(excessive 
toxicity) 
Median 
P(DLT) 
1 
200 mg Q3W 
6 
0 
200 mg Q3W 
0.324 
0.018 
0.131 
2 
200 mg Q3W 
6 
1 
200 mg Q3W 
0.5 
0.065 
0.173 
3 
200 mg Q3W 
6 
2 
200 mg Q3W 
0.594 
0.178 
0.225 
4 
200 mg Q3W 
6 
3 
200 mg Q3W 
0.530 
0.378 
0.290 
5 
200 mg Q3W 
6 
3 
  
  
200 mg Q6W 
6 
0 
200 mg Q6W 
0.665 
0.042 
0.193 
6 
200 mg Q3W 
6 
3 
  
  
  
  
200 mg Q6W 
6 
1 
200 mg Q6W 
0.737 
0.100 
0.223 
7 
200 mg Q3W 
6 
3 
  
  
  
  
200 mg Q6W 
6 
2 
200 mg Q6W 
0.724 
0.195 
0.254 
8 
200 mg Q3W 
6 
3 
  
  
  
  
200 mg Q6W 
6 
3 
200 mg Q6W 
0.610 
0.358 
0.294 
Note that the overdose criterion is defined as P(excessive toxicity) < 0.25. 
Table 16-16 
Dose decisions recommended by BLRM for pemetrexed plus cisplatin 
chemotherapy regimen under EWOC 
Scenario 
Canakinumab 
regimen with 
Pembrolizumab
 in combination 
with 
pemetrexed+ci
splatin 
chemotherapy  
Number of 
Next dose level 
patients 
DLTs 
Canakinumab 
regimen with 
Pembrolizumab 
in combination 
with 
pemetrexed+ci
splatin 
chemotherapy  
P(Target 
toxicity) 
P(excessive 
toxicity) 
Median 
P(DLT) 
1 
200 mg Q3W 
6 
0 
200 mg Q3W 
0.168 
0.008 
0.095 
2 
200 mg Q3W 
6 
1 
200 mg Q3W 
0.352 
0.040 
0.137 

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Scenario 
Canakinumab 
regimen with 
Pembrolizumab
 in combination 
with 
pemetrexed+ci
splatin 
chemotherapy  
Number of 
Next dose level 
patients 
DLTs 
Canakinumab 
regimen with 
Pembrolizumab 
in combination 
with 
pemetrexed+ci
splatin 
chemotherapy  
P(Target 
toxicity) 
P(excessive 
toxicity) 
Median 
P(DLT) 
3 
200 mg Q3W 
6 
2 
200 mg Q3W 
0.504 
0.143 
0.195 
4 
200 mg Q3W 
6 
3 
200 mg Q3W 
0.498 
0.355 
0.275 
5 
200 mg Q3W 
6 
3 
  
  
  
  
200 mg Q6W 
6 
0 
200 mg Q6W 
0.471 
0.030 
0.16 
6 
200 mg Q3W 
6 
3 
  
  
  
  
200 mg Q6W 
6 
1 
200 mg Q6W 
0.612 
0.087 
0.198 
7 
200 mg Q3W 
6 
3 
  
  
  
  
200 mg Q6W 
6 
2 
200 mg Q6W 
0.645 
0.206 
0.244 
8 
200 mg Q3W 
6 
3 
  
  
  
  
200 mg Q6W 
6 
3 
200 mg Q6W 
0.545 
0.396 
0.299 
Note that the overdose criterion is defined as P(excessive toxicity) < 0.25. 
Table 16-17 
Dose decisions recommended by BLRM for carboplatin plus paclitaxel 
chemotherapy regimen under EWOC 
Scenario 
Canakinumab 
regimen with 
Pembrolizumab
 in combination 
with 
carboplatin+pa
clitaxel 
chemotherapy 
Number of 
Next dose level 
patients 
DLTs 
Canakinumab 
regimen with 
Pembrolizumab 
in combination 
with 
carboplatin+pa
clitaxel 
chemotherapy  
P(Target 
toxicity) 
P(excessive 
toxicity) 
Median 
P(DLT) 
1 
200 mg Q3W 
6 
0 
200 mg Q3W 
0.512 
0.042 
0.170 
2 
200 mg Q3W 
6 
1 
200 mg Q3W 
0.635 
0.110 
0.210 
3 
200 mg Q3W 
6 
2 
200 mg Q3W 
0.639 
0.239 
0.255 
4 
200 mg Q3W 
6 
3 
200 mg Q3W 
0.523 
0.430 
0.310 
5 
200 mg Q3W 
6 
3 
  
  
  
  
200 mg Q6W 
6 
0 
200 mg Q6W 
0.837 
0.068 
0.229 
6 
200 mg Q3W 
200 mg Q6W 
6 
6 
3 
1 
200 mg Q6W 
0.825 
0.126 
0.25 
200 mg Q6W 
6 
1 
200 mg Q6W 
0.825 
0.126 
0.25 
7 
200 mg Q3W 
6 
3 
  
  
  
  
  
6 
2 
200 mg Q6W 
0.761 
0.218 
0.273 
8 
200 mg Q3W 
6 
3 
  
  
  
  
  
6 
3 
200 mg Q6W 
0.649 
0.342 
0.298 
Note that the overdose criterion is defined as P(excessive toxicity) < 0.25. 
For all 3 chemotherapy regimens : 
-If <=2 DLTs are observed in the first 6 evaluable patients, the probability of excessive toxicity 
(i.e. DLT rate of ≥ 33%) with dosing regimen of canakinumab 200 mg Q3W is < 25%, satisfying 

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the EWOC criteria. In this case, it would be recommended to continue with Q3W dosing of 
Canakinumab 
-If 3 or more DLTs are observed in the first 6 evaluable patients, the probability of excessive 
toxicity with dosing regimen of canakinumab 200 mg Q3W does not satisfy the EWOC criteria. 
In this case, it would be recommended to test the lowest dose regimen (i.e. canakinumab 200 
mg Q6W) 
If 3 or more DLTs are observed in the first 6 evaluable patients at the lowest dose regimen of 
canakinumab (i.e. canakinumab 200 mg Q6W), the probability of excessive toxicity does not 
satisfy the EWOC criteria. In this case, it would be recommended not to proceed with the 
regimen. 
16.3.4 
References (available upon request) 
Akaike H (1974) A new look at the statistical model identification. IEEE Transactions on 
Automatic Control; 19::716-23. 
Dempster AP, Laird NM, Rubin DB (1977) Maximum Likelihood from Incomplete Data via 
the EM Algorithm. J R Stat Soc Series B Stat Methodol; 39:1-38. 
Neuenschwander B, Matano A, Tang Z, Roychoudhury S, Wandel S and Bailey S (2014). A 
Bayesian Industry Approach to Phase I Combination Trials in Oncology. In: Statistical 
Methods in Drug Combination Studies. Zhao W, Yang H, (eds). Chapman & Hall/CRC. 
16.4 
Appendix 4: Medications to be used with caution with 
paclitaxel/nab-paclitaxel while on study 
Table 16-18 
Drugs to be used with caution with paclitaxel/nab-paclitaxel while on 
study 
Strong CYP3A4/5 inhibitors 
Macrolide antibiotics: 
Antivirals: 
Antifungals: 
Others: 
clarithromycin 
indinavir 
itraconazole 
conivaptan 
telithromycin 
lopinavir/ritonavir 
ketoconazole 
elvitegravir 
troleandomycin 
nelfinavir 
posaconazole 
mibefradil 
  
ritonavir 
voriconazole 
nefazodone 
  
indinavir/ritonavir 
  
cobicistat 
  
saquinavir 
  
grapefruit juice 
  
saquinavir/ritonavir 
  
  
  
telaprevir 
  
  
  
tipranavir/ritonavir 
  
  
  
danoprevir/ritonavir 
  
  
  
elvitegravir/ritonavir 
  
  
  
boceprevir 
  
  
Strong CYP2C8 inhibitors 
gemfibrozil 
  
  
  
Strong CYP3A/5 inducers 
avasimibe 
carbamazepine 
phenobarbital 
phenytoin 
rifabutin 
rifampin 
St. John’s wort 
mitotane 

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enzalutamide 
  
  
  
Source: This list is adapted from Oncology Clinical Pharmacology Drug-Drug Interaction Database (release 
date: April 2015) which was compiled from the Indiana University School of Medicine’s “Clinically Relevant” 
Table and supplemented with the FDA Draft Guidance for Industry, Drug Interaction Studies – Study Design, 
Data Analysis, and Implications for Dosing and Labeling (February 2012), and the University of Washington’s 
Drug Interaction Database. The lists provided may not be exhaustive. 

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16.5 
Appendix 5: Medications to be used with caution with 
canakinumab while on study 
Table 16-19 
CYP3A substrates with narrow therapeutic index, or sensitive CYP2C9 
substrates with narrow therapeutic index** 
CYP2C9 substrates with narrow therapeutic index 
warfarin 
phenytoin 
CYP3A4/5 substrates with narrow therapeutic index 
astemizole* 
diergotamine 
pimozide 
alfentanil 
cisapride* 
ergotamine 
quinidine* 
terfenadine* 
cyclosporine 
fentanyl 
tacrolimus 
sirolimus 
*Compounds known to increase QTc interval that are also primarily metabolized by CYP3A4/5.  
For an updated list of CYP2C9 substrates, CYP3A substrates, inhibitors and inducers, please reference the 
Novartis Oncology Clinical Pharmacology internal memo: drug-drug interactions (DDI) database, Oct 2010, which 
is compiled primarily from the FDA’s “Guidance for Industry, Drug Interaction Studies”, the Indiana University 
School of Medicine’s Drug Interactions Database, and the University of Washington’s Drug Interaction Database. 
**Sensitive substrates: Drugs that exhibit an AUC ratio (AUCi/AUC) of 5-fold or more when co-administered with 
a known potent inhibitor.Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response 
indicates that increases in their exposure levels by the concomitant use of potent inhibitors may lead to serious 
safety concerns (e.g., Torsades de Pointes). 
16.6 
Appendix 6: Safety follow-up flow chart (post implementation of 
protocol amendment 05) 
 
 
 

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16.7 
Appendix 7: Pembrolizumab Dose Modification Guidelines 
Table 16-20 
Dose Modification and Toxicity management Guidelines for Immune-
related Adverse Events associated with Pembrolizumab 
General instructions: 
1. 
Corticosteroids taper should be initiated upon AE improving to Grade 1 or less and continue to taper over 
at least 4 weeks. 
2. 
For situations where pembrolizumab has been withheld, pembrolizumab can resumed after AE has been 
reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently 
discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to 
≤10 mg prednisone or equivalent per day within 12 weeks. 
3. 
For severe and life-threatening irAEs, IV corticosteroid should beinitiated first followed by oral steroid. 
Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
Immune 
related 
AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management 
with corticosteroid 
and/or other therapies 
Monitor and follow-up 
Pneumoniti
s 
Grade 2 
Withhold 
• 
Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper 
• 
Monitor participants for 
signs and symptoms of 
pneumonitis 
• 
Evaluate participants with 
suspected pneumonitis 
with radiographic imaging 
and initiate corticosteroid 
treatment 
• 
Add prophylactic 
antibiotics for 
opportunistic infections 
Grade 3 or 4, or 
recurr·ent Grade 
2 
Permanently 
discontinue 
Diarrhea / 
Colitis 
Grade 2 or 3 
Withhold 
• 
Administer 
corticosteroids (initi
al dose of 1-
2 mg/kg 
prednisone or 
equivalent) 
followed by taper 
• 
Monitor participants for 
signs and symptoms of 
enterocolitis (ie, diarrhea, 
abdominal pain, blood or 
mucus in stool with or 
without fever) and of 
bowel perforation (ie, 
peritoneal signs and 
ileus). 
• 
Participants with ≥ Grade 
2 diarrhea suspecting 
colitis should consider GI 
consultation and 
performing endoscopy to 
rule out colitis. 
• 
Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids. If 
sufficient oral fluid intake 
is not feasible, fluid and 
electrolytes should be 
substituted via IV infusion. 
Grade 4 
Permanently dis
continue 
AST /ALT 
elevation 
or 
Increased 
bilirubin 
Grade 2 
Withhold 
• 
Administer 
corticosteroids (initi
al dose of 0.5-
1 mg/kg 
prednisone or 
equivalent) 
followed by taper 
• 
Monitor with liver function 
tests (consider weekly or 
more frequently until liver 
enzyme value retumed to 
baseline or is stable). 

Novartis 
Confidential 
Page 223 of 224 
Amended Protocol Version 06 (Clean) 
 
Protocol No. CACZ885U2301 
 
General instructions: 
1. 
Corticosteroids taper should be initiated upon AE improving to Grade 1 or less and continue to taper over 
at least 4 weeks. 
2. 
For situations where pembrolizumab has been withheld, pembrolizumab can resumed after AE has been 
reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently 
discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to 
≤10 mg prednisone or equivalent per day within 12 weeks. 
3. 
For severe and life-threatening irAEs, IV corticosteroid should beinitiated first followed by oral steroid. 
Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
Immune 
related 
AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management 
with corticosteroid 
and/or other therapies 
Monitor and follow-up 
Grade 3 or 4 
Permanently dis
continue 
• 
Administer 
corticosteroids (initi
al dose of 1-
2 mg/kg 
prednisone or 
equivalent) 
followed by taper 
Type 1 
diabetes 
mellitus 
(TIDM) or 
Hyperglyce
mia 
Newly 
onsetT1DM or 
Grade 3 or 4 
hyperglycemia 
associated 
withevidence of 
beta-cell failure 
Withhold 
• 
Initiate insulin 
replacement 
therapy for 
participants with 
T1DM 
• 
Administer anti-
hyperglycemic in 
participants with 
hyperglycemia 
• 
Monitor participants for 
hyperglycemia or other 
signs and symptoms of 
diabetes. 
Hypophysit
is 
Grade 2  
Withhold 
• 
Administer 
corticosteroids and 
initiate harmonal 
replacements as 
clinically indicated. 
• 
Monitor for signs and 
symptoms of 
hypophysitis (including 
hypopituitarism and 
adrenal insufficiency) 
Grade 3 or 4  
Withhold or 
permanently 
discontinue1 
Hyperthyro
idism 
Grade 2  
Continue 
• 
Treat with non-
selective beta-
blockers (eg, 
propranolol) or 
thionamides as 
appropriate 
• 
Monitor for signs and 
symptoms of thyroid 
disorders. 
Grade 3 or 4  
Withhold or 
permanently 
discontinue1 
Hypothyroi
dism 
Grade 2-4 
Continue 
• 
Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyroinine) per 
standard of care 
• 
Monitor for signs and 
symptoms of thyroid 
disorders. 
Nephritis 
and Renal 
dysfunction 
Grade 2 
Withhold 
• 
Administer 
corticosteroids (initi
al dose of 1-
2 mg/kg 
prednisone or 
equivalent) 
followed by taper 
• 
Monitor changes of renal 
function 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2  
Withhold 
• 
Based on severity 
of AE, administer 
corticosteroids 
• 
Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes 
Grade 3 or 4  
Permanently 
discontinue 

Novartis 
Confidential 
Page 224 of 224 
Amended Protocol Version 06 (Clean) 
 
Protocol No. CACZ885U2301 
 
General instructions: 
1. 
Corticosteroids taper should be initiated upon AE improving to Grade 1 or less and continue to taper over 
at least 4 weeks. 
2. 
For situations where pembrolizumab has been withheld, pembrolizumab can resumed after AE has been 
reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently 
discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to 
≤10 mg prednisone or equivalent per day within 12 weeks. 
3. 
For severe and life-threatening irAEs, IV corticosteroid should beinitiated first followed by oral steroid. 
Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
Immune 
related 
AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management 
with corticosteroid 
and/or other therapies 
Monitor and follow-up 
All other 
immune-
related 
AEs 
Intolerable/persi
stent Grade 2 
Withhold 
• 
Based on type and 
severity of AE, 
administer 
corticosteroids 
• 
Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes 
Grade 3 
Withhold 
ordiscontinue 
basedon the 
type of event. 
Events that 
require 
discontinuation 
include and not 
limited to: 
Gullain- Barre 
Syndrome, 
encephalitis 
Grade 4 
orrecurrent 
Grade 3 
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician. 
Note: For participants with Grade 3 or 4 immune-related endocrinopathy where withholdof pembrolizumab is 
required, pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal 
replacement therapy or achieved metabolic control (in case of T1DM)