Conditions: Non-Small Cell Lung Cancer
Keywords: Non-Small Cell Lung Cancer NSCLC ACZ885 canakinumab adjuvant AJCC/UICC v. 8 stages II-IIIA and IIIB (T>5cm N2)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1382
Healthy volunteers: no

Brief summary:
The primary purpose of the study was to compare the efficacy and safety of canakinumab versus placebo as adjuvant therapy in adult subjects with stages II -IIIA according to the 8th edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) and the subset of IIIB (T\>5cm N2 disease) completely resected (R0) non-small cell lung cancer (NSCLC).

Detailed description:
This was a phase III, multicenter, randomized, double-blind study to evaluate the efficacy and safety of canakinumab as adjuvant therapy in adult patients with stages AJCC/UICC v.8 II-IIIA and IIIB (T\>5 cm N2) completely resected (R0) NSCLC.

Approximately 1500 patients were planned to be randomized 1:1 to canakinumab, 200 mg subcutaneously (s.c.) every 3 weeks or matching placebo s.c. every 3 weeks. Patients were planned to continue their assigned treatment until they completed 18 cycles (cycle= 21 days) or experienced any one of the following: non-small cell lung cancer (NSCLC) disease recurrence as determined by Investigator; unacceptable toxicity that precluded further treatment; treatment discontinuation at the discretion of the Investigator or patient; start of a new antineoplastic therapy; death, or loss to follow-up, whichever occurred first. All patients who discontinued from the study treatment were to be followed up every 12 weeks for survival until the final OS analysis or death, loss to follow-up or withdrawal of consent for survival follow-up.

Arms:
arm 1: Participants received 200mg of canakinumab subcutaneously every 3 weeks for up to 18 cycles (approximately 54 weeks) arm 2: Participants received canakinumab placebo subcutaneously every 3 weeks for up to 18 cycles (approximately 54 weeks)

Interventions: intervention 1: Canakinumab intervention 2: Placebo
Intervention descriptions: intervention 1: 200 mg of canakinumab administered subcutaneously on day 1 of every 21-day cycle for 18 cycles. Canakinumab solution for injection was provided by Novartis as ready-to-use pre-filled syringes to be administered by study personnel. intervention 2: Placebo administered subcutaneously on day 1 of every 21-day cycle for 18 cycles. Placebo solution for injection was provided by Novartis as ready-to-use pre-filled syringes to be administered by study personnel.

Protocol document:
Prot_000.pdf: 


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Table of contents 
Table of contents .................................................................................................................2
List of figures ......................................................................................................................6
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................11
Protocol summary:.............................................................................................................13
Amendment 03 (03-Feb-2022)..........................................................................................19
Amendment 02 (05-Feb-2020)..........................................................................................24
Amendment 01 (11-Dec-2018)..........................................................................................28
1
Background........................................................................................................................32
1.1
Clarification statement regarding staging system used to assess subject 
eligibility in this study ...........................................................................................32
1.2
Overview of disease pathogenesis, epidemiology and current treatment..............32
1.3
Introduction to investigational treatment(s) and other study treatment(s).............34
1.3.1
Overview of canakinumab ....................................................................34
2
Rationale............................................................................................................................38
2.1
Study rationale and purpose...................................................................................38
2.2
Rationale for the study design ...............................................................................40
2.3
Rationale for dose and regimen selection..............................................................41
2.4
Rationale for choice of combination drugs............................................................45
2.5
Rationale for choice of comparators drugs............................................................45
2.6
Risks and benefits..................................................................................................45
2.7
Rationale for public health emergency mitigation procedures..............................47
3
Objectives and endpoints...................................................................................................47
4
Study design ......................................................................................................................51
4.1
Description of study design ...................................................................................51
4.2
Timing of interim analyses and design adaptations...............................................53
4.3
Definition of end of study......................................................................................53
4.4
Early study termination..........................................................................................53
5
Population..........................................................................................................................54
5.1
Subject population .................................................................................................54
5.2
Inclusion criteria (applicable for main study)........................................................54
5.2.1
Inclusion criteria applicable for sub-study (CACZ885T2301A) ..........55
5.3
Exclusion criteria (applicable for main study).......................................................55
6
Treatment...........................................................................................................................58
6.1
Study treatment......................................................................................................58


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6.1.1
Dosing regimen.....................................................................................58
6.1.2
Ancillary treatments..............................................................................58
6.1.3
Rescue medication ................................................................................59
6.1.4
Guidelines for continuation of treatment ..............................................59
6.1.5
Treatment duration................................................................................59
6.2
Dose escalation guidelines.....................................................................................59
6.2.1
Starting dose rationale...........................................................................59
6.2.2
Provisional dose levels..........................................................................59
6.3
Dose modifications................................................................................................59
6.3.1
Dose modification and dose delay ........................................................59
6.3.2
Dose adjustments for QTcF prolongation.............................................67
6.3.3
Follow-up for toxicities.........................................................................67
6.4
Concomitant medications ......................................................................................69
6.4.1
Permitted concomitant therapy .............................................................70
6.4.2
Prohibited concomitant therapy ............................................................70
6.5
Subject numbering, treatment assignment or randomization ................................71
6.5.1
Subject numbering ................................................................................71
6.5.2
Treatment assignment or randomization...............................................71
6.5.3
Treatment blinding................................................................................72
6.6
Study drug preparation and dispensation...............................................................73
6.6.1
Study treatment packaging and labeling ...............................................74
6.6.2
Drug supply and storage........................................................................74
6.6.3
Study drug compliance and accountability ...........................................74
6.6.4
Disposal and destruction .......................................................................75
7
Visit schedule and assessments .........................................................................................75
7.1
Study flow and visit schedule................................................................................75
7.1.1
Molecular pre-screening........................................................................87
7.1.2
Screening...............................................................................................87
7.1.3
Treatment period...................................................................................89
7.1.4
Discontinuation of study treatment .......................................................89
7.1.5
Withdrawal of consent ..........................................................................91
7.1.6
Follow up evaluations ...........................................................................92
7.1.7
Lost to follow-up...................................................................................92
7.2
Assessment types...................................................................................................92
7.2.1
Recurrence assessments ........................................................................92
7.2.2
Safety and tolerability assessments.......................................................94


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7.2.3
Pharmacokinetics, immunogenicity and pharmacodynamics ...............99
..........................................................................................101
7.2.5
Other assessments ...............................................................................106
7.2.6
Patient reported outcomes...................................................................106
8
Safety monitoring and reporting......................................................................................108
8.1
Adverse events.....................................................................................................108
8.1.1
Definitions and reporting ....................................................................108
8.1.2
Laboratory test abnormalities..............................................................110
8.1.3
Adverse events of special interest.......................................................110
8.2
Serious adverse events.........................................................................................111
8.2.1
Definitions...........................................................................................111
8.2.2
SAE Reporting ....................................................................................112
8.3
Emergency unblinding of treatment assignment .................................................113
8.4
Pregnancies..........................................................................................................114
8.5
Warnings and precautions....................................................................................114
8.6
Data Monitoring Committee................................................................................114
8.7
Steering Committee .............................................................................................115
9
Data collection and management.....................................................................................115
9.1
Data confidentiality .............................................................................................115
9.2
Site monitoring ....................................................................................................116
9.3
Data collection.....................................................................................................116
9.4
Database management and quality control..........................................................116
10 Statistical methods and data analysis ..............................................................................117
10.1
Analysis sets ........................................................................................................117
10.1.1
Full Analysis Set .................................................................................117
10.1.2
Safety set .............................................................................................117
10.1.3
Dose-determining analysis set.............................................................118
10.1.4
Pharmacokinetic analysis set...............................................................118
10.1.5
Other analysis sets...............................................................................118
10.2
Subject demographics/other baseline characteristics...........................................118
10.3
Treatments (study treatment, concomitant therapies, compliance) .....................118
10.4
Primary objective.................................................................................................119
10.4.1
Variable...............................................................................................119
10.4.2
Statistical hypothesis, model, and method of analysis........................119
10.4.3
Handling of missing values/censoring/discontinuations.....................119
10.4.4
Supportive and Sensitivity analyses....................................................120


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10.5
Secondary objectives ...........................................................................................120
10.5.1
Key secondary objective(s).................................................................120
10.5.2
Other secondary efficacy objectives ...................................................121
10.5.3
Safety objectives .................................................................................122
10.5.4
Pharmacokinetics, pharmacodynamics and immunogenicity .............123
10.5.5
Resource utilization.............................................................................124
10.5.6
Patient-reported outcomes...................................................................124
.........................................................................................126
..........................................................................................126
10.7
Interim analysis....................................................................................................127
10.7.1
Disease free survival (DFS) ................................................................127
10.7.2
Key secondary endpoint: Overall survival (OS).................................128
10.8
Sample size calculation........................................................................................130
10.9
Power for analysis of key secondary variables....................................................130
10.10 Sample size consideration in the sub-study.........................................................131
11 Ethical considerations and administrative procedures ....................................................131
11.1
Regulatory and ethical compliance......................................................................131
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................131
11.3
Informed consent procedures...............................................................................132
11.4
Discontinuation of the study................................................................................133
11.5
Publication of study protocol and results.............................................................133
11.6
Study documentation, record keeping and retention of documents.....................133
11.7
Confidentiality of study documents and subject records.....................................134
11.8
Audits and inspections.........................................................................................134
11.9
Financial disclosures............................................................................................134
12 Protocol adherence ..........................................................................................................134
12.1
Amendments to the protocol................................................................................135
13 References (available upon request)................................................................................136
14 Appendices ......................................................................................................................140
14.1
Appendix 1: Instructions for use of the safety syringe.........................................140
Parts of the safety syringe....................................................................................140
14.2
Appendix 2: AJCC v.8 Prognostic Stage Groups (adapted from the AJCC 
Cancer Staging Manual 2017) .............................................................................143


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List of figures
Figure 2-1
Median change from baseline in hs-CRP by treatment arms in 
confirmed lung cancer subjects from the CANTOS study....................43
Figure 2-2
Proportions of subjects with hs-CRP < 2.3 mg/L by baseline hs-
CRP deciles in all subjects from the CANTOS study...........................44
Figure 4-1
Study Design .........................................................................................52
Figure 4-2
Biomarker sub-study design..................................................................52
List of tables
Table 1-1
Canakinumab characteristics.................................................................34
Table 2-1
Incidence rate per 100 subject years and hazard ratios for any 
cancer, fatal cancer, lung cancer and fatal lung cancer (Ridker 
2017b) ...................................................................................................39
Table 2-2
Subject eligibility based on AJCC/UICC v.8 Stage Provided that 
All Tumor is completely Resected and Based Upon Pathological 
Staging (Adapted from Goldstraw, 2016).............................................41
Table 2-3
Summary of AEs, SAEs, & discontinuations due to AEs & SAEs 
are comparable between canakinumab and placebo .............................46
Table 2-4
Summary of Adverse Events, regardless of relationship to study 
medication experienced by ≥ 10% of subjects in CANTOS.................46
Table 3-1
Objectives and related endpoints ..........................................................48
Table 3-2
Objectives and related endpoints applicable for sub-study 
(CACZ885T2301A)*............................................................................50
Table 6-1
Injection Description.............................................................................58
Table 6-2 ￼
Criteria for dose interruption and re-initiation of treatment for 
adverse drug reactions...........................................................................61
Table 6-3
Clinical and diagnostic assessments for observed LFT 
abnormalities.........................................................................................68
Table 6-4
Supply and storage of study treatments ................................................74
Table 7-1
Visit evaluation schedule (main study, CACZ885T2301)....................77
Table 7-2
Sub-study visit evaluation schedule (CACZ885T2301A)**** ............86
Table 7-3
Imaging Assessment Collection Plan....................................................94
Table 7-4
ECOG Performance Status....................................................................95
Table 7-5
Clinical laboratory parameters collection plan .....................................96
Table 7-6
Blood collection (serum) for canakinumab pharmacokinetics (PK), 
immunogenicity (IG) and pharmacodynamics (PD)...........................100
...................................................102
Table 10-1
Simulated probabilities to stop for futility or efficacy at the interim 
or final DFS analysis...........................................................................128


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Table 10-2
Simulated cumulative power to stop for efficacy on overall survival 
at final DFS analysis or final OS analysis...........................................129
Table 10-3
Power to reject the null hypotheses in the biomarker subgroup of 
interest for different sample sizes in the sub-study.............................131


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List of abbreviations
ACRped
American College of Rheumatology Pediatric Response Criteria
ADA
AE
AESI
Anti-drug antibodies  
Adverse Event
Adverse Event of Special Interest
AJCC
American Joint Committee on Cancer
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
ANA
Antinuclear Antibody
ASMA
Anti-Smooth Muscle Antibody
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
BLQ
CAPS
Below limit of quantitation
Cryopyrin-Associated Periodic Syndromes
CD-transferrin
Carbohydrate Deficient-transferrin
CHF
Congestive Heart Failure
CMO&PS
Chief Medical Office and Patient Safety
COVID-19
CRO
Corona Virus Disease 2019
Contract Research Organization
CSR
Clinical study report
CSR addendum
CTCAE
CT Scan
An addendum to Clinical Study Report (CSR) that captures all the additional information 
that is not included in the CSR
Common Terminology Criteria for Adverse Events
Computerised Tomography Scan
CVD
Cardiovascular Disease
DFS
Disease-free survival
DILI
Drug Induced Liver Injury
DNA
Deoxyribonucleic Acid
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
ECG
EDC
Electrocardiogram
Electronic Data Capture
eCRF
ELISA
EORTC
EOT
ePRO
EORTC
EQ-5D-5L
Electronic Case Report/Record Form
Enzyme-Linked Immunosorbent Assay
European Organization for Research and Treatment of Cancer Quality of Life
End of Treatment
Electronic Patient Reported Outcomes
European Organisation for Research and Treatment of Cancer
EuroQoL-5 Dimension - % Level
ERCP
Endoscopic Retrograde Cholangiopancreatography


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eSAE
FAS
FMF
GGT
HA
HAV
HBsAg
HBV
HCV
hCG
HEV
HGRAC
HIDS
HR
Hs-CRP
Electronic Serious Adverse Event
Full Analysis Set
Familial Mediterranean Fever
Gamma-glutamyltransferase
Health Authority
Hepatitis A Virus
Hepatitis B virus surface antigen
Hepatitis B Virus
Hepatitis C Virus
human chorionic gonadotropin
Hepatitis E Virus
Human Genetics Resources Administration of China
Hyperimmunoglobulin D Syndrome
Hazard Ratio
High-sensitivity C-reactive protein
IA
Interim Analysis
i.v.
ICF
intravenous(ly)
Informed Consent Form
ICH
International Council for Harmonisation
IEC
IG
IgA
IgE
IgG
IgM
IHC
IL-1β
IL-6
IMP
IN
INR
Independent Ethics Committee
Immunogenicity 
Immunoglobulin A
Immunoglobulin E
Immunoglobulin G
Immunoglobulin M
Immunohistochemistry
Interleukin-1β
Interleukin-6
Investigational Medical Product
Investigator Notification
International normalized ratio
IRB
Institutional Review Board
IRT
IUD
IUS
LCSS
LFT
LLN
LPLV
MACE
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System
Intrauterine device
Intrauterine system
Lung cancer specific survival 
Liver Function Tests
Lower limit of normal
Last Patient Last Visit
Major adverse cardiovascular events
MCV
mg
Mean Corpuscular Volume
Miligram
MI
MKD
mL
MRI
Myocardial infarction
Mevalonate Kinase Deficiency
Mililiter
Magnetic Resonance Imaging
NSCLC
Non-small cell lung cancer


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OS
PD
PK
overall survival
Pharmacodynamics
Pharmacokinetics
PHI
PPS
PRO
PT
PTS
q3w
QFT-PLUS
QLQ
QoL
R0
Protected Health Information
Per protocol set
Patient-Reported Outcome
Prothrombin Time
Post treatment surveillance
Every 3 weeks
QuantiFERON®-TB Gold Plus assay
Quality of Life Questionnaire
Quality of Life
Completely resected
RDE
Recommended dose for expansion
REB
Research Ethics Board
RNA
Ribonucleic Acid
R Value
ALT/ALP in x ULN
SAE
SAP
s.c.
SJIA
SS
SST
SUSAR
Serious Adverse Event
Statistical Analysis Plan
Subcutaneous
Systemic Juvenile Idiopathic Arthritis
Survival Status
Serum Seperating Tube
Suspected Unexpected Serious Adverse Reaction
T1D
T3
T4
TBIL
TNF
TRAPS
TSH
UICC
ULN
Type 1 Diabetes
Triiodothyronine
Thyroxine
Total bilirubin
Tumor Necrosis Factor
Tumor Necrosis Factor Receptor Associated Periodic Syndrome
Thyroid-Stimulating Hormone
Union for International Cancer Control
Upper limit of normal
VES
Visit Evaluation Schedule


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study subject or study subject
Control drug
A study treatment used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or evaluate 
comparative effects of the investigational drug
Cohort
A group of individuals who share a common exposure, experience or 
characteristic, or a group of individuals followed-up or traced over time
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g.: q28 days)
Discontinuation from study 
Point/time when the subject permanently stops receiving the study treatment 
and further protocol required assessments or follow-up, for any reason. No 
specific request is made to stop the use of their samples or data.
Discontinuation from study
treatment
Point/time when the subject permanently stops receiving the study treatment 
for any reason (prior to the planned completion of study drug administration, 
if any). Subject agrees to the other protocol required assessments including 
follow-up. No specific request is made to stop the use of their samples or 
data.
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 200 mg 
every 21 days)
Electronic Data Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces. EDC 
includes the use of Electronic Case Report Forms (eCRFs) which are used 
to capture data transcribed from source data/documents used at the point of 
care.
Enrollment
Point/time of subject entry into the study; at which informed consent must be 
obtained. The action of enrolling one or more subjects
Investigational drug/ treatment
Drug whose properties are being tested in the study.
Medication number
A unique identifier on the label of medication kits 
Other treatment
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy)
Subject Number (Subject No. 
NOVDD) Subject Number 
(Subject No. NCDS)
A unique identifying number assigned to each subject/subject/healthy 
volunteer who enrolls in the study
Patient-Reported Outcome
(PRO)
A measurement based on a report that comes directly from the
patient about the status of a subject’s health condition without
amendment or interpretation of the patient's report by a clinician
or anyone else
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and will 
be used in clinical trial database setup and eventually in analysis
Perpetrator drug
Is the drug which affects the pharmacokinetics of the other drug
Personal Data
Subject information collected by the Investigator that is coded and transferred 
to Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples.
Randomization
The process of assigning trial subjects to investigational drug or
control/comparator drug using an element of chance to determine the 
assignments in order to reduce bias.
Randomization number
A unique identifier assigned to each randomized subject 


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Re-screening
If a subject fails the initial screening and is considered as a Screen Failure, 
he/she can be invited once for a new Screening visit after medical judgment 
and as specified by the protocol
Remote
Describes any trial activities performed at a location that is not
the investigative site.
Screen Failure
A subject who did not meet one or more criteria that were required for 
participation in the study
Source Data/Document
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource
Stage related to study timeline
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc.
Stage in cancer
The extent of a cancer in the body. Staging is usually based on the size of 
the tumor, whether lymph nodes contain cancer, and whether the cancer has 
spread from the original site to other parts of the body.
Stop study participation
Point/time at which the subject came in for a final evaluation visit or when 
study treatment was discontinued whichever is later.
Study treatment
Any drug or combination of drugs or intervention administered to the study 
subject as part of the required study procedures; includes investigational 
drug(s), control(s) or background therapy 
Study treatment discontinuation
Point/time when subject permanently stops taking study treatment for any 
reason.
Supportive treatment
Refers to any treatment required by the exposure to a study treatment, e.g. 
premedication of vitamin supplementation and corticosteroid for pemetrexed 
disodium.
Treatment arm/group
A treatment arm/group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts. 
Variable (or endpoint)
The variable (or endpoint) to be obtained for each subject that is required to 
address the clinical question. The specification of the variable might include 
whether the subject experiences an intercurrent event.
Withdrawal of consent 
Withdrawal of study consent: Withdrawal of consent from the study occurs 
only when a subject does not want to participate in the study anymore, does 
not allow any further collection of personal data. 


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Protocol summary:
Title
A phase III, multicenter, randomized, double blind, placebo-controlled study evaluating 
the efficacy and safety of canakinumab versus placebo as adjuvant therapy in adult 
subjects with stages AJCC/UICC v. 8 II-IIIA and IIIB (T>5cm N2) completely resected 
(R0) non-small cell lung cancer (NSCLC)  
Brief title
Study of efficacy and safety of canakinumab as adjuvant therapy in adult subjects with 
stages AJCC/UICC v. 8 II-IIIA and IIIB (T>5cm N2) completely resected non-small cell 
lung cancer
Sponsor and 
Clinical Phase
Novartis,
Phase III
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
This is a multicenter, randomized, double blind, placebo-controlled study evaluating the 
efficacy and safety of canakinumab versus placebo as adjuvant therapy in adult 
subjects with stages AJCC/UICC v. 8 II-IIIA and the subset of IIIB with (T>5cm N2 
disease) completely resected (R0) non-small cell lung cancer (NSCLC).
Primary 
Objective(s) and 
Key Secondary 
Objective
The primary objective is to compare the Disease-free survival (DFS) in the 
canakinumab versus placebo arms as determined by local investigator assessment.
The key secondary objective is to compare overall survival (OS) in the canakinumab 
arm versus placebo arm
Secondary 
Objectives
1. To compare DFS by local investigator assessment and OS in the canakinumab 
versus placebo arms in subgroups defined by PD-L1 and CD8 expression levels, 
respectively.
2. To compare lung cancer specific survival in the canakinumab arm versus placebo 
arm
3.
To characterize the safety profile of canakinumab
4.
To characterize the pharmacokinetics of canakinumab therapy 
5.
To characterize the prevalence and incidence of immunogenicity (anti-drug 
antibodies, ADA) of canakinumab
6.
To assess the effect of canakinumab versus placebo on PROs (EORTC QLQ-C30 
with QLQ-LC13 incorporated and EQ-5D) including functioning and health-related 
quality of life
Study design
This phase III, multicenter, randomized, double blind study will evaluate the efficacy and 
safety of canakinumab as adjuvant therapy in adult subjects with stages AJCC/UICC v. 
8 II-IIIA and IIIB (T>5cm N2) completely resected (R0) non-small cell lung cancer 
(NSCLC). Subjects may be screened after undergoing complete surgical resection of 
their NSCLC and having R0 status confirmed (negative margins on pathologic review), 
after completing adjuvant cisplatin-based doublet chemotherapy if applicable, (Radiation 
therapy is allowed if indicated as per local guidelines or practice). And after all entry 
criteria are met. Subjects must not have had preoperative neo-adjuvant chemotherapy 
or radiotherapy to achieve the R0 status. Approximately 1500 subjects will be 
randomized 1:1 to canakinumab, 200 mg subcutaneously (s.c.) every 3 weeks or 
matching placebo, s.c., every 3 weeks (Figure 4-1). Randomization will be stratified by 
AJCC/UICC v. 8 stage: IIA versus IIB versus IIIA versus IIIB with T>5cm, N2 disease; 
Histology: squamous versus non-squamous; and Region: Western Europe and North 
America vs. eastern Asia vs. Rest of the world (RoW)
Population
This phase III study will enroll approximately 1500 adult subjects with completely 
resected (R0) NSCLC AJCC/UICC v. 8 stages II-IIIA and IIIB (T>5 cm N2) disease. 
These groups have been included to allow all subjects that are able to achieve complete 
resection of their cancer with negative margins (R0 status). The inclusion of these 
subjects is consistent with other adjuvant NSCLC studies as they are at a significant risk 
of relapse to merit inclusion in adjuvant trials. 
Applicable for Sub-study (CACZ885T2301A)*: Will enroll adult subjects with NSCLC 
Stage IIA-IIIA, IIIB (N2 disease only) who are candidates for complete resection surgery 


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(and therefore prospective candidates for the main study, CACZ885T2301). Biomarker 
samples pre- and post-surgery will be collected from these subjects. 
*For China only: biomarker collection is conditional upon approval from HA, EC and 
additional authorities (i.e. HGRAC).
Inclusion 
criteria 
(applicable for 
main study)
1. Written informed consent must be obtained prior to any screening procedures.
2. Age ≥ 18 years
3aCompletely resected (R0) NSCLC AJCC/UICC v. 8 stage IIA- IIIA and IIIB (T>5cm, 
N2 disease only). Minimal treatments considered adequate prior to study enrollment 
are:
Treatment modality
Minimum extent of treatment required prior to study 
entry
Surgery

Complete surgical resection (R0) is mandatory for all 
subjects. 

R0 is considered when in microscopic pathology 
evaluation there are no cancer cells in the surgical 
margin or within 1mm of the margin. 
Chemotherapy

Cisplatin-based chemotherapy is mandatory for all 
subjects (Exception: In subjects with stage IIA disease 
with no nodal involvement, cisplatin-based 
chemotherapy can be administered if recommended by 
the treating physician). 

When required, a minimum of two cycles of cisplatin-
based chemotherapy is mandatory, after which 
additional therapies can be given based upon local 
clinical practice and/or guidelines.

Typically, chemotherapy is initiated within 60 days of 
surgery.
Radiation therapy

Radiation therapy is allowed if indicated as per local 
guidelines or practice.
The maximum number of days allowed from surgery to randomization is:

70 days if subjects were treated with surgery, but did not receive chemotherapy 
or radiation.

182 days if subjects were treated with surgery and chemotherapy, but no 
radiation.

259 days if subjects were treated with surgery, chemotherapy and radiation.
Note: 

Subjects may enter the study earlier than the maximum number of days allowed, 
if fully recovered from surgery and adjuvant therapies. 

A window of +7 days is allowed to accommodate subject scheduling if needed.

In case of chemotherapy treatment delays due to toxicities, additional window of 
+14 days is allowed.
4. Criterion removed. 
5. Criterion removed. 
6. Criterion removed. 
7a. Subjects must have recovered from all toxicities related to prior systemic therapy to 
grade ≤ 1 (CTCAE v 5.0). Exception to this criterion: subjects with any grade of 
alopecia, neuropathy (grade ≤2), and subjects meeting the laboratory specifications 
described in inclusion 8.
8. Subjects must have adequate organ function including the following laboratory 
values at the screening visit:

Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 

Platelets ≥ 100 x 109/L


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
Hemoglobin (Hgb) > 9 g/dL

Creatinine clearance greater than 45 mL/min using Cockcroft-Gault formula

Total bilirubin ≤ 1.5 x ULN

Aspartate transaminase (AST) ≤ 3 x ULN

Alanine transaminase (ALT) ≤ 3 x ULN
9. ECOG performance status (PS) of 0 or 1.
10. Willing and able to comply with scheduled visits, treatment plan and laboratory tests.
Inclusion criteria 
applicable for sub-
study 
(CACZ885T2301A):
1. Written informed consent to sub-study must be obtained prior to any collections.
2. Age ≥ 18 years
3. Subjects with NSCLC Stage IIA-IIIA, IIIB (T>5cm, N2 disease only) who are 
candidates for complete resection surgery.
Exclusion criteria 
(applicable for 
main study)
1. Subjects with unresectable or metastatic disease, positive microscopic margins on the 
pathology report, and/or gross disease remaining at the time of surgery.
2. Subjects who received any neoadjuvant treatment. 
3a. Presence or history of a malignant disease, other than the resected NSCLC, that has 
been diagnosed and/or required therapy within the past 3 years. Exceptions to this 
exclusion include the following: completely resected basal cell and squamous cell skin 
cancers, completely resected carcinoma in situ of any type and hormonal 
maintenance for breast and prostate cancer >3 years. 
4a. History of clinically significant interstitial lung disease (≥grade 2). If radiological 
changes alone are present at baseline (CTC grade 1 interstitial lung disease) should 
be added to past medical history/concurrent medical conditions at baseline.
5a. History or current diagnosis of cardiac disease, including any of the following:

recent myocardial infarction or coronary artery bypass graft (CABG) surgery 
within last 6 months,

uncontrolled congestive heart failure (CHF),

unstable angina (within last 6 months),

clinically significant (symptomatic) cardiac arrhythmias. 
6a. Thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting cycle 1 day 1 or subjects 
who have not recovered from radiotherapy-related toxicities.
7. Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior 
to randomization or who have not recovered from side effects of such procedure. 
Video-assisted thoracic surgery (VATS) and mediastinoscopy will not be counted as 
major surgery and subjects can be enrolled in the study ≥1 week after the procedure.
8. Uncontrolled diabetes as defined by the investigator.
9. Known active or recurrent hepatic disorder including cirrhosis, hepatitis B and C 
(positive or indeterminate central laboratory results
10a. Subjects must be evaluated for tuberculosis as per local treatment guidelines or 
clinical practice. Subjects with active tuberculosis are not eligible. In subjects without 
active tuberculosis, if the results of the evaluation require treatment per local 
guidelines, then the treatment should be initiated before randomization (unless 
otherwise required by Health Authorities or Institutional Review Board (IRB) in which 
case curative treatment must be completed prior to screening)
11a. Subjects with suspected or proven immunocompromised state or infections, 
including:  
a.
Known history of testing positive for Human Immunodeficiency Virus (HIV) 
infections. 
b.
Those with any other medical condition such as active infection, treated or 
untreated, which in the opinion of the investigator places the subject 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.
c.
Allogeneic bone marrow or solid organ transplant


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d.
Those requiring systemic or local treatment with any immune modulating agent 
in doses with systemic effects e.g.:
i.
Prednisone >20 mg (or equivalent) oral or intravenous daily for >14 days;
ii.
Prednisone > 5 mg and ≤ 20 mg (or equivalent) daily for > 30 days;
iii.
Equivalent dose of methotrexate >15 mg weekly.
Note: Daily glucocorticoid-replacement for conditions such as adrenal or 
pituitary insufficiency is allowed. 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 as per local standard 
of care are permitted.
12a. Live or attenuated vaccination within 3 months prior to first dose of study drug (e.g. 
MMR, Yellow Fever, Rotavirus, Smallpox, etc.).
13. Prior treatment with canakinumab or drugs of a similar mechanism of action (IL-1β 
inhibitor).
14. History of hypersensitivity to canakinumab or drugs of a similar class.
15. Subjects who have received an investigational drug or device within 30 days prior to 
first dose of study drug or those who are expected to participate in any other 
investigational drug or device during the conduct of the study.
16. Subjects who received any biologic drugs targeting the immune system at any time. 
17. Any medical condition resulting in a life expectancy of less than 5 years, other than 
the risk for recurrent lung cancer. 
18. Pregnant or nursing women, 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
19a. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception during 
dosing of study treatment and for up to 3 months after last dose of study drug. 
Effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception

Male sterilization (at least 6 months prior to screening). For female subjects on 
the study, the vasectomized male partner should be the sole partner for that 
subject

Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps). For UK: with spermicidal foam/gel/film/cream/ vaginal 
suppository

Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception 
or placement of an intrauterine device (IUD) or intrauterine system (IUS)
In case of use of oral contraception women should have been stable on the same pill for 
a minimum of 3 months before taking study treatment.  Prior to entry into this study, 
cisplatin-based chemotherapy, which may be toxic to the fetus, may be given. The time 
between the end of cisplatin-based chemotherapy and the start canakinumab/placebo 
treatment is variable, resulting in a variable need for continuation of highly effective 
contraception.
Women are considered post-menopausal and not of childbearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(i.e. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy, or bilateral tubal ligation 
at least six weeks prior to first dose of study drug. In the case of oophorectomy alone, 
only when the reproductive status of the woman has been confirmed by follow up 
hormone level assessment is she considered not of childbearing potential. If local 
regulations deviate from the contraception methods listed above to prevent pregnancy, 
local regulations apply and will be described in the Informed Consent Form (ICF).






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Protocol No. CACZ885T2301
Amendment 03 (03-Feb-2022)
Amendment rationale 
As of 03-Feb-2022, 1840 patients have been screened and 1382 patients have been randomized 
and treated in the CANOPY A trial. On 23-Apr-2021, the interim analysis of DFS related to 
futility was performed by independent Data Monitoring Committee (DMC) when 201 DFS 
events were documented on 01-Feb-2021. The trial was recommended to continue without 
modification. The last independent DMC review of the safety data from 1234 randomized 
patients (cut-off date 01-Sep-2021), and the serious adverse events (cut-off date 21-Nov-2021) 
took place on 12-Dec-2021. The DMC recommendation was that the study can continue without 
modifications.
The main purpose of this protocol amendment is to:

Remove the second interim analysis for Disease Free Survival (DFS) originally planned

Include the comparison between the canakinumab and placebo arms of DFS by investigator 
local assessment and OS in subgroups defined respectively by PD-L1 and CD8 expression 
as secondary endpoint.

Add time to first 10 point deterioration for symptoms and global health status/QoL as a 
secondary patient-reported outcomes variable of interest 

Add disruption proofing language
Rationale for updating the interim analysis plan for DFS
The originally planned 2nd interim analysis of DFS in this event-driven trial was not performed 
since the pre-specified number of DFS for this interim analysis (294) had been reached before 
the planned 1500 subjects were randomized and did not have at least one post-baseline efficacy 
assessment, which is required by the protocol. As such all the relevant wording in section 4 and 
10 are not applicable anymore and have been removed.
As per protocol, the final DFS analysis is planned to be performed when approximately 392 
progression events have been observed and all enrolled subjects have a minimal efficacy follow-
up of 3 months to ensure all subjects have at least one post-baseline recurrence assessment.
Per sponsor’s decision, considering the projected number of DFS events approaching the target 
for the final DFS analysis the screening activities ended on December 7th, 2021. A total of 1382 
subjects were randomized, which is less than 1500 subjects originally planned.
Rationale for including PD-L1 subgroup analysis as a secondary endpoint
PD-L1 expression has shown to be predictive of DFS benefit for adjuvant anti-PD-L1 therapy 
in the recently reported trial IMpower010 (Felip et al. 2021), which evaluated atezolizumab for 
the adjuvant treatment of NSCLC. Patients with negative PD-L1 expression (<1%) do not 
benefit from this therapy, whereas patients with PD-L1 ≥ 1-49% benefit less as shown by DFS 
HR of 0.87 as compared to 0.43 in PD-L1 ≥ 50% subgroup. Based on those findings, DFS and 
OS will be compared in the canakinumab versus placebo arms in the PD-L1 subgroups based 
on ≥1% and ≥50% expression levels.




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
Section 6.3.1: clarified that after a dose missed, subject should resume treatment on the 
original schedule per C1D1.

Table 6-2: The table has been updated to correct typos, to add clarity on the 
recommendations to omit/re-start/discontinue drug, asymptomatic amylase and/or lipase 
elevation. Reference to CTCAE version updated from “Grade” to “Version”

Section 6.3.2: central ECG removed as per protocol amendment v01.

Section 6.3.3.2 updated for clarification regarding potential drug-induced liver injury (DILI)

Section 6.5.3: Removal of term “efficacy” in relation to interim DFS analysis

Section 6.6.3.2: clarified that drug accountability can be performed at remote monitoring 
visit

Section 7.1: Updated the visit window from ±7 to ±14 days for imaging assessments during 
years 1-3.

Section 7.1: added clarification on IMP reconciliation and reference to newly added section 
2.7 for public health emergencies. Added clarification that Imaging assessments are to 
continue regardless of starting a new antineoplastic therapy after discontinuation of study 
treatment, if the patient has not progressed from their NSCLC or been diagnosed with new 
lung primary. Clarified that subjects who discontinue from study treatment are to return for 
the end of treatment visit as soon as possible, and attend the follow-up visits as indicated in 
the Assessment Schedule.

Table 7-1: update to record all imaging evaluations in the clinical database. Added definition 
of SS in footnote 

Section 7.1.4: Rearranged to distinguish discontinuation from study treatment and 
discontinuation from study.

Section 7.1.6.2. clarified that Additional survival assessments may be performed outside the 
12 weeks follow-up schedules 

Section 7.1.7: Further clarification provided on Lost to follow up procedure

Section 7.2.1 Visit window updated from ±7 to ±14 days for imaging assessments during 
years 1-3

Table 7-3: Visit window of ±7 definition removed for first the first year for consistency with 
other time periods. Visit windows for imaging assessments defined in Section 7.2.1. 

Section 7.2.2: as part of the latest protocol template, it has been added that safety monitoring 
of patient’s health can be done via phone or virtual call.

Table 7-5: Updated to include “pancreatic amylase (as needed)”.

Section 7.2.2.6.6: as part of the latest protocol template, it has been added that urine 
pregnancy test may be done at home.

Section 7.2.3.1: added clarification that PK/PD/IG will not be collected for subjects that 
start new antineoplastic therapy after discontinuing study treatment and clarified blood 
collection volumes. Collection of PK, PD and/or IG samples may be stopped upon decision 
of the Sponsor under specific circumstances.

Table 7-6: Cycle 18 row for PK, PD, and IG samples collections removed and a footnote 
added to provide further clarification

Section 7.2.3.2: updated analytical method specifications




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
Section 10.5.3.4: clarified the notable vital sign values will be summarized and a listing of 
these subjects will be produced by treatment arm with notable values flagged

Section 10.5.6: time to first 10 point deterioration for symptoms and for global health 
status/QoL is added together with the definition of the event, analysis and presentation 
modalities

Section 10.7.1: Removed the second interim analysis for DFS, revised the boundary values 
according to EAST 6.4 and modified Table 10-1 with the updated interim plan

Section 10.7.2: Removed the first interim analysis for OS and DMC responsibility for it;  
modified Table 10-2 with the updated interim plan

Section 10.8: Revised sample size calculation for DFS to have only one futility interim 
analysis for DFS

Section 10.9: Clarified the power calculation to align with the updated number of analyses 
for OS

Section 11.3: as part of the latest protocol template, it has been added that ICF may be 
collected remotely. Updated ICH GCP to ICH E6 GCP for consistency throughout protocol.

Section 11.5: Clarified that any data analysis carried out independently by the Investigator 
should be submitted to Novartis before publication or presentation. Additionally, summary 
results of primary and secondary endpoints will be disclosed based upon the global Last 
Patient Last Visit (LPLV) date, since multinational studies are locked and reported based 
upon the global LPLV.

Section 13: New references added

Appendix 2: addition of stage group IV.
The protocol summary has been updated to reflect the changes throughout the document as well 
as the list of abbreviations and glossary of terms.
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 02 (05-Feb-2020) 
Amendment rationale 
As of 05-Feb-2020, 742 patients have been screened and 507 patients have been randomized 
and treated.
The purpose of the protocol amendment is to allow local laboratory hematology, chemistry, and 
coagulation to be performed for scheduled safety monitoring visits. Canakinumab has a well-
defined safety profile, as outlined in the canakinumab Investigator’s Brochure (current Edition 
18). Allowing sites the flexibility to perform hematology, chemistry, and coagulation based on 
local laboratory results allows for same-day safety evaluations. The remaining blood specimens 
collected as part of safety monitoring (e.g., HIV screen, HbsAg, HCV antibody) will continue 
to be performed by central laboratory.
Rationale for lipase and amylase grade 2, 3, and 4 update: Definition of grades 2, 3, and 4 
lipase and amylase are updated in the dose modification table based on CTCAE v 5.0.
Rationale for increasing window for CT scan after first occurrence of ≥ grade 3 amylase 
and/or lipase increase: The window for complementary imaging (e.g.CT scan) to assess the 
pancreas, liver, and gallbladder performed after first occurrence of any ≥ grade 3 amylase and/or 
lipase is increased to 2 weeks in order to allow for a comprehensive assessment of potential 
organ injury related to enzyme increase.
Rationale for visit window changes for Post treatment Surveillance, Survival follow up, 
and Imaging assessments: Visit windows for Survival follow-up visits and Post treatment 
surveillance visits are increased to +/-7 days in years 2 and 3 in order to harmonize with visit 
windows for imaging assessments, and +/- 21 days in years 4 and 5 to provide greater flexibility 
to accommodate the subject’s schedule. Imaging assessment windows in years 4 and 5 are 
increased to ±21 days to provide greater flexibility for the subject’s schedule.
Rationale for PK samples reduction (C1D2, C1D3, C6D2, C6D3, C15D1): The PK of 
canakinumab has been characterized well in other clinical trials. Therefore, additional PK 
collection at these time points (C1D2, C1D3, C6D2, C6D3, C15D1) is not required as the 
current number of samples collected is sufficient for representation of those time points. 
Collection of pre-dose PK sample in cycles, 1, 2, 4, 6, 9, 12 and 18 and samples on day 8 and 
15 in cycle 1 is needed for population PK analysis.
Rationale for IG sample reduction (C15D1): The collection of immunogencity sample on 
C15D1 is removed as the immunogencity of canakimumab has been characterized well in other 
clinical trials and in this trial. The current immunogenicity samples collected at C15D1 and the 
immunogencity samples which will continue to be collected at pre-dose on cycles 1, 2, 4, 6, 9, 
12, 18 and at end of treatment is considered sufficient to characterize the immunogencity.
Rationale for acceptable alternative brain imaging: MRI with contrast is required but MRI 
without contrast may be allowed for subjects with contraindication to MRI contrast. Each case 
will be reviewed and approved by a Novartis study physician.
Rationale for language regarding biomarker collection in China: China requires additional 
specific review and approval of biomarker samples collections by the HGRAC (Human 
Genetics Resources Administration of China) other than HA and EC. Therefore for China, 








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Amended Protocol Version 03 (Clean)
Protocol No. CACZ885T2301
Amendment 01 (11-Dec-2018)
Amendment rationale
As of 11 December 2018, 105 subjects have been screened to the study. 63 subjects have been 
randomized and treated.
The main purpose of this protocol amendment is to:
1. Include a biomarker sub-study which collects pre- and post- resection surgery blood 
samples.
2. Central ECG collection will be replaced by local ECG at screening and as clinically 
indicated.
3. Update dose interruption schedule related to Drug Induced Liver Injury (DILI).
4. Update the contraception language.
5. Reduce number of C1D2 and C1D3 pharmacokinetics samples.
6. Make clarifications, editorial and typographic changes. 
Rationale for including biomarker sub-study (CACZ885T2301A): 
The sub-study will be identified as CACZ885T2301A. Biomarker samples will be collected to 
understand how resection surgery may impact hs-CRP, other cytokines and additional 
biomarker levels in blood. This will be assessed based upon the following two objectives:

To assess the levels of hs-CRP, other cytokines and additional biomarker levels in blood at 
pre- and post- surgery.  

To determine whether there is an association between pre- and post-surgery biomarker 
levels with canakinumab efficacy (e.g. DFS, OS). 
Rationale for central ECG removal: Canakinumab is IgG-type antibody with a large 
molecular size that displays no evidence of drug-related changes to electrocardiogram (ECG). 
Moreover, no clinical signs or qualitative or quantitative electrocardiographic changes 
attributable to canakinumab administration were observed in the toxicology studies performed. 
In addition, no abnormal binding to cardiac or cardiovascular tissues was identified in any of 
the cross reactivity studies using marmoset and human tissues. QT prolongation and 
Cardiotoxicity is not considered a safety concern for canakinumab and it is not included in the 
Risk Management Plan (RMP) as identified or potential risk. In CANTOS study, QT 
prolongation AEs were reported 23, 26 and 27 subjects (1%; 1.1% and 1.2%) in the 
canakinumab 300mg; 150mg and 50mg arm respectively, while 46 subjects (1.4%) experienced 
QT prolongation AEs in the placebo arm. Based upon above data, ECG collection is not 
required to be collected centrally and can be performed locally once at screening and on study 
if clinically indicated. 
Rationale for updating the dose interruption schedule related to Drug Induced Liver 
Injury (DILI): Sections to Table 6-2 has been updated include the new DILI language and the 
dose modification table for hepatotoxicity was updated based on the updated Novartis 
Hepatotoxicity Clinical Safety Guideline (2018).


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Rationale for revising contraception language: In an embryo-fetal development study in 
marmosets canakinumab showed no maternal toxicity, embryo-toxicity or teratogenicity when 
administered throughout organogenesis. In addition, canakinumab did not elicit adverse effects 
on fetal or neonatal growth when administered throughout late gestation, delivery and 
nursing. Based on this data, the protocol is being updated to require basic contraception (from 
highly) for women of childbearing potential treated with canakinumab monotherapy as per the 
Novartis standards. The duration of contraception after discontinuation of the study drug was 
amended from 130 days to 3 months after last dose in line with the canakinumab IB and 
EuSmPC.
Rationale for reducing PK samples at C1D2 and C1D3: The C1D2 and C1D3 PK time points 
will be reduced and only a subset of approximately 400 subjects will have these time points 
taken. Collection of these post-dose PK samples during the absorption phase is needed to allow 
population PK analysis in the targeted population. This will be adequate to capture the 
absorption profile and derive the associated absorption parameters after SC injection of 
canakinumab.
Additional summary of changes:
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
Brief description of the change and/or new text 
List of abbreviations
Updates made to list of abbreviations.
Glossary of terms
Updated to include the updated definitions.
Protocol summary
Protocol summary sections have been updated to match the body of the 
protocol.
Section 1.3.1.2.1 
This section is to provide information on clinical experience. Therefore, texts 
providing instructions to Investigators has been moved to the Adverse event 
of special interest (AESI) Section 8.1.3.  
Section 2.2 
Table 2-2 was removed as it did not provide the full AJCC/UICC v 8 staging 
guidelines. Additionally, text was updated to include specifications for sub-
study.
Section 3
Minor changes have been made to Table 3-1 to clarify wording on endpoints.
Table 3-2 containing sub-study objectives" has been included.
Section 4.1 
Updated to provide information on the sub-study study design, including 
Figure 4-2.
Section 5.1
Redundant text has been removed. Table 5-1 has been removed as it did not 
include the full scope of staging guidelines. Inclusion criteria has been 
revised to clarify what is the minimum requirement to enter study. Description 
on sub-study population was also added.
Section 5.2 
Inclusion criteria 3, 4, 5, 6 (now 3a) have been revised into one to provide 
clarity.
Section 5.2
Inclusion criteria 5 (now 5a) has been updated to indicate CTCAE v 5.0 will 
be used and added clarification text.
Section 5.2.1
Inclusion criteria 1, 2, 3 for the sub-study has been created.
Section 5.3
Exclusion criteria 3, 4, 5, 6, 10, 11, and 12 have been revised to provide 
more clarification. Revised criterions has letter “a” added.


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Section 5.3
Exclusion criteria 19 has been revised to reflect the requirements of basic 
methods of contraception and continued use of contraception for up to 3 
months after last dose of study drug. Add in language to clarify that it is 
bilateral tubal ligation.
Section 6.1.5, Section 7.1, Section 
7.1.3, Section 7.1.4, Section 
7.1.6.1, Section 7.2.1, and Section 
8.1.1
These sections have been updated to include guidance on what must be 
done upon start of new antineoplastic therapy. 
Section 6.3.3.2 and Table 6-2
Has been updated to include the new DILI language and the dose 
modification table for hepatotoxicity was updated based on the updated 
Novartis Hepatotoxicity Clinical Safety Guideline (2018).
Section 6.4
Text updated to provide clarity on types of virus excluded. Added 
‘supplements.Drug-drug Interaction language not applicable for adjuvant 
setting has been removed.
Section 6.4.2.1
Further information on examples for immune modulating agent in doses with 
systemic effects has been included.
Section 6.4.2.2
Other anticancer therapy section has been included to provide further clarity 
to the protocol.
Section 6.5.1
Updated to include subject number for sub-study.
Section 6.6 and Section 14.1
Study drug preparation has been revised to be in line with the latest 
instructions. 
Section 7.1
Table 7-1 has been updated to include corrections including: Disease 
recurrence was clarified to specify that it is referring to NSCLC recurrence. 
Visit numbers have been corrected. Missing IG time points were added. PK 
time points revised. Updates/corrections have been made to the protocol 
section numbering, time points for the following has been updated: Whole 
body bone scan, ECG and Adverse events.
Table 7-2 has been added to list all of the assessments to be performed for 
the sub-study. Footer has been clarified to specify the number of subjects 
that will need to provide samples for Cycle 1 Day 2, Cycle 1 Day 3, Cycle 6 
Day 2, and Cycle 6 Day 3.
Section 7.1.2
Re-screening information has been added. Updated to include information on 
the screening procedures to be performed for sub-study participants. Details 
related to sub-study participants have been added.
Section 7.1.2.2
Information to be collected on screen failure subjects has been updated.
Section 7.1.2.4
Added in section to clarify the information to be collected on sub-study 
participants
Section 7.1.4
Details on discontinuation process has been clarified.
Section 7.1.5
Withdrawal of consent language has been updated to include the GDPR 
requirements.
Section 7.2.1
Recurrence assessment has been clarified and allowance of Brain CT has 
been included.
Section 7.2.2.1
Tuberculosis language has been simplified.
Section 7.2.2.6
Table 7-5 was updated to include missing tests.
Section 7.2.2.6.6
Updated to specify that it is bilateral tubal ligation and at least six weeks prior 
to first dose of study drug.
Removed sentence referring to male subjects notifying investigator or partner 
pregnancy. This applicable for this study.
Section 7.2.2.7.1, and Section 9.3
Sections have been revised as central ECG collection is not needed. 
Language has been updated to include one collection at screen and as 
clinically indicated for local ECG collection.


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Section 7.2.3.1
PK and PD sample handling has been revised. Table 7-6 has been revised to 
reduce PK sampling at Cycle 1 Day 2 and Cycle 1 Day 3. The Dose ID 
numbering has been corrected and IL-1β sample number has been added. 
The foot note has been clarified.
Section 7.2.4.1
The minimum number of slides required has been revised in the Biomarker 
sample collection plan.
Section 7.2.4.2
Biomarker sub-study section has been included.
Section 7.2.6.2
Removed sentence stating investigator has to review ePROs for potential 
AEs or SAEs as this is not required.
Section 8.1.1
Sentence regarding malignancy has been removed and updated language 
has been added to section 8.2.2.
Section 8.1.3
Examples of AESI has been updated. Text on infections and neutropenia 
was added to this section from Section 1.3.1.2.1.
Section 8.2.2
Details on SAE reporting has been included for instances of NSCLC 
recurrence, new primary lung cancer and new primary malignancy in organs 
other than lung.
SAE reporting items applicable to sub-study has been added.
Section 8.6
Revised the DMC safety review time points.
Section 10.4.1 and section 10.4.4
In these sections and throughout the document, disease recurrence was 
clarified to specify that it is referring to NSCLC recurrence.
Section 10.4.2
Clarified the time points at which DFS estimates will be summarized.
Section 10.5.3.3 and throughout 
the document
CTCAE version has been updated to 5.0
Section 10.5.3.4
Clarified the planned ECG analysis in reflection of changes to ECG related 
collection.
Section 10.5.6
Clarified the event occurrence for time definitive deterioration. 
Section 10.6.1
Added analysis details for sub-study.
Section 10.7.2
Footnote for Table 10-2 has been revised to clarify that OS will be tested only 
if either 2nd interim or the final DFS analysis is significant.
Section 10.10
Sample size consideration in the sub-study has been added.
IRB/IEC
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 Study 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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1
Background
1.1
Clarification statement regarding staging system used to assess 
subject eligibility in this study
Please note that, unlike publications referenced in this protocol, inclusion and exclusion criteria 
are based on the new IASLC staging system (AJCC v.8) (AJCC Cancer Staging Manual). The 
complete list of changes from prior American Joint Committee on Cancer (AJCC) v.7 to AJCC 
v.8 are summarized by Goldstraw et al (2016) and include the following, which are important 
for eligibility purpose: Stage IB subjects with T>4-5cm become Stage IIA; Stage IIIA subjects 
with T>5cm N2 become stage IIIB.  Both groups are eligible for this study if completely 
resected with negative margins (see Section 5 for complete list of inclusion/exclusion criteria).  
The inclusion of these subjects is consistent with other adjuvant NSCLC studies as they are at 
a significant risk of relapse to merit inclusion in adjuvant trials.
1.2
Overview of disease pathogenesis, epidemiology and current 
treatment
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). Non-small cell lung cancer 
(NSCLC) accounts for 85% of the lung cancer diagnoses (Jemal 2011). 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 (ACS 2012-2013). Meta-analysis 
of five large adjuvant cisplatin based chemotherapy versus observation trials demonstrated an 
absolute improvement in 5-year survival of 5.4% in subjects with resected stages IB through 
IIIA (Pignon 2008). Subjects with stage IB disease and large tumors demonstrated a trend 
toward benefit from adjuvant chemotherapy with a survival HR=0.93 (not statistically 
significant), whereas, subjects with stages II-III had a statistically significant improvement in 
survival with HR=0.83 (Pignon 2008). The standard of care for stages IIA-IIIA is entire surgical 
resection (margins free of cancer), followed by 4 cycles of cisplatin based chemotherapy 
(NCCN guideline July 2017).  Radiation therapy is suggested in addition to chemotherapy for 
subjects with IIIA N2 disease (NCCN guideline July 2017). Despite adjuvant chemotherapy, 
only approximately 60% of subjects with stage IB disease will be alive at 5 years, only 
approximately 50% of stage II subjects and only approximately 40% of subjects with stage IIIA 
diseases will be alive at 5 years (Douillard et al 2006). Thus, new adjuvant therapies continue 
to be urgently needed to improve the disease-free and overall survival of NSCLC subjects.
Recently, a new IASLC staging system has been published which harmonizes AJCC and UICC 
staging systems to ensure subjects with similar prognosis are regrouped within the same stage 
category. The changes are summarized by (Goldstraw 2016).  As an example, subjects with 
stage IB per AJCC v.7 have a 5 year overall survival of 71% (Goldstraw 2016). Those subjects 
with stage IB with primary tumors of >4-5cm have a 5 year survival of 66% are more similar 
to the IIA N0 who have primary tumors of >5-6 cm, who have a 63% 5-year survival; therefore 
these prior IB subjects are now moved to stage IIA in the new AJCC and UICC harmonized 
version 8 staging system. The AJCC v. 7 stage IB subjects have a 5 year OS of 71% now in 
AJCC v. 8 have a 73% 5 year OS. Similarly, subjects with AJCC v. 7 Stage IIIA N2 disease 
become stage IIIB with T>5 cm N2 disease in the new IASLC system.


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Chronic inflammation plays an important role in the development of non-small cell lung cancer 
(NSCLC). Key etiological risk factors such as smoking, second-hand smoke exposure, chronic 
infections such as tuberculosis, and exposure to environmental toxins such as asbestos, silica 
dust, and various metal dusts cause a chronic inflammatory milieu that plays a critical role in 
carcinogenesis, particularly, in lung cancer (O’Callaghan 2010, Krysan 2008). Indeed, elevation 
of the general inflammatory marker high-sensitivity C-reactive protein (hs-CRP) is associated 
with an increased risk of developing lung cancer (Chaturvedi 2010).  It is also well established 
that smoking, a lung cancer risk factor, induces chronic pulmonary inflammation and this 
inflammation is thought to be one of the mechanisms that drive tumor promotion (Bracke 2006).  
Finally, there is also evidence that anti-inflammatory drugs can reduce the risk of lung cancer 
development.  In a meta-analysis of lung cancer studies, Khuder et al. demonstrated a 21% 
relative risk reduction in the development of lung cancer for those subjects reporting 
nonsteroidal anti-inflammatory drug (NSAID) use (Khuder 2005). Taken together, these 
observations suggest an important role for inflammation in the development of lung cancer.
The cytokine interleukin-1β (IL-1β) is thought to be one of the mediators of pulmonary 
inflammation that promotes lung cancer.  Genetic evidence also links IL-1β to lung cancer risk.  
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 2013).  In addition to this 
clinical data, there is extensive preclinical data to support the role of IL-1β in several distinct 
steps in carcinogenesis.  These steps include tumor initiation, promotion, angiogenesis, and 
metastasis (Dalgleish 2006, Mantovani 2008, O’Byrne 2000, O’Byrne 2001). 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 2016).  In a mouse model of tumor initiation, the genetic loss of 
IL-1β resulted in an attenuation of 3-MCA-induced tumor formation (Krelin 2007, 
Voronov 2010). The ability of IL-1β to promote tumor initiation is thought to be mediated 
through the induction of 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 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 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 adhesion. Using a mouse model of lung cancer metastasis, 
Yano and colleagues demonstrated that tumors genetically programed to express high levels of 
IL-1β developed lung metastasis more rapidly than controls, while treatment with an anti-IL-
1β antibody inhibited formation of lung metastasis (Yano 2003).  Taken together, these results 
suggest an important role for IL-1β in multiple steps of carcinogenesis.  
Given the evidence for the importance of IL-1β signaling in carcinogenesis, some in the 
scientific community have already proposed to treat cancer with IL-1β blockade (Jenkins 2017, 
Wu 2016). Lung cancer is the largest cause of cancer deaths on the globe. In 2015, lung cancer 
was responsible for 1.68 million deaths (WHO Cancer FACT Sheet Feb 2017). Despite adjuvant 


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chemotherapy, only approximately 60% of subjects with stage IB disease will be alive at 5 
years, only approximately 50% of stage II subjects and only approximately 40% of subjects 
with stage IIIA diseases will be alive at 5 years (Douillard et al 2006). Thus, treatments to 
improve the survival of subjects resected for cure are urgently needed.
1.3
Introduction to investigational treatment(s) and other study 
treatment(s)
1.3.1
Overview of canakinumab
Canakinumab is a high-affinity human anti-Interleukin-1β (IL-1β) monoclonal antibody that 
belongs to the IgG1/κ isotype subclass. The relative molecular mass of canakinumab based on 
the amino acid sequence without post-translational modification (e.g., glycosylation), but 
including N-terminal pyroglutamate formation and the C-terminal lysine residues at the heavy 
chains, is MW = 145157 Da. Canakinumab is manufactured in a murine SP2/0 cell line.
Table 1-1
Canakinumab characteristics
Chemical name:
          Recombinant human monoclonal antibody ACZ885
INN:
                        Canakinumab
Proprietary name:         ILARIS®
Drug class:                     Anti-inflammatory
Laboratory code:            ACZ885
1.3.1.1
Non-clinical experience
1.3.1.1.1
Non- clinical pharmacokinetics and metabolism
Canakinumab exhibits typical immunoglobulin G (IgG) kinetics with a limited volume of 
distribution, a slow clearance and a long terminal half-life. The bioavailability of canakinumab 
estimated after single subcutaneous (s.c.) dose administration was 60% using cross-study 
comparison of exposure between intravenous (i.v.) and s.c. routes of administration. Exposure 
to canakinumab was linear and dose proportional within the dose range investigated in 
marmoset. 
For further details, please refer to Section 4.2 of the current [canakinumab Investigator’s 
Brochure].
1.3.1.1.2
Non clinical pharmacology
Canakinumab neutralizes the bioactivity of human IL-1β by preventing its binding to the IL-1β 
receptor. Canakinumab specifically binds human IL-1β with a Kd of 40-60 picomolar and has 
no cross-reactivity with human IL-1α (IL-1F1), human IL-1 receptor antagonist (IL-1Ra, IL-
1F3) or other members of the IL-1 family (IL-1F4-IL-1F9). Canakinumab is selective for human 
and marmoset IL-1β (IL-1F2) but does not bind to mouse, rat, rabbit, rhesus nor cynomolgus 
monkey IL-1β. Because canakinumab does not react with rodent IL-1β, the in vivo activity of 
canakinumab was demonstrated in models on inflammation induced by human IL-1β in rodents. 
Canakinumab inhibited the IL-1β induced effect. For further details, please refer to the current 
[canakinumab Investigator’s Brochure].


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1.3.1.1.3
Toxicology
An extensive program of toxicology studies was performed. The marmoset monkey was 
characterized as an appropriate model to predict human safety. Regarding toxicokinetics, 
exposure to canakinumab was demonstrated. Following i.v. or s.c. administration, canakinumab 
was well tolerated in marmosets at all dose levels investigated without any relevant adverse 
findings. No anti-drug antibodies were detected.  Long-term animal studies have not been 
performed to evaluate the carcinogenic potential of canakinumab.  The mutagenic potential of 
canakinumab was not evaluated. No significant treatment-related effects were observed with 
respect to male or female fertility in a mouse model using a murine analog of canakinumab. For 
further details, please refer to the current [canakinumab Investigator’s Brochure].
1.3.1.2
Clinical experience
Seventy-four (74) Novartis-sponsored canakinumab studies (66 interventional studies, 5 
integrated managed subject access programs, and 3 post-authorization safety studies) and 16 
Third Party (Investigator Initiated) trials had been initiated by 30-Jun-2017. A total of 15,902 
subjects had been enrolled in the Novartis-sponsored, interventional canakinumab studies. It is 
estimated that 10,939 subjects were exposed to canakinumab treatment in these trials, with the 
majority of subjects (6,717) being enrolled in the pivotal CACZ885M2301 study (Canakinumab 
ANti-inflammatory Thrombosis Outcomes Study, CANTOS) investigating the prevention of 
recurrent cardiovascular events in subjects with a prior myocardial infarction (MI) and an 
elevated hs-CRP. It is additionally estimated that 528 unique pediatric subjects aged <1 to 17 
years were exposed to canakinumab treatment in Novartis-sponsored interventional studies
[canakinumab Investigator’s Brochure].
The safety, tolerability and efficacy data of canakinumab in completed Novartis-sponsored 
interventional studies (studies with a clinical study report as of 30-Jun-2017) are available from 
3,861 male or female subjects exposed to the drug; these include 326 healthy subjects, 458 
subjects with Cryopyrin-Associated Periodic Syndromes (CAPS), 324 with Systemic Juvenile 
Idiopathic Arthritis (SJIA), 441 with Rheumatoid Arthritis (RA), 1,179 with gouty arthritis, 95 
with respiratory indications, 673 with Type 2 Diabetes Mellitus (T2DM), 144 with 
cardiovascular indications, e.g. atherosclerosis and periphery artery disease, 64 with 
osteoarthritis and 157 with other indications. The doses administered ranged from 0.5 mg/kg to 
9 mg/kg s.c., 0.03 mg/kg to 10 mg/kg i.v., and fixed doses of 5 mg to 600 mg s.c. and 150 mg 
to 600 mg i.v. The frequency of dosing ranged from a single dose to quarterly repeated 
administration or treatment upon flare (in gouty arthritis) [canakinumab Investigator’s 
Brochure].
1.3.1.2.1
Clinical Safety 
Due to the mode of action of all inhibitors of the IL-1 pathway, infections, predominately of the 
upper respiratory system, are the main risk in subjects treated with canakinumab.  Canakinumab 
is associated with an increased incidence of serious infections during and after treatment. 
Although the majority of reports of infection resolved spontaneously or with standard therapy, 
severe, serious and fatal infections have been reported, including reports of fatal complicated 
perforated diverticulitis and sepsis. Opportunistic infections have also been reported.


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Neutropenia has been observed with medicinal products that inhibit IL-1, including 
canakinumab.  Other than neutropenia, thrombocytopenia, and uric acid increase specific for 
active gouty arthritis, there was no evidence of other clinically relevant drug-related changes in 
vital signs, electrocardiogram (ECG) or laboratory values (see local label for Ilaris®).
Both i.v. and s.c. injections of canakinumab are well tolerated as evidenced by a low rate of
injection-site events and discontinuations. Low treatment-related immunogenicity (<3%) has
been detected, and no clinical consequences to detected anti-drug antibodies were evident. No
apparent impact on canakinumab pharmacokinetics or on total IL-1β concentration
(pharmacodynamics) were evident; or any evidence of immune-related loss of efficacy.
Overall, the immunogenicity profile is entirely consistent across all disease areas.
1.3.1.2.2
Clinical Efficacy 
Canakinumab has demonstrated efficacy in a variety of non-oncologic indications. 
In CAPS subjects, the first approved indication of canakinumab, canakinumab treatment (150 
mg or 2 mg/kg s.c. every 8 weeks) produces a rapid and complete resolution of signs and 
symptoms in almost all subjects, starting within 1 day of treatment, along with an immediate 
and sustained normalization of serological and hematological parameters of inflammation. 
Pediatric subjects and those with a severe CAPS phenotype may require higher than usual doses 
to attain full clinical response and current labeling for Ilaris allows for dose escalation to 8 
mg/kg for subjects ≤ 40 kg and to 600 mg for subjects > 40 kg. 
Significant improvement in disease activity was demonstrated in subjects with period fever 
syndromes including Familial Mediterranean Fever (FMF), Tumor Necrosis Factor Receptor 
Associated Periodic Syndrome (TRAPS) and Hyperimmunoglobulin D Syndrome (HIDS)/
Mevalonate Kinase Deficiency (MKD) who had received canakinumab treatment (150 mg 
every 4 weeks). Canakinumab treatment showed resolution of index disease flare and 
prevention of new flares. Canakinumab also demonstrated normalization of serological and 
hematological parameters of inflammation. Subjects with HIDS/MKD may require higher than 
usual doses to attain full clinical response. The response to treatment was long-lasting and 
sustained in all evaluated age-groups, both genders, and between all indications.
In SJIA, subjects treated with a single dose of canakinumab (300 mg or 4 mg/kg), 83% of all 
children were classified responders and achieved at least an adapted American College of 
Rheumatology Pediatric Response Criteria score of ACRped30 at Day 15 of a 4-week 
randomized double-blind study. One third of subjects achieved an ACRped100.
In subjects with gouty arthritis who had an acute gout attack and who are refractory or 
contraindicated to NSAIDs and/or colchicine, treatment with canakinumab (150 mg s.c.), 
showed statistically significant efficacy, both in terms of pain relief and preventing the onset of 
a new flare, compared to triamcinolone acetonide 40 mg intramuscularly (i.m.). In confirmatory 
gout studies, canakinumab has showed sustained efficacy with a consistent safety profile over 
repeated treatment.
In subjects with atherosclerosis and Type II Diabetes Mellitus or Impaired Glucose Tolerance, 
the rate of progression of atherosclerotic plaque burden (as measured by vessel wall area) in 
three vascular beds (proximal ascending aorta, left carotid, right carotid) was attenuated after 
12 months of treatment with canakinumab.


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In subjects with intermittent claudication, an improvement in maximum and pain-free walk 
distance in the canakinumab-treated group was observed, but no statistically significant 
between-treatment difference in mean vessel wall area ratio was determined as compared to 
baseline.
For further details, please refer to the [canakinumab Investigator’s Brochure].
Efficacy in the CANTOS study
The CANTOS study has demonstrated a clinically and statistically significant effect of 
canakinumab 150 mg and 300 mg every 3 months over matching placebo in reducing the risk 
of major adverse cardiovascular events (MACE), a composite endpoint of cardiovascular death, 
non-fatal MI and non-fatal stroke in subjects with a history of MI and inflammatory 
atherosclerosis. With the positive results of the CANTOS study, canakinumab is the first 
treatment to significantly reduce cardiovascular risk by directly targeting inflammation. The 
results of the CANTOS study also recently reported that inhibition of IL-1β dose dependently 
reduced the occurrence of lung cancers in post myocardial infarction (atherosclerotic) subjects 
with elevated hs-CRP, who were previously cancer free (see Section 2.1).
1.3.1.2.3
Clinical Pharmacokinetics, Pharmacodynamics and Immunogenicity
Canakinumab is a human anti-human IL-1β monoclonal IgG1/κ antibody which was derived 
from a genetically engineered mouse carrying the human immunoglobulin repertoire. During 
the development of canakinumab, three changes relevant to drug substance manufacturing 
process were introduced. The four drug forms were termed as Product Types A, B, C and D. 
The rate and extent of absorption following s.c. administration were independently estimated 
for the four product types for the CAPS extension registration dossier. Bioavailabilities and 
absorption rate constants of the product types were similar, ranging from 63 to 76 % and 0.28 
to 0.38 day-1, respectively. The bioavailability assessments of product types C and D (marketed 
product) were 76% and 66%, respectively. Based on the relative bioavailability of D/C of 0.87 
± 0.11 (mean ± SEM), it was concluded that there was no apparent difference in the two product 
types. Two different formulations of canakinumab have been administered during its 
development: a lyophilized powder form and a solution for injection formulation. A 
bioequivalence study, CACZ885A2104, demonstrated the bioequivalence of the lyophilized 
form of canakinumab and the canakinumab solution for injection in a pre-filled syringe, one of 
the presentations of the liquid formulation. Other presentations of the liquid formulation include 
an auto-injector and the liquid in a vial. Study CACZ885M2101 demonstrated bioequivalence 
of canakinumab in a liquid formulation administered via auto-injector or pre-filled syringe. No 
difference in bioavailability of the solution in a vial compared to powder for solution for 
injection was detected in a population PK analysis of PK data from Study CACZ885N2301.
The peak serum canakinumab concentration (Cmax) occurred approximately 7 days following 
single s.c. administration of 150 mg in adult CAPS subjects. Based on a population PK analysis 
in the CAPS population including children from 2 years of age, the absolute bioavailability of 
s.c. administration of canakinumab was estimated to be 66 %. Exposure parameters (such as 
AUC and Cmax) increased in proportion to dose over the dose range of 0.30 to 10.0 mg/kg given 
as i.v. infusion or from 150 to 600 mg as s.c. injection. 


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The serum clearance (CL) and volume of distribution of canakinumab varied according to body 
weight (6.01 L and 0.174 L/day in a typical CAPS subject weighting 70 kg). The mean terminal 
half-life was 26 days. After accounting for body weight differences, no clinically significant 
differences in the PK properties of canakinumab were observed between CAPS, TRAPS, 
HIDS/MKD, FMF, SJIA and gouty arthritis subjects. There was no indication of accelerated 
clearance or time-dependent change in the PK properties of canakinumab following repeated 
administration.
Canakinumab binds to human IL-1β, and blocks the interaction of this cytokine with its 
receptors, thereby functionally neutralizing its bioactivity. The resulting complex of 
canakinumab and IL-1β is eliminated at a much slower rate than the free IL-1β, resulting in 
elevation of total IL-1β (free plus complex) following canakinumab administration. Thus, 
measurement of free plus complexed IL-1β, i.e. total IL-1β, is a relevant PD biomarker for 
canakinumab indicative of binding of IL-1β by the antibody. An increase in total IL-1β was 
observed in both healthy subjects as well as subject populations, after canakinumab dosing. 
Canakinumab treatment was associated with a decrease of IL-1β-induced downstream 
mediators including IL-1β itself, IL-1β pathway related genes, acute phase proteins such as 
serum amyloid (SAA) and C-reactive protein (CRP). This adds to the evidence that 
canakinumab neutralizes the activity and down-regulates the production of IL-1β in vivo.
Overall, the immunogenicity profile of canakinumab is entirely consistent across all disease 
areas. The incidence of treatment-emergent anti-drug antibodies (ADAs) remains very low, in 
the range of 0.5% to 2.9% and no clinical consequences to these detected antibodies are evident. 
No neutralizing antibodies were detected post-baseline in any study.
For further details, please refer to the [canakinumab Investigator’s Brochure].
2
Rationale
2.1
Study rationale and purpose
As described in Section 1.2, inflammation (as measured through hs-CRP levels for example) 
plays an important role in the development of lung cancer. Prior publications examining hs-
CRP levels in Stage I through Stage III NSCLC subjects show that higher stage is correlated 
with higher hs-CRP levels and poorer prognosis (Alifano et al 2011, Hara et al 2010, 
Vaguliene et al 2011). The cytokine interleukin-1β (IL-1β) is thought to be one of the mediators 
of pulmonary inflammation that promotes lung cancer and is critical in multiple steps of the 
carcinogenesis process. Canakinumab is a high-affinity human anti-interleukin-1β (IL-1β) 
monoclonal antibody approved for the treatment of subjects with various IL-1β driven auto-
inflammatory diseases. Results from the CANTOS study indicated that canakinumab was 
associated with dose-dependent reductions in the risks of lung cancer occurrence and lung 
cancer mortality among study participants (Ridker 2017b). The maximal reduction in lung 
cancer occurrence and mortality was seen in subjects who received 300 mg s.c. every 3 months 
(highest dose group).
CANTOS (Study CACZ885M2301) is a double-blind, placebo-controlled, Phase-III trial of 
10,061 randomized subjects who were in stable condition after a prior myocardial infarction 
(MI). It was designed to evaluate the efficacy, safety, and tolerability of canakinumab in 


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combination with standard of care in the prevention of recurrent cardiovascular (CV) events in 
subjects with inflammatory atherosclerosis, as defined by the presence of hs-CRP, a known 
marker of inflammation, at levels of  ≥2 mg/L. Subjects were ineligible if they had a pre-existing 
malignancy (other than basal cell skin carcinoma). Trial participants were randomized to 
receive treatment with one of three doses of canakinumab (300 mg, 150 mg, or 50 mg) or 
placebo administered subcutaneously every 3 months. Treatment was to be administered for a 
period of 6 years but was to be discontinued if any malignancy developed.  The median age of 
subjects enrolled in CANTOS was 61.1 years, 25.7% of the subjects were female, and the 23.5% 
of subjects were current smokers with an additional 47.3% of subjects were former smokers.  
All subjects had a hs-CRP greater than 2 mg/L at entry and the median hs-CRP at entry was 4.2 
mg/L for all subjects enrolled. The median hs-CRP at entry in CANTOS subjects who were 
subsequently diagnosed with cancer was 6.0 mg/L. 
Data on cancer occurrence, as reported by the investigator, were collected as adverse events 
(AEs) and serious adverse events (SAEs). These events were adjudicated by an 8-member panel 
of external oncologists (the Malignancy Adjudication Committee (MAC)) blinded to treatment 
allocation. All malignancies that coded to a Medical Dictionary for Regulatory Activities 
(MedDRA (version 20.0)) preferred term (PT) of ‘malignant or unspecified tumors’ were 
forwarded to the MAC for assessment; the remit of the MAC was to categorize and evaluate 
whether investigator-reported malignancy AEs and SAEs occurred (or not). Any fatalities 
occurring during the trial were reviewed and categorized by the Clinical Endpoint Committee 
(CEC) for cause(s) of death. Deaths were adjudicated to be one of three major subtypes: (1) CV; 
(2) non-CV; and (3) unknown (presumed CV). Use of both the MAC and CEC was predefined 
in the study protocol.
Canakinumab treatment resulted in dose-dependent decreases in hs-CRP of 26-41% and IL-6 
decreases of 25-43% (Ridker 2017b). As shown in Table 2-1, lung cancer incidence was less 
frequent in the 150 and 300 mg treated groups, with HR of 0.61 (95%CI 0.39-0.97) and 0.33 
(95%CI 0.18-0.59), respectively (Ridker 2017b). Lung cancer mortality was significantly less 
in the canakinumab 300 mg treated group (HR=0.23 [95%CI 0.10-0.54)] and in the pooled 
canakinumab subjects (Ridker 2017b). Total cancer mortality was significantly lower in the 
pooled canakinumab groups versus the placebo group (p=0.0007), but only the 300 mg 
canakinumab group had statistically significant lowering (HR=0.49, 95%CI 0.31, 0.75, 
p=0.0009) (Ridker 2017b). 
Table 2-1
Incidence rate per 100 subject years and hazard ratios for any cancer, 
fatal cancer, lung cancer and fatal lung cancer (Ridker 2017b)
Event
Placebo
n=3344
Can* 50 mg 
s.c. quarterly
n=2170
Can 150 mg 
s.c. quarterly
n=2284
Can 300 mg 
s.c. quarterly
n=2263
All Doses Can
n=6717
p value
(trend 
across 
doses)
Any Cancer
Incidence rate(n)
1.88 (231)
1.85 (144)
1.69 (143)
1.72 (144)
1.75 (431)
0.31
HR
(95% CI)
1 (ref)
0.99 
(0.80-1.22)
0.90
(0.73-1.11)
0.91
(0.74-1.12)
0.93
(0.79-1.09)
P
Ref
0.91
0.31
0.38
0.38
Any Cancer 
(fatal)


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Incidence rate (n)
0.64 (81)
0.55 (44)
0.50 (44)
0.31 (.27)
0.45 (115)
0.0007
HR
(95% CI)
1 (ref)
0.86
(0.59-1.24)
0.0.54-1.13)
0.49
(0.31-0.75)
0.71
(0.53-0.94)
Ref
0.42
0.19
0.0009
0.0158
Lung Cancer
Incidence rate (n)
0.49 (61)
0.35 (28)
0.30 (26)
0.16 (14)
0.27 (68)
<0.0001
HR
(95% CI)
1 (ref)
0.74
(0.47-1.17)
0.61
(0.39-0.97)
0.33
(0.18-0.59)
0.55
(0.39-0.78)
P
Ref
0.20
0.0337
<0.0001
0.0007
Lung Cancer 
(fatal)
Incidence rate (n)
0.30 (38)
0.20 (16)
0.19 (17)
0.07 (6)
0.15 (39)
0.0002
HR
(95% CI)
1 (ref)
0.67
(0.37-1.20)
0.64
(0.36-1.14)
0.23
(0.10-0.54)
0.51
(0.33-0.80)
P
Ref
0.18
0.13
0.0002
0.0026
*Canakinumab
Lung cancer occurrence and mortality
Canakinumab therapy was associated with a reduction in the risk of primary lung cancer 
occurrence relative to placebo, with a dose-dependent response evident across the canakinumab 
arms (Table 2-1).  Maximal risk reduction was observed for the canakinumab 300 mg arm.
These data suggest that anti-inflammatory therapy with canakinumab targeting the IL-1β innate 
immunity pathway is associated with a dose-dependent reduction in the risk of primary lung 
cancer occurrence. Furthermore, treatment with canakinumab was also associated with a dose 
response in the risk reduction of primary lung cancer mortality.
Given the hypothesis-generating clinical data in CANTOS and the preclinical data that supports 
IL-1β plays a role in cancer development from initiation, promotion, angiogenesis, and through 
to metastasis (Dalgleish 2006, Mantovani 2008, O’Byrne 2000, O’Byrne 2001), a phase III 
study is proposed using canakinumab as adjuvant treatment in NSCLC subjects who are at high 
risk for recurrence.
2.2
Rationale for the study design
This is a multicenter, randomized, double blind, placebo-controlled study evaluating the 
efficacy and safety of canakinumab versus placebo as adjuvant therapy in adult subjects with 
stages AJCC/UICC v. 8 II-IIIA and the subset of IIIB with T>5cm N2 disease completely 
resected (R0) non-small cell lung cancer (NSCLC). The randomized, double-blind, placebo-
controlled, multicenter, parallel-group design of this study minimizes allocation bias, balancing 
both known and unknown prognostic factors in the assignment of treatments. This phase III 
study CACZ885T2301 will enroll adult subjects with completely resected (R0) NSCLC 
AJCC/UICC v. 8 stages II-IIIA and IIIB (T>5cm and N2) disease. Subjects will complete 
standard of care adjuvant treatments for their NSCLC, including cisplatin-based chemotherapy 
and mediastinal radiation therapy (if applicable), before being screened or randomized for this 
study. 


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Table 2-2
Subject eligibility based on AJCC/UICC v.8 Stage Provided that All 
Tumor is completely Resected and Based Upon Pathological Staging 
(Adapted from Goldstraw, 2016) 
Table 2-2 is removed. Refer to Section 5.1 for details on the inclusion/exclusion criteria.
Randomization will be stratified by the three following factors:

AJCC/UICC v. 8 stage: IIA versus IIB versus IIIA versus IIIB with T>5cm, N2 disease

Histology: squamous versus non-squamous
Both staging and histology are key determinants of prognosis.

Region: Western Europe and North America vs. eastern Asia vs. Rest of the world (RoW), 
to account for possible differences in standard of care 
The primary endpoint is disease-free survival (DFS) determined by local investigator 
assessment to reflect a reduced risk of lung cancer recurrence, with overall survival (OS) as a 
key secondary endpoint. Tumor assessments and follow-up visits for assessment of recurrence 
will be performed as per the NCCN guidelines for NSCLC version 8, 14 July 2017. It is 
postulated that 18 cycles (approximately one year) of adjuvant treatment will provide an 
acceptable benefit to risk ratio in subjects who have intermediate or high risk of developing 
disease recurrence.
Applicable for the sub-study*: Rationale to include the biomarker sub-study is to understand 
how resection surgery may impact the levels of hsCRP, other cytokines and biomarkers in 
blood. Adult subjects with NSCLC Stage IIA-IIIA, IIIB (T>5cm, N2 disease only) who are 
candidates for complete resection surgery (and therefore prospective candidates for the main 
study, CACZ885T2301) will be enrolled in the sub-study. 
*For China only: biomarker collection is conditional upon approval from HA, EC and 
additional authorities (i.e. HGRAC).
2.3
Rationale for dose and regimen selection
The 200 mg s.c. every 3 weeks (q3w) dosing regimen of canakinumab is selected as the dosing 
schedule for the development program in NSCLC.
The every three week dosing regimen is feasible for canakinumab, based on its > 3 weeks half-
life, and has proven its ability to neutralize IL-1β and suppress hs-CRP for at least 1 month 
across a wide range of doses. 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. Every three weeks is preferred over every four weeks as the dosing 
regimens of combination partners (checkpoint inhibitors, chemotherapy) for future planned 
NSCLC trials often follow the every three week schedule. 


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Sub-sections below provide further details for the various considerations for dose and regimen 
selection:
PK and PD consideration:
Canakinumab displays PK properties typical of an IgG1 antibody, with a mean terminal half-
life of 26 days. Every 3 weeks dosing schedule of canakinumab is feasible based on its half-life 
of 26 days, and its ability to suppress hs-CRP for at least 1 month as previously demonstrated 
in two single-dose phase 2 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). 
Efficacy consideration:
Canakinumab has demonstrated clinical benefit and is approved in 68 countries, including EU 
and US for the treatment of subjects with various IL-1β-driven auto-inflammatory diseases. For 
CAPS, the approved dosing regimen in US is 150 mg s.c. every 8 weeks (q8w) in adults (up-
titration up to 600 mg s.c. q8w is allowed in EU). In other approved indications such as SJIA, 
TRAPS, HIDS/ MKD, and FMF, a starting dose at 4 mg/kg (max. 300 mg) every 4 weeks (q4w) 
or up-titration to 4 mg/kg or 300 mg q4w is required to achieve adequate efficacy in adults and 
children. If a full treatment response is subsequently achieved, the intensified dosing regimen 
of 300 mg q4w should be maintained. The different dosing regimens across indications could 
be due to differences in drug sensitivity across diseases likely caused by different clinical 
conditions and inflammatory status.
For the CANTOS study, the dose selection was primarily based on Study CACZ885I2202, a 
key dose finding study in subjects with diabetes, who were treated with 5, 15, 50 and 150 mg 
s.c. monthly doses, with 4-month treatment period (see [canakinumab Investigator’s 
Brochure]). 
As observed in Study CACZ885I2202, the largest observed reduction in hs-CRP at 4-month 
was found at a dose of 50 mg s.c. monthly. However, PK/PD modeling has predicted maximal 
hs-CRP reduction at doses between 75 and 100 mg s.c. monthly. Therefore, 50 mg s.c. monthly 
(or 150 mg s.c. quarterly) was considered as an efficacious dose while 15 mg s.c. monthly (or 
50 mg s.c. quarterly) as a sub-optimal dose, and 100 mg s.c. monthly (or 300 mg s.c. quarterly) 
as the dose predicted to achieve the maximal hs-CRP reduction (see [Study M2301, Section 
3.3] and [canakinumab Investigator’s Brochure], [CACZ885I2202 study]). 
Consistent with the modeling prediction, among the three dosing regimens tested in the 
CANTOS study (50, 150, and 300 mg s.c. quarterly), maximal hs-CRP reduction at 48 months 
was observed in the 300 mg s.c. quarterly dose (median reduction from baseline is 26%, 37%, 
and 41% in the 50 mg, 150 mg, and 300 mg groups, respectively), as compared with placebo, 
among atherosclerosis subject with elevated baseline hs-CRP who did not have a prior diagnosis 
of cancer (Ridker 2017a). In regards to clinical effects, 150 mg s.c. quarterly met the primary 
endpoint with 15% relative hazard reduction for MACE; 50 mg s.c. quarterly did not show 
significant effect compared to placebo, while 300 mg s.c. quarterly did not provide additional 
benefit versus 150 mg s.c. quarterly, with nearly identical magnitude of hazard reduction.
The CANTOS study also 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-






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received study drug between 74 and 87 days. In Study CACZ885A2204, a 26-week phase II 
randomized, double-blind, placebo-controlled study in rheumatoid arthritis subjects, 
canakinumab was given at a dose of 600 mg i.v. q4w along with methotrexate. Of 52 subjects 
randomized to canakinumab plus methotrexate, 47 subjects received all 8 i.v. infusions of 
canakinumab, where the other 5 subjects received 2 to 7 i.v. infusions. This study reported no 
patient deaths and only 4 serious adverse events (SAEs); 2 in each treatment group. The SAEs 
in the methotrexate + placebo group were non-cardiac chest pain and upper gastrointestinal 
hemorrhage.  The 2 SAEs in the methotrexate+ canakinumab group were elective cataract 
surgery, which was planned prior to study entry for pre-existing cataracts, and lip edema, which 
resulted in permanent discontinuation of canakinumab. The occurrence of infectious adverse 
events in the treatment groups was similar; 40.4% in the methotrexate + canakinumab group 
and 42.3% in the methotrexate + placebo group. No infectious SAEs were reported. These 
studies did not reveal clinically relevant differences in the types and severity of reported AEs 
across different dose groups. The AEs observed were mostly mild and moderate in severity, and 
similar to that of the placebo group. In addition, the AEs appear to be independent from duration 
of exposure and dose, and with consistent safety profile across indications.
In summary, with approval in many markets for use in multiple indications, the large body of 
accumulated safety data of canakinumab provides sufficient safety margin to evaluate 
canakinumab s.c. at the dose of 200 mg every three weeks.
2.4
Rationale for choice of combination drugs
Not Applicable
2.5
Rationale for choice of comparators drugs
Not applicable
2.6
Risks and benefits
Canakinumab is approved in several inflammatory disorders in many countries and is marketed 
under the trade name Ilaris. No dose limiting toxicities of canakinumab have been observed in 
subjects receiving doses of up to 600 mg I.V. q 4 weeks for 26 weeks (CACZ885A2204) or 
with chronic dosing of up to 300 mg s.c. every 4 weeks for over 2 years (CACZ885G2301, a 
two-part study).
The CANTOS study randomized 6717 subjects to canakinumab treatment. The most common 
adverse events (AEs), experienced by ≥ 10% of subjects, regardless of study drug relationship 
were viral upper respiratory tract infection and hypertension, in 12.5-13.9% and 10.1-10.3% of 
canakinumab-treated subjects versus 12.3% and 10.1% in the placebo group, respectively 
(Table 2-4). The most commonly reported serious adverse event (SAE) in ≥ 1% of subjects was 
pneumonia, which occurred in 3.4-3.7% in canakinumab-treated subjects versus 3.3% in the 
placebo group.  Additional infectious SAEs included cellulitis and sepsis in 0.9-1.5% and 1.0-
1.4% of canakinumab-treated subjects versus 3.3% and 0.8% in the placebo group, respectively. 
Deaths from infection and sepsis occurred in 0.07-0.19% and 0.15-2.1% in the canakinumab 
groups versus 0.06 and 0.13% in the placebo-treated subjects, respectively.


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Safety in CANTOS
Table 2-3
Summary of AEs, SAEs, & discontinuations due to AEs & SAEs are 
comparable between canakinumab and placebo
Event
Can. 300 mg
N=2263
n (%)
Can. 150 mg 
N=2285
n (%)
Can. 50 mg
N=2170
n (%)
Placebo
N=3348
n (%)
Subjects with at least one AE
1987 ( 87.8)
1970 ( 86.2)
1872 ( 86.3)
2914 ( 87.0)
Subjects with at least one SAE
836 ( 36.9)
812 ( 35.5)
741 ( 34.1)
1203 ( 35.9)
AEs suspected to be related to study 
drug
355 ( 15.7)
350 ( 15.3)
267 ( 12.3)
474 ( 14.2)
Subjects who permanently 
discontinued study drug due to AEs
175 ( 7.7)
164 ( 7.2)
142 ( 6.5)
244 ( 7.3)
Discontinued due to SAEs
135 ( 6.0)
130 ( 5.7)
117 ( 5.4)
197 ( 5.9)
Discontinued due to non-serious 
AEs
40 ( 1.8)
34 ( 1.5)
25 ( 1.2)
47 ( 1.4)
AEs leading to study drug 
interruption  
268 ( 11.8)
270 ( 11.8)
228 ( 10.5)
399 ( 11.9)
Table 2-4
Summary of Adverse Events, regardless of relationship to study 
medication experienced by ≥ 10% of subjects in CANTOS
Preferred term
Can300mg 
N=2263
n (%)
Can150mg
N=2285
n (%)
Can50mg 
N=2170
n (%)
Placebo 
N=3348
n (%)
Subjects with at least one AE
1987 ( 87.8)
1970 ( 86.2)
1872 ( 86.3)
2914 ( 87.0)
Viral upper respiratory tract infection
282 ( 12.5)
318 ( 13.9)
278 ( 12.8)
411 ( 12.3)
Hypertension
229 ( 10.1)
235 ( 10.3)
222 ( 10.2)
339 ( 10.1)
Angina pectoris
191 ( 8.4)
207 ( 9.1)
169 ( 7.8)
306 ( 9.1)
Back pain
189 ( 8.4)
202 ( 8.8)
171 ( 7.9)
301 ( 9.0)
Non-cardiac chest pain
190 ( 8.4)
196 ( 8.6)
157 ( 7.2)
304 ( 9.1)
Arthralgia
183 ( 8.1)
201 ( 8.8)
155 ( 7.1)
273 ( 8.2)
Upper respiratory tract infection
166 ( 7.3)
168 ( 7.4)
148 ( 6.8)
273 ( 8.2)
Bronchitis
153 ( 6.8)
183 ( 8.0)
135 ( 6.2)
269 ( 8.0)
Cough
169 ( 7.5)
169 ( 7.4)
129 ( 5.9)
252 ( 7.5)
Diarrhea
148 ( 6.5)
168 ( 7.4)
160 ( 7.4)
233 ( 7.0)
Dyspnea
157 ( 6.9)
147 ( 6.4)
137 ( 6.3)
236 ( 7.0)
Urinary tract infection
159 ( 7.0)
164 ( 7.2)
121 ( 5.6)
224 ( 6.7)
Influenza
162 ( 7.2)
162 ( 7.1)
126 ( 5.8)
205 ( 6.1)
Pain in extremity
160 ( 7.1)
155 ( 6.8)
110 ( 5.1)
227 ( 6.8)
Edema peripheral
146 ( 6.5)
153 ( 6.7)
142 ( 6.5)
197 ( 5.9)
Dizziness
128 ( 5.7)
138 ( 6.0)
145 ( 6.7)
212 ( 6.3)
Pneumonia
132 ( 5.8)
153 ( 6.7)
128 ( 5.9)
208 ( 6.2)
Headache
145 ( 6.4)
120 ( 5.3)
126 ( 5.8)
196 ( 5.9)
Fatigue
125 ( 5.5)
108 ( 4.7)
93 ( 4.3)
183 ( 5.5)
Osteoarthritis
109 ( 4.8)
95 ( 4.2)
94 ( 4.3)
202 ( 6.0)


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The most common AE in CANTOS was upper respiratory infection and the most common SAE 
was pneumonia. 
The occurrence of sepsis was reported in a slightly higher percentage of subjects 1.0-1.4 % in 
the canakinumab-treated groups versus 0.8% in the placebo group.
Due to the mode of action of all inhibitors of the IL-1 pathway, infection is an important 
concern. Subjects should be closely monitored for signs or symptoms of infection and 
appropriate treatment instituted in a timely manner (see Section 6.3.3). Reported infections are 
usually mild to moderate in severity. Although the majority of reported infections resolved 
spontaneously or with standard therapy, severe, serious and fatal infections have been reported. 
Relevant to increased infections, mild to moderate neutropenia has been reported. No CTC 
grade 3 or 4 episodes of neutropenia or thrombocytopenia have been reported in clinical trials 
with canakinumab. Inclusion/exclusion criteria (Section 5), on treatment visits and monitoring 
(Section 7) as well as dose adjustments (Section 6) have been included in the study protocol to 
mitigate these risks.
Canakinumab showed a dose-related reduction in the occurrence of lung cancer in the CANTOS 
study, as detailed in Section 2.1 and Section 2.3. Given an expected benefit of a 28.4% decrease 
in the recurrence of NSCLC and a manageable risk of potential infections, canakinumab has a 
favorable risk-benefit ratio in the defined enrollment population.
2.7
Rationale for public health emergency mitigation procedures
In the event of a public health emergency as declared by local or regional authorities (i.e. 
pandemic, epidemic or natural disaster,), mitigation procedures may be required to ensure
subject safety and trial integrity and are listed in relevant sections of the study protocol. 
Notification of the public health emergency should be discussed with Novartis/Sponsor prior to 
implementation of mitigation procedures and permitted/approved by local or regional health 
authorities and ethics committees as appropriate.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 and Table 3-2 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4.
The primary objective is to compare the Disease-free 
survival (DFS) in the canakinumab versus placebo 
arms as determined by local investigator assessment.
DFS determined by local investigator assessment 
Key secondary
Refer to Section 10.5.1.
To compare overall survival (OS) in the canakinumab 
arm versus placebo arm
OS
Other secondary
Refer to Section 10.5.2, 
Section 10.5.3, 
Section 10.5.4, 
Section 10.5.6,
1. To compare DFS by local investigator 
assessment and OS in the canakinumab versus 
placebo arms in subgroups defined respectively 
by PD-L1 and CD8 expression levels
2. To compare lung cancer specific survival in the 
canakinumab arm versus placebo arm
3. To characterize the safety profile of canakinumab
4. To characterize the pharmacokinetics of 
canakinumab therapy 
5. To characterize the prevalence and incidence of 
immunogenicity (anti-drug antibodies, ADA) of 
canakinumab
6. To assess the effect of canakinumab versus 
placebo on PROs (EORTC QLQ-C30 with QLQ-
LC13 incorporated and EQ-5D) including 
functioning and health-related quality of life
1. DFS by local investigator assessment and OS in PD-L1 and CD8 
subgroups
2.
Lung cancer specific survival (LCSS)
3.
Frequency of AEs, ECGs and laboratory abnormalities
4.
Serum concentration-time profiles of canakinumab and appropriate individual 
PK parameters based on population PK model
5.
Anti-drug antibodies (ADA) prevalence at baseline and ADA incidence on-
treatment of canakinumab
6.
Time to definitive 10 point deterioration symptom scores of pain, cough and 
dyspnea per QLQ-LC13 questionnaire are primary PRO variables of interest. 
Time to 10 point definitive deterioration of global health status/QoL, 
shortness of breath and pain per QLQ-C30 questionnaire, time to first 
deterioration for symptom scores of pain, cough, dyspnea per QLQ-LC13 
questionnaire, time to first 10 point deterioration for global health status/QoL, 
shortness of breath and pain per QLQ-C30 questionnaire together with the 
utilities derived from EQ-5D-5L are secondary PRO variables of interest


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Objective
Endpoint
Analysis


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Table 3-2
Objectives and related endpoints applicable for sub-study (CACZ885T2301A)*
Objective
Endpoint
Analysis
For all subjects participating into sub-study:
•
To assess the levels of hs-CRP, other cytokines and 
additional biomarker levels in blood at pre- and post-
surgery. 
For subjects who will also enroll into the main study:
•
To determine whether there is an association 
between pre- and post-surgery biomarker levels with 
canakinumab efficacy (e.g. DFS, OS).
Summary statistics of hs-CRP and other PD biomarkers  
DFS and OS by hs-CRP and other PD biomarkers 
Refer to Section 10.6.1  
Refer to Section 10.6.1
*For China only: biomarker collection is conditional upon approval from HA, EC and additional authorities (i.e. HGRAC).


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4
Study design
4.1
Description of study design
This phase III study CACZ885T2301 (main study) will enroll adult subjects with completely 
resected (R0) NSCLC AJCC/UICC v. 8 stages II-IIIA and IIIB (T>5cm N2) disease.Subjects 
may be screened after undergoing complete surgical resection of their NSCLC and having R0 
status confirmed (negative margins on pathologic review), after completing adjuvant cisplatin-
based doublet chemotherapy if applicable, (radiation therapy is allowed if indicated as per local 
guidelines or practice) and after all entry criteria are met. Subjects must not have had 
preoperative neo-adjuvant chemotherapy or radiotherapy to achieve the R0 status. 
NSCLC subjects who are candidates for complete resection surgery (and therefore prospective 
candidates for the main study, CACZ885T2301) will be asked to participate in a biomarker sub-
study (CACZ885T2301A).  Unless otherwise noted that it is specific for the sub-study, the 
protocol will be referring to the conduct of the main study.
In this sub-study, an additional consent will be obtained to collect pre- and post-surgery blood 
samples to understand how resection surgery may impact hs-CRP, other cytokines and 
additional biomarker levels in blood (Figure 4-2). 
These subjects may later be eligible for the main study after the completion of the post-surgery 
standard of care treatment (i.e. cisplatin based chemotherapy with or without radiation). Further 
details are provided in Section 7.2.4.2.
In the main study, approximately 1500 subjects will be randomized 1:1 to canakinumab, 200 
mg subcutaneously (s.c.) every 3 weeks or matching placebo, s.c., every 3 weeks (Figure 4-1). 
Randomization will be stratified by AJCC/UICC v. 8 stage: IIA versus IIB versus IIIA versus 
IIIB with T>5cm, N2 disease; Histology: squamous versus non-squamous; and Region: 
Western Europe and North America vs. eastern Asia vs. Rest of the world (RoW). Subjects will 
continue their assigned treatment until they complete 18 cycles or experience any one of the 
following: NSCLC disease recurrence as determined by Investigator, unacceptable toxicity that 
precludes further treatment, treatment discontinuation at the discretion of the Investigator or 
subject, or start of a new antineoplastic therapy, or death, or lost to follow-up, whichever occurs 
first. It is postulated that the one year duration of adjuvant treatment will provide an acceptable 
benefit in subjects who have intermediate or high risk of developing disease recurrence. If 
NSCLC disease recurrence is not observed during the treatment phase, subjects will be followed 
until NSCLC disease recurrence, withdrawal of consent by the subject, subject is lost to follow 
up, death or the sponsor terminates the study for up to five years. All subjects who discontinue 
from the study treatment will be followed up every 12 weeks for survival until the final overall 
survival (OS) analysis or death, lost to follow-up or withdrawal of consent for survival follow-
up. 
The purpose of this prospective, multicenter, randomized, double blind, placebo-controlled 
phase III study is to evaluate the efficacy and safety of canakinumab as adjuvant therapy, 
following standard of care for completely resected (R0) AJCC/UICC v. 8 stages II-IIIA and 
stage IIIB (T>5cm N2) NSCLC subjects.




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4.2
Timing of interim analyses and design adaptations 
One interim analysis (IA) will be performed for DFS for futility when approximately 196 (50%) 
of the 392 DFS events have been observed. The primary intent of this IA is to determine whether 
there is a need to stop the study early for lack of efficacy (futility, there is no plan to stop the 
study for efficacy at this IA). 
In addition, a hierarchical testing procedure will be adopted and the statistical tests for OS will 
be performed only if the primary efficacy endpoint DFS is statistically significant.
A maximum of three analyses are planned for OS (OS will be statistically tested only if DFS 
meets statistical significance at final DFS analysis): 

At the time of final DFS analysis (provided DFS is statistically significant at final DFS 
analysis), at which point a total of approximately 318 (63%) deaths are expected 

An additional IA for OS when a total of approximately 418 (83%) deaths are expected 
(expected 52 months from the date of the first subject being randomized) 

A final analysis for OS when approximately 504 deaths are expected (expected 63 months 
from the date of the first subject being randomized).
4.3
Definition of end of study
The primary analysis of DFS will occur when approximately 392 DFS events are reached, (refer 
to Section 10.4). At this time, the primary clinical study report (CSR) will be produced.
After the primary analysis of DFS, the study will remain open provided the DFS demonstrates 
treatment benefit. Subjects still being followed on the study after the primary analysis time point 
will continue as per the schedule of assessments.
The study will end once the final OS analysis is performed when approximately 504 deaths are 
observed or when statistical significance is reached for OS analysis at interim analysis (refer to 
Section 10.7) and the final analysis of study data is conducted. All available data from all 
subjects up to this cutoff date will be analyzed.
If the primary analysis of DFS does not demonstrate treatment benefit, the follow-up for OS 
will end.
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the subject should be seen as soon as possible and the same assessments should be performed 
as described in Section 7 for a discontinued or withdrawn subject. 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 will be responsible for 
informing IRBs and/or ECs of the early termination of the trial.


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5
Population
5.1
Subject population
This phase III study CACZ885T2301 will enroll adult subjects with completely resected (R0) 
NSCLC AJCC/UICC v. 8 stages II-IIIA and IIIB (T>5 cm N2) disease. These groups have been 
included to allow all subjects that are able to achieve complete resection of their cancer with 
negative margins (R0 status).  The inclusion of these subjects is consistent with other adjuvant 
NSCLC studies as they are at a significant risk of relapse to merit inclusion in adjuvant trials. 
See inclusion criteria (Section 5.2) for complete information on required adjuvant cisplatin-
based doublet therapy. Subjects will be randomized after completing adjuvant cisplatin-doublet 
chemotherapy and meeting entry criteria.
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.
Applicable for the sub-study: The sub-study, CACZ885T2301A, will enroll adult subjects 
with NSCLC Stage IIA-IIIA, IIIB (T>5cm, N2 disease only) who are candidates for complete 
resection surgery (and therefore prospective candidates for the main study, CACZ885T2301). 
Biomarker samples pre-
and post-surgery will be collected from these subjects. 
See Sections 5.2.1 and Section 7.2.4.2 for further details.
5.2
Inclusion criteria (applicable for main study)
Subjects eligible for inclusion in this study have to meet all of the following criteria at the time 
of screening:
1. Written informed consent must be obtained prior to any screening procedures.
2. Age ≥ 18 years 
3a. Completely resected (R0) NSCLC AJCC/UICC v. 8 stage IIA-IIIA and IIIB (T>5cm, N2 
disease only). Minimal treatments considered adequate prior to study enrollment are:
Treatment modality

Minimum extent of treatment required prior to study entry
Surgery

Complete surgical resection (R0) is mandatory for all subjects. 

R0 is considered when in microscopic pathology evaluation there are no cancer cells 
in the surgical margin or within 1mm of the margin. 
Chemotherapy

Cisplatin-based chemotherapy is mandatory for all subjects (Exception: In subjects 
with stage IIA disease with no nodal involvement, cisplatin-based chemotherapy can 
be administered if recommended by the treating physician). 

When required, a minimum of two cycles of cisplatin-based chemotherapy is 
mandatory, after which additional therapies can be given based upon local clinical 
practice and/or guidelines.

Typically, chemotherapy is initiated within 60 days of surgery.
Radiation therapy

Radiation therapy is allowed if indicated as per local guidelines or practice.
The maximum number of days allowed from surgery to randomization is:

70 days if subjects were treated with surgery, but did not receive chemotherapy or radiation.

182 days if subjects were treated with surgery and chemotherapy, but no radiation.

259 days if subjects were treated with surgery, chemotherapy and radiation.


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Note: 

Subjects may enter the study earlier than maximum number of days allowed, if fully 
recovered from surgery and adjuvant therapies. 

A window of +7 days is allowed to accommodate subject scheduling if needed.

In case of case of chemotherapy treatment delays due to toxicities, additional window of 
+14 days is allowed.
4. Criterion removed. 
5. Criterion removed. 
6. Criterion removed. 
7a. Subjects must have recovered from all toxicities related to prior systemic therapy to grade 
≤ 1 (CTCAE v 5.0). Exception to this criterion: subjects with any grade of alopecia, 
neuropathy (grade ≤2), and subjects meeting the laboratory specifications described in 
inclusion 8.
8. Subjects must have adequate organ function including the following laboratory values at the 
screening visit:

Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 

Platelets ≥ 100 x 109/L

Hemoglobin (Hgb) > 9 g/dL

Creatinine clearance greater than 45 mL/min using Cockcroft-Gault formula

Total bilirubin ≤ 1.5 x ULN

Aspartate transaminase (AST) ≤ 3 x ULN

Alanine transaminase (ALT) ≤ 3 x ULN
9. ECOG performance status (PS) of 0 or 1.
10.Willing and able to comply with scheduled visits, treatment plan and laboratory tests.
5.2.1
Inclusion criteria applicable for sub-study (CACZ885T2301A)
1. Written informed consent to sub-study must be obtained prior to any collections.
2. Age ≥ 18 years
3. Subjects with NSCLC Stage IIA-IIIA, IIIB (T>5cm, N2 disease only) who are candidates 
for complete resection surgery.
5.3
Exclusion criteria (applicable for main study)
Subjects eligible for this study must not meet any of the following criteria at the time of 
screening:
1. Subjects with unresectable or metastatic disease, positive microscopic margins on the 
pathology report, and/or gross disease remaining at the time of surgery.
2. Subjects who received any neoadjuvant treatment. 
3a. Presence or history of a malignant disease, other than the resected NSCLC, that has been 
diagnosed and/or required therapy within the past 3 years. Exceptions to this exclusion 
include the following: completely resected basal cell and squamous cell skin cancers, 


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completely resected carcinoma in situ of any type and hormonal maintenance for breast and 
prostate cancer >3 years. 
4a. History of clinically significant interstitial lung disease (≥ grade 2). If radiological changes 
alone are present at baseline (CTC grade 1 interstitial lung disease) should be added to past 
medical history/concurrent medical conditions at baseline.
5a. History or current diagnosis of cardiac disease, including any of the following:

recent myocardial infarction or coronary artery bypass graft (CABG) surgery within 
last 6 months,

uncontrolled CHF,

unstable angina (within last 6 months),

clinically significant (symptomatic) cardiac arrhythmias 
6a.Thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting cycle 1 day 1 or subjects who 
have not recovered from radiotherapy-related toxicities. 
7. Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior to 
randomization or who have not recovered from side effects of such procedure. Video-assisted 
thoracic surgery (VATS) and mediastinoscopy will not be counted as major surgery and 
subjects can be enrolled in the study ≥1 week after the procedure.
8. Uncontrolled diabetes as defined by the investigator.
9. Known active or recurrent hepatic disorder including cirrhosis, hepatitis B and C (positive or 
indeterminate central laboratory results).
10a.Subjects must be evaluated for tuberculosis as per local treatment guidelines or clinical 
practice. Subjects with active tuberculosis are not eligible. In subjects without active 
tuberculosis, if the results of the evaluation require treatment per local guidelines, then 
the treatment should be initiated before randomization (unless otherwise required by 
Health Authorities or IRB in which case curative treatment must be completed prior to 
screening).
11a. Subjects with suspected or proven immunocompromised state or infections, including:  
a. Known history of testing positive for Human Immunodeficiency Virus (HIV) 
infections. 
b. Those with any other medical condition such as active infection, treated or untreated, 
which in the opinion of the investigator places the subject 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.
c. Allogeneic bone marrow or solid organ transplant
d. Those requiring systemic or local treatment with any immune modulating agent in 
doses with systemic effects e.g.:
i.
Prednisone >20 mg (or equivalent) oral or intravenous daily for >14 days;
ii. Prednisone > 5 mg and ≤ 20 mg (or equivalent) daily for > 30 days;
iii. Equivalent dose of methotrexate >15 mg weekly.
iv. Note: Daily glucocorticoid-replacement for conditions such as adrenal or pituitary 
insufficiency is allowed. Topical, inhaled or local steroid use in doses that are not 


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considered to cause systemic effects are permitted. Steroids for pre-medication 
related to chemotherapy as per local standard of care are permitted.
12a. Live or attenuated vaccination within 3 months prior to first dose of study drug (e.g. MMR, 
Yellow Fever, Rotavirus, Smallpox, etc.).
13. Prior treatment with canakinumab or drugs of a similar mechanism of action (IL-1β 
inhibitor).
14. History of hypersensitivity to canakinumab or drugs of a similar class.
15. Subjects who have received an investigational drug or device within 30 days prior to first 
dose of study drug or those who are expected to participate in any other investigational drug 
or device during the conduct of the study.
16. Subjects who received any biologic drugs targeting the immune system at any time. 
17. Any medical condition resulting in a life expectancy of less than 5 years, other than the risk 
for recurrent lung cancer. 
18. Pregnant or nursing women, 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
19a.Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception during dosing 
of study treatment and for up to 3 months after last dose of study drug. Effective 
contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject

Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps). For UK: with spermicidal foam/gel/film/cream/ vaginal 
suppository

Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS)
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.  Prior to entry into this study, cisplatin-
based chemotherapy, which may be toxic to the fetus, may be given. The time between the end 
of cisplatin-based chemotherapy and the start canakinumab/placebo treatment is variable, 
resulting in a variable need for continuation of highly effective contraception.
Women are considered post-menopausal and not of childbearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with 
or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks prior 
to first dose of study drug. In the case of oophorectomy alone, only when the reproductive status 


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of the woman has been confirmed by follow up hormone level assessment is she considered not 
of childbearing potential.
If local regulations are more stringent than the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the Informed Consent Form (ICF).
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
Canakinumab (ACZ885) or matching placebo solution for injection will be provided by
Novartis as ready-to-use pre-filled syringes to be administered by study center personnel.
Two strengths and respective corresponding matching placebos will be supplied:

Canakinumab 50 mg in 0.5 mL solution for injection and one placebo formulation
matching to this active drug formulation.

Canakinumab 150 mg in 1 mL solution for injection and one placebo formulation
matching to this active drug formulation.
6.1.1
Dosing regimen
The study is double-blind. All eligible subjects will be randomized to one of the following two 
treatment arms in a 1:1 ratio:

Canakinumab 200 mg s.c. on day 1 of every 21-day cycle for 18 cycles

Placebo s.c. on day 1 of every 21-day cycle for 18 cycles
The study drug will be given as subcutaneous injections on C1D1 and then every cycle (21 
days) for 18 cycles. All injections (one syringe of 1 ml and one syringe of 0.5 ml) will be
administered at study sites by trained site staff, facilitating both compliance and long-term
follow-up for both safety and efficacy outcomes.
Study drug should not be administered on the same day or same limb as non-live vaccines in 
order to distinguish any potential injection related reactions.
Table 6-1
Injection Description
Treatment Groups
Injections at all planned dosing visits
Canakinumab 200 mg sc
1 x canakinumab 150 mg and
1 x canakinumab 50 mg
Placebo
1 x placebo matching canakinumab 150 mg and 
1 x placebo matching canakinumab 50 mg
6.1.2
Ancillary treatments
Not applicable


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6.1.3
Rescue medication 
Not applicable
6.1.4
Guidelines for continuation of treatment 
Not applicable
6.1.5
Treatment duration
Subjects will be treated with canakinumab or placebo for 18 cycles (approximately 54 weeks) 
or until they experience any of the following: first NSCLC recurrence as determined by the 
investigator, unacceptable toxicity that precludes further treatment, treatment discontinuation 
at the discretion of the Investigator or subject, or start of a new antineoplastic therapy, or death, 
or lost to follow-up, whichever occurs first.
6.2
Dose escalation guidelines 
Not applicable
6.2.1
Starting dose rationale
The 200 mg s.c. every 3 weeks (q3w) dosing regimen of canakinumab is selected as the dosing 
schedule for the development program in NSCLC. This dosing regimen is selected based on the 
pharmacokinetic (PK) and pharmacodynamics (PD) properties of canakinumab, the observed 
safety, biomarker and efficacy data from the CANTOS study, the safety data from completed 
and ongoing canakinumab studies, as well as the dosing schedule for combination drugs for 
future NSCLC studies (See Section 2.3). 
6.2.2
Provisional dose levels
Not applicable
6.3
Dose modifications
6.3.1
Dose modification and dose delay
For subjects who do not tolerate the protocol-specified dosing schedule, dose interruptions are 
either recommended or mandated in order to allow subjects to continue the study treatment. 
There are no dose reductions allowed in this study.
These dose modifications are summarized in Table 6-2. If mandatory dose interruptions are not 
performed, deviations will be noted.  Permanent treatment discontinuation is mandatory for 
specific events indicated as such in Table 6-2 or listed in Section 7.1.4.
Scheduled dosing of study drug may, at the discretion of the Investigator, be delayed by up to 
7 days if subjects present with conditions that require withholding of study drug, e.g., presence 
of skin ulcer or evidence for active infection (treated or untreated). Outside of this 7 day 
window, the dose will be considered missed. After a dose is missed, the subject should resume 
treatment on the original schedule of study drug administration per C1D1. If a subject requires 
a dose interruption of greater than 42 days from the intended day of the next scheduled dose, 


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then the subject must be discontinued from the study. Subjects who discontinue the study for a 
study related adverse event or an abnormal laboratory value must be followed as described in 
Section 7.1.4.
Infections
Infections are the most common adverse event and may be related to study medication.  Subjects 
should be followed closely for any signs or symptoms of infection and receive prompt 
appropriate treatment for any suspected infection. Respiratory infections are common in 
subjects who have had lung cancer, in part due to underlying lung diseases such as chronic 
obstructive pulmonary disease and other smoking or second-hand smoke related lung diseases. 
Subjects will have a urinalysis performed at every study visit (screening and throughout the 
study treatment); occult urinary tract infections, if not promptly treated may result in urosepsis. 
Site personnel should be aware of this concern and review urinalysis results and take action if 
treatment of the subject for a urinary tract infection is required. 


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Table 6-2
Criteria for dose interruption and re-initiation of treatment for adverse drug reactions
Dose Schedule modifications for Canakinumaba
Worst toxicity
CTCAE Version 5.0 during a cycle of therapy
Infections fall under many CTC terms
Grade 1
Grade 2
Grade 3
Grade 4
Recommendation: maintain dose level
Recommendation: maintain dose level
Recommendation: Omit dose until resolved to ≤ Grade 2, then maintain dose level
Mandatory: Permanently discontinue study medication
Investigations (Hematologic)
Neutropenia (ANC)
Grade 1 (ANC < LLN - 1500/mm3)
May maintain dose level
Grade 2 (ANC < 1500 - 1000/mm3)
May maintain dose level
Grade 3 (ANC < 1000 - 500/mm3)
Mandatory: Omit dose until resolved to ≤ Grade 2, then maintain dose level
Grade 4 (ANC < 500/mm3)
Mandatory: Permanently Discontinue study medication
Febrile neutropenia (ANC < 1.0 x 109/L, fever ≥ 
38.5°C)
Mandatory: Permanently Discontinue study medication
Thrombocytopenia
Grade 1 (PLT < LLN - 75,000/mm3)
May maintain dose level
Grade 2 (PLT < 75,000 - 50,000/mm3)
May maintain dose level
Grade 3 (PLT < 50,000 - 25,000/mm3)
Recommendation: Omit dose until resolved to ≤ Grade 1, then:
If resolved in ≤ 7 days, then maintain dose level
If resolved in > 7 days, permanently discontinue study medication (mandatory)
Grade 4 (PLT < 25,000/mm3)
Mandatory: permanently discontinue study medication


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Dose Schedule modifications for Canakinumaba
Worst toxicity
CTCAE Version 5.0 during a cycle of therapy
Investigations (Renal)
Serum creatinine
Grade 1 (> ULN - 1.5 x ULN)
May maintain dose level
Grade 2 (> 1.5 - 3.0 x ULN)
Recommendation: May maintain dose level
Grade 3 (> 3.0 - 6.0 x ULN)
Recommendation: Omit dose until resolved to ≤ Grade 2 or baseline.
If not resolved within 14 days, then permanently discontinue subject from study drug treatment 
Grade 4 (> 6.0 x ULN)
Mandatory: Discontinue subject from study drug treatment 
Investigations (Hepatic) 
Isolated total Bilirubin elevation
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 LFTsb within 48-72 hours, then monitor LFTs weekly until resolution to ≤ 
Grade 1 or to baseline.
Grade 3 (> 3.0 - 10.0 x ULN)*

Interrupt treatment.  Repeat LFTs within 48-72 hours, then monitor LFTs weekly until resolution to ≤ 
Grade 1 or to baseline.
Grade 4 (> 10.0 x ULN)*

See footnote** - otherwise discontinue study treatment.
*Note: If total bilirubin > 3.0 x ULN is due to the indirect (non-conjugated) component only, and hemolysis as the etiology has been ruled out as per institutional 
guidelines (e.g., review of peripheral blood smear and haptoglobin determination), continue treatment at the discretion of the investigator.
**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.
Isolated AST or ALT elevation 
With normal baseline AST/ALT:
> ULN - 3.0 x ULN
Recommendation: Maintain dose level


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Dose Schedule modifications for Canakinumaba
Worst toxicity
CTCAE Version 5.0 during a cycle of therapy
> 3.0 - 5.0 x ULN
Recommendation: Maintain dose level. Repeat LFTsb as soon as possible, preferably within 48-72 hours 
from awareness of the abnormal results; if abnormal lab values are confirmed upon the repeat test, then 
monitor LFTsb weekly, or more frequently if clinically indicated, until resolved to
≤ 3.0 x ULN
Maintain dose level

Grade 3: AST or ALT (>5.0 –  20.0) x ULN 
If AST or ALT > 5.0 - 10.0 x ULN

Interrupt treatment. Repeat LFTsb within 48-72 hours, then monitor LFTsb weekly until recovery to 
Grade ≤1 or to baseline, then resume study drug.

If interruption > 42 days then subject must be discontinued. 
If AST or ALT > 10.0 - 20.0 x ULN 

Interrupt treatment. Repeat LFTsb within 48-72 hours, then monitor LFTsb weekly until recovery to 
Grade ≤1 or to baseline, then resume study drug.

If interruption > 42 days then subject must be discontinued. 
•
Grade 4: AST or ALT (> 20.0 x ULN)
Permanently discontinue study treatment. 
With abnormal baseline ALT/AST (up to Grade 1: ≤  3.0 ULN):

ALT/AST > 2.0 x baseline AND > 5.0 x ULN 

ALT/AST > 3.0 x baseline AND >10 x ULN
Grade 4: AST or ALT (>20 x ULN)

Interrupt treatment. Repeat LFTsb within 48-72 hours, then monitor LFTsb weekly until recovery to 
baseline, then resume study drug.

If interruption > 42 days then subject must be discontinued. 

Interrupt treatment. Repeat LFTsb within 48-72 hours, then monitor LFTsb weekly until recovery to 
baseline, then resume study drug.

If interruption > 42 days then subject must be discontinued. 
Permanently discontinue study treatment.
Concomitant elevations of AST or ALT and total bilirubin c
With normal baseline LFTs:
Grade 2 ALT/AST ( >3.0 x ULN)  with bilirubin > 2.0 x 
ULN without evidence of cholestasisd
(unless Gilbert's syndrome)
Interrupt study treatment. Assess if case is true DILI 
(Note: If total bilirubin > 3.0 x ULN is due to the indirect (non-conjugated) component only, and hemolysis 
as the etiology has been ruled out as per institutional guidelines (e.g., review of peripheral blood smear 
and haptoglobin determination), continue treatment at the discretion of the investigator.)
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. 


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Worst toxicity
CTCAE Version 5.0 during a cycle of therapy
Note: For additional information on follow-up of potential drug induced liver injury cases, refer to
Section 6.3.3.2.
With abnormal baseline LFTs: 
ALT or AST >2 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. 
Note: For additional information on follow-up of potential drug induced liver injury cases, refer to 
Section 6.3.3.2.
Investigation (metabolic)
Asymptomatic amylase and/or lipase elevation
Grade 1 (> ULN - 1.5 x ULN)
May maintain dose level
Grade 2 (> 1.5 - 2.0 x ULN; > 2.0 -5.0 X ULN and 
asymptomatic)
May maintain dose level
Grade 3* (> 2.0 - 5.0 x ULN with signs or symptoms; > 
5.0 ULN and asymptomatic)
Recommendation: Omit dose :
If resolved to grade ≤ 1 or baseline in ≤ 7 days, then maintain dose level
If resolved to grade ≤ 1 or baseline in > 7 days, then discontinue subject from study medication 
(mandatory)
Grade 4* (> 5.0 x ULN and with signs or symptoms)
Mandatory: Discontinue subject from study drug treatment.
*Note: A CT scan or other imaging study to assess the pancreas, liver, and gallbladder must be performed within 2 weeks of the first occurrence of any ≥ Grade 3 of 
amylase and/or lipase. If asymptomatic Grade 2 elevations of lipase and/or amylase occur again after restarting therapy, subjects will be discontinued permanently 
from study treatment.
Vascular disorders
Hypertension
CTCAE Grade 3
Recommendation: Omit dose until resolved ≤ Grade 1, then maintain level
CTCAE Grade 4
Mandatory: Discontinue subject from study drug treatment
Gastrointestinal
Pancreatitis
Grade 2
Recommendation: Maintain dose level
Grade ≥ 3
Mandatory: Discontinue subject from study drug treatment


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Dose Schedule modifications for Canakinumaba
Worst toxicity
CTCAE Version 5.0 during a cycle of therapy
Diarrhea
Note: antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools or overt diarrhea
Grade 1
May maintain dose level but initiate anti-diarrhea treatment
Grade 2
Recommendation: Omit dose until resolved to ≤ Grade 1, then maintain dose level.
Grade 3
Recommendation: Discontinue subject from study drug treatment
Grade 4
Mandatory: Discontinue subject from study drug treatment
Skin and subcutaneous tissue disorders
Rash/photosensitivity
Grade 1
May maintain dose level. Consider to initiate/institute appropriate skin toxicity therapy (such as 
antihistamines and/or topical corticosteroids)
Grade 2
May maintain dose level, but initiate/intensify appropriate skin toxicity therapy (such as antihistamines 
and/or topical corticosteroids).
Grade 3, despite skin toxicity therapy
Recommendation: Omit dose until resolved to Grade ≤1, then:
If resolved resolved  in ≤ 7 days, then maintain dose level
If resolved resolved  in > 7 days (despite appropriate skin toxicity therapy), then discontinue subject from 
study drug treatment (mandatory)
Grade 4, despite skin toxicity therapy
Mandatory: Discontinue subject from study drug treament
Fatigue/ Asthenia (General disorders and administration site conditions)
Grade 1 or 2
May maintain dose level
Grade 3
Recommendation: Omit dose until resolved to ≤ grade 1, then :
If resolved in ≤ 14 days, then maintain dose level
If resolved in > 14 days, then discontinue subject from study drug treatment (mandatory)
Other adverse events
Grade 1 or 2
May maintain dose level
Grade 3
Recommendation: Omit dose until resolved to ≤ grade 1, maintain dose level
Grade 4, except alopecia
Recommendation: Discontinue from study drug treatment


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Dose Schedule modifications for Canakinumaba
Worst toxicity
CTCAE Version 5.0 during a cycle of therapy
All dose modifications should be based on the worst preceding toxicity.
a Common Toxicity Criteria for Adverse Events (CTCAE Version 5.0)
b Core LFTs consist of ALT, AST, GGT, total bilirubin (fractionated [direct and indirect], if total bilirubin > 2.0 x ULN), and alkaline phosphatase (fractionated [quantification 
of isoforms], if alkaline phosphatase > 2.0 x ULN.)
c “Concomitant” defined as total bilirubin increase to the defined threshold concurrently with ALT/AST increase to the defined threshold
If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please follow the instructions for isolated elevation of total bilirubin and 
isolated elevation of AST/ALT, and take a conservative action based on the degree of the elevations (e.g. discontinue treatment at the situation when omit dose is needed 
for one parameter and discontinue treatment is required for another parameter). After all elevations resolve to the defined thresholds that allow treatment re-initiation, re-
start the treatment at the same dose 
d The 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.
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


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6.3.2
Dose adjustments for QTcF prolongation
In case of QTcF >500 msec, (or QTcF prolongation >60 msec from baseline)
1. Assess the quality of the ECG recording and the QT value and repeat if needed
2. Determine serum electrolyte levels (in particular hypokalemia, hypomagnesemia). If 
abnormal, correct abnormalities before resuming study drug treatment.
3. Review concomitant medication associated with QT prolongation, including drugs with a 
“Known”, “Possible”, or “Conditional risk of Torsades de Pointes, and drugs with the 
potential to increase the risk of study drug exposure related QT prolongation 
4. Check study drug dosing schedule and treatment compliance
5. Consider collecting a time-matched PK, and record time and date of last study drug intake.
After confirming ECG reading at site, if QTcF > 500 msec

Interrupt study treatment

Repeat ECG and confirm ECG diagnosis by a cardiologist 

If QTcF confirmed > 500 msec:

Correct electrolytes, eliminate culprit concomitant treatments, and identify and address 
clinical conditions that could potentially prolong the QT as per the ECG and QTc 
Clinical Safety Standards Guidelines Section 3.3.1.

Consult with a cardiologist (or qualified specialist)

Increase cardiac monitoring as indicated, until the QTcF returns to ≤ 480 msec.

After resolution to ≤ 480 msec, consider re-introducing treatment, and increase ECG 
monitoring for the next treatment(s):

If QTcF remains ≤ 500 msec after re-introducing treatment, continue planned ECG 
monitoring during subsequent treatment

If QTcF recurs > 500 msec after re-introducing treatment, discontinue subject from 
study treatment.
6.3.3
Follow-up for toxicities
6.3.3.1
Follow up for infections
Subjects should be followed closely for any signs or symptoms of infection and receive prompt 
appropriate treatment for any suspected infection.
6.3.3.2
Follow up on potential drug-induced liver injury (DILI) cases
DILI Diagnosis
Subjects with elevated transaminases combined with an increase in total bilirubin (TBIL) may 
be indicative of potentially severe DILI. These events should therefore be considered as 
clinically important and should be assessed appropriately to establish the cause of the abnormal 
liver function. 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.


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The threshold for potential DILI may depend on the subject’s baseline AST/ALT and TBIL 
value (Table 6-2 in Section 6.3.1); 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 > 2 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 international normalized ratio (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 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 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 6-3 provides guidance on specific clinical and diagnostic assessments to be (OR which 
can be) performed locally to rule out possible alternative causes of the observed LFT 
abnormalities. 
Table 6-3
Clinical and diagnostic assessments for observed LFT abnormalities
Disease
Assessment
Hepatitis A, B, C, E
IgM anti-HAV; HBsAg, IgM & IgG anti-HBc, HBV DNA; anti-HCV, HCV 
RNA, IgM & IgG anti-HEV, HEV RNA
CMV, HSV, EBV infection
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV
Autoimmune hepatitis
ANA & ASMA titers, total IgM, IgG, IgE, IgA
Alcoholic hepatitis
Ethanol history, GT, MCV, CD-transferrin
Nonalcoholic steatohepatitis
Ultrasound or MRI
Hypoxic/ischemic hepatopathy
Medical history: acute or chronicCHF, hypotension, hypoxia, hepatic 
venous occlusion. Ultrasound or MRI.
Biliary tract disease
Ultrasound or MRI, ERCP as appropriate.
Wilson disease (if <40 yrs old)
Caeruloplasmin
Hemochromatosis
Ferritin, transferrin
Alpha-1-antitrypsin deficiency
Alpha-1-antitrypsin


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Other causes should also be considered based upon subject’s 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 possible causes of 
liver injury combined. The term “drug-induced” indicates probably caused by the drug, not by 
something else, and only such a case can be considered a DILI case and should be reported as 
an SAE. 
DILI Management
In the absence of cholestasis, these subjects should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc.
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase.
2 . A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected.
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary tract) 
may be warranted.
4. Obtain 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.
5. Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), autoimmune 
hepatitis or liver biopsy may be considered as clinically indicated or after consultation with 
specialist/hepatologist.
All cases 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, met the definition of SAE (Section 8.2.1) 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.
6.4
Concomitant medications
The investigator should instruct the subject to notify the study site about any new medications 
he/she takes after signing the informed consent. All medications including supplements and 
herbal/natural medications, surgeries, and significant non-drug therapies (including physical
therapy and blood transfusions) taken within 30 days of screening and administered after the 
subject has signed informed consent must be listed on the appropriate eCRF.
For any antineoplastic therapy, surgery, or radiotherapy initiated after the start of study 
treatment, the reason for its use must be clearly documented and cancer recurrence must 
be assessed and documented. 


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Prior treatment for TB infection should be listed on the eCRF. Influenza vaccines administered 
two years prior to study start and pneumococcal vaccines administered five years prior to study 
start should be recorded on the eCRF. Vaccinations taken during the trial should also be reported 
on the eCRF. Subjects must be discontinued from the trial if administered any live and attenuated 
vaccines during the course of the study (see Section 6.4.2).
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. This is a
general precautionary measure because canakinumab is not expected to interact with warfarin.
Drug-drug interaction potential
No formal drug-drug interaction studies have been conducted with canakinumab. Elimination
pathways for IgG type monoclonal antibodies such as canakinumab are distinct from
metabolic pathways of small molecules. The IgG-based molecules are cleared from the body
by a combination of processes such as proteolysis by the liver, elimination by the 
Reticuloendothelial System and nonspecific endocytosis, whereas small molecular weight
drugs are typically eliminated
through CYP450-mediated oxidation pathways and are
therefore not expected to affect the pharmacokinetics of canakinumab. The expression of
hepatic CYP450 enzymes may be suppressed by the cytokines that stimulate chronic
inflammation, such as IL-1β. Thus, CYP450 expression may be normalized when potent
cytokine inhibitory therapy, such as canakinumab is introduced.
6.4.1
Permitted concomitant therapy
Potential drug interactions between study drug and concomitant medications should always be 
taken into consideration. 
6.4.2
Prohibited concomitant therapy
6.4.2.1
Immunosuppressants
Use of any treatments below is 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 study treatment. 
If a subject chooses to continue one of the medications below, they would still be required to 
be followed as per protocol to assess for NSCLC disease recurrence.

Any anti retro-virals and / or any biologic drugs targeting the immune system (e.g., TNF
blockers, anakinra, rituximab, abatacept, tocilizumab)

immune modulating agent in doses with systemic effects e.g.:
i.
Prednisone >20 mg (or equivalent) oral or intravenous daily for >14 days;
ii. Prednisone > 5 mg and ≤ 20 mg (or equivalent) daily for > 30 days;
iii. Equivalent dose of methotrexate >15 mg weekly.

Live or attenuated vaccines within 90 days of study treatment and after initiation of study 
drug. Subjects must be discontinued from the trial if administered any live or attenuated 
vaccine during the course of the study.


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6.4.2.2
Other anti-cancer therapy
Anti-cancer therapy (chemotherapy, targeted therapy, biologic therapy, radiation therapy, and 
anti-cancer surgery) other than the study treatment must not be given to subjects during the 
treatment phase of the study. If such agents are required then the subjects must be permanently 
discontinued from the study drug and evaluation of NSCLC disease recurrence must be 
performed.  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 and 
hormonal maintenance for breast and prostate cancer >3 years.
6.5
Subject numbering, treatment assignment or randomization
6.5.1
Subject numbering
Each subject is identified in the study by a Subject Number (Subject No.), that is assigned when 
the subject is first enrolled for 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 informed consent form, the subject is assigned to the next sequential Subject 
No. available to the investigator through the Clinical Data Management interface.
The investigator or designated staff will contact the Interactive Response Technology (IRT) and 
provide the requested identifying information for the subject to register them into the IRT. Once 
assigned, the Subject No. must not be reused for any other subject and the Subject No. for that 
individual must not be changed. If the subject fails to be randomized or start treatment for any 
reason, the reason will be entered into the disposition page. IRT must be notified within 2 days 
that the subject was not randomized.
Applicable for sub-study:
Each subject is identified in the sub-study by a Subject Number (Subject No.) that is assigned 
when the subject is first enrolled into sub-study. This number will be different from the subject 
number given if subject enrolls into the main study. 
If subjects from sub-study enroll into the main study, both subject IDs will be linked and 
subjects will continue with subject ID provided in main study. 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.
6.5.2
Treatment assignment or randomization
Randomization will be performed using the following procedure to ensure that treatment 
assignment is unbiased and concealed from subjects and investigator staff. Random permuted 
blocks scheme will be used for this study.
A randomization list will be produced by or under the responsibility of Novartis Drug Supply 
Management using a validated system that automates the random assignment of treatment 


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groups to randomization numbers in the specified ratio. The randomization list will be reviewed 
by a Biostatistics Quality Assurance Group and locked by them after approval.
Prior to dosing, all subjects who fulfill all inclusion/exclusion criteria will be assigned the 
lowest available number on the randomization list.
Subjects will be assigned to one of the two treatment arms (Section 4.1 and Section 6.1) in a 
ratio of 1:1. Randomization will be stratified by:

AJCC/UICC v.8 stage: IIA vs. IIB vs. IIIA vs. IIIB with T>5cm, N2 disease

Histology: squamous versus non-squamous

Region: Western Europe and North America vs. eastern Asia vs. Rest of the world (RoW)
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A subject 
randomization list will be produced by the (IRT) provider using a validated system that 
automates the random assignment of subject numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication randomization list will be produced by or under 
the responsibility of Novartis Drug Supply Management using a validated system that 
automates the random assignment of medication numbers to medication packs containing each 
of the study treatments. 
Prior to dosing, all subjects who fulfill all inclusion/exclusion criteria will be randomized via 
IRT to one of the treatment arms. The investigator or his/her delegate will log on to the IRT and 
confirm that the subject fulfills all the inclusion/exclusion criteria. The IRT will assign a 
randomization number to the subject, which will be used to link the subject to a treatment arm 
and will specify a unique medication number for the first package of study treatment to be 
dispensed to the subject. The randomization number will not be communicated to the site staff.
6.5.3
Treatment blinding
This is a double blind study. In particular, subjects, investigators, study team, or anyone 
involved in the study conduct will remain blinded to the identity of the treatment from the time 
of randomization until unblinding of the study.
Randomization data are kept strictly confidential until the time of unblinding, and will not be 
accessible to anyone involved in the conduct of the study, with the exception of the external 
independent statistical group, which needs to prepare safety interim DFS analysis reports for 
the DMC, the PK bioanalyst, modeler and modeling programmer. These personnel will not be 
involved in any other trial activities and treatment allocation information will be kept 
confidential until clinical database lock. The study bioanalyst will receive a copy of the 
randomization schedule to facilitate analysis of the samples. The identity of the treatments will 
be concealed by the use of investigational drugs (canakinumab or placebo) that are identical in 
packaging, labeling, schedule of administration and in appearance. Confidentiality of 
randomization data is required to limit the occurrence of potential bias arising from the 
influence that the knowledge of treatment may have on the recruitment and allocation of 
subjects. Unblinding will only occur in the case of subject emergencies (see Section 8.3),


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following the Data Monitoring Committee (DMC) recommendations (e.g. after the interim 
analyses) (see Section 10.7), for regulatory reporting purposes and at the end of the study. 
 
 
An independent statistical group (external to and independent of Novartis), not involved in the 
trial conduct, will prepare data reports for the DMC. Details will be presented in the DMC 
charter (see Section 8.6).
6.6
Study drug preparation and dispensation
Each study site will be supplied by Novartis with study treatment in packaging of identical
appearance per product volume. For allocation of the study medication, IRT will be used by the 
site personnel at the Investigator’s site. 
The study treatment packaging has a 2-part label. A unique medication number is printed on
each part of this label which corresponds to one of the four formulations provided (2 active
and 2 corresponding placebo forms). Investigator staff will identify the two study treatment
packages for the subject at each dispensing visit by contacting the IRT and obtaining the
medication numbers. Immediately before administering the study treatment, the investigator 
staff will detach the outer parts of the labels from the packaging and affix them to the source 
document (Drug Label Form) for that subject’s unique subject number.
Appropriate documentation of the subject specific dispensing process must be maintained.
Study drug will be administered as a subcutaneous injection by appropriately trained study 
center personnel.
Following the first dose on Cycle 1 Day 1, subsequent doses will be on Day 1 of every 21-day 
cycle for 18 cycles. The treatment visits must occur within ±3 days of the target date. 
All dosages prescribed and dispensed to the subject and all dose interruptions during the study 
must be recorded on the appropriate eCRF.
Giving the injection
All injections must be administered by the site staff only.
1. Choose an injection site on the upper arm, upper thigh, or abdomen. Do not use an area that 
has a rash or broken skin, or is bruised or lumpy. Avoid injecting into scar tissue- as this may 
lead to insufficient exposure to canakinumab. Avoid injecting into a vein.
2. Clean the injection site with a new alcohol swab. Allow the area to dry. Uncap the injection 
needle.
3. Gently pinch the skin up at the injection site. Hold the syringe at an approximately 45-
degree angle and in a single, smooth motion, push the needle completely into the skin.
4. Keep the needle all the way in the skin while slowly pushing the syringe plunger down until 
the barrel is empty. Release the pinched skin and pull the needle straight out. Dispose of the 
needle and syringe in the sharps container without recapping or removing the needle.


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5. After the injection: Do not rub the injection area. If bleeding occurs, apply a clean, dry 
cotton swab over the area, and press gently for 1 to 2 minutes, or until bleeding stops. Then 
apply an adhesive bandage.
6.6.1
Study treatment packaging and labeling
Study treatment, canakinumab, will be provided as global clinical blinded supply and will be 
packed and labeled under the responsibility of Novartis, Drug Supply Management.
Study treatment labels will comply with the legal requirements of each country and will include 
storage conditions, a unique medication number (corresponding to study treatment and 
strength).
6.6.2
Drug supply and storage
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, the study treatment should be stored according to the 
instructions specified on the drug labels and in the [canakinumab Investigator’s Brochure].
Upon receipt, all study treatment should be stored in the refrigerator at 2-8 degrees C (36-46
degrees F, do not freeze) and protected from light. Study treatment temperature should be
verified and documented daily (business days) with a minimal / maximum thermometer or
another equivalent temperature recording tool. Clinical supplies are to be dispensed only in
accordance with the protocol.
Table 6-4
Supply and storage of study treatments
Study treatments
Supply
Storage
Canakinumab or 
placebo
Centrally supplied by Novartis
Refrigerate at 2-8 degrees C (36-46 degrees 
F), Do not freeze and protect from light. 
6.6.3
Study drug compliance and accountability
6.6.3.1
Study drug compliance
Study treatment will be administered at the clinic by the investigative staff with the dosing 
record captured within each visit on the appropriate eCRF.
Compliance will be assessed by the investigator and/or study personnel at each subject visit 
and information provided by the subject and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each 
subject visit.
6.6.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site or remote monitoring visits and at the completion of the study. 


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All drug supplies are to be used only for this protocol and not for any other purpose. 
Unless specifically instructed by Novartis, the Investigator must not destroy any drug labels, or 
any partly used or unused drug supply.
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
6.6.3.3
Handling of other study treatment
Not applicable.
6.6.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility or third party, as 
appropriate, or locally at the site only if permitted by local regulations and authorized by 
Novartis.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. Each treatment cycle is 21 days (the 21 day cycle length is fixed regardless of 
whether the dose of canakinumab is withheld). All visits are to be scheduled according to the 
appropriate number of calendar days from study drug administration on Cycle 1 Day 1. A visit 
window of +/- 1 day in Cycle 1 and +/- 3 days in Cycle 2 onwards through EOT and Safety 
follow up is allowed. For Post treatment surveillance and Survival follow up, visit windows of 
± 7 days will apply in years 2 and 3, and visit windows of ± 21 days for years 4 and 5. Imaging 
evaluations may be performed ± 14 days of the due date of the assessment during years 1-3 and 
± 21 days in years 4 and 5. Note: If treatment with canakinumab/placebo is withheld or 
discontinued at any time during the study, all study visits, safety and efficacy assessments 
should continue according to the appropriate number of calendar days from Cycle 1 Day 
1 as per the schedule of assessments. 
Imaging assessments are to continue regardless of starting a new antineoplastic therapy after 
discontinuation of study treatment, if the patient has not progressed from their NSCLC or been 
diagnosed with new lung primary. All data obtained from these assessments must be supported 
in the subject’s source documentation. 
Subjects who discontinue from study treatment are to return for the end of treatment visit as 
soon as possible, and attend the follow-up visits as indicated in the Assessment Schedule
Subjects who discontinue study treatment before completing the study, and those who withdraw 
from the study for any reason, should be scheduled for a visit as soon as possible, at which time 
all of the assessments listed for the final visit will be performed.
As per Section 2.7, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, alternative 


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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 participant´s home, can replace certain 
protocol assessments, for the duration of the disruption until it is safe for the participant 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.
Table 7-2 provides details on the assessments to be performed for the sub-study. 


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Table 7-1
Visit evaluation schedule (main study, CACZ885T2301)
Protocol 
Section
Screening 
Phase
Treatment Phase 
Canakinumab / placebo (18 cycles / 54 weeks)
Post treatment 
surveillance (PTS)
Follow up 
phase
Visit Name
Screening
Cycle 1
Cycles 
2 to 17
C18/ 
EOT
Safety follow up (every 28d 
for 130d)
Post treatment 
surveillance
Survival 
follow up
Study/treatment cycle 
day
-28 to -1
C1D1
C1D8
C1D15
C2D1, 
C3D1, 
etc.
C18/EOT
Safety 1
Safety 2
Safety 3
Safety 4
Safety 5
Years 2 
and 3
Years 4 
and 5
Every 12 
weeks
Visit Number
1
110
140
150
210, 
310, 
etc.
1999
2010
2020
2
0
3
0
2
0
4
0
2
0
5
0
3010, 
3020,
3030, 
3040 etc.
3050
3060
SS
Obtain Study Informed 
Consent
7.1.2
X
IRT Screening (after 
ICF)
7.1.2
S
Study Disposition Form
7.1.4
Completed upon end of study treatment or when a subject exits the study for any reason (X)
Demography
7.1.2.3
X
Inclusion/exclusion 
criteria
5.2, 5.3
X
Medical history
7.1.2.3
X
Smoking history
7.1.2.3
X
Diagnosis, stage and 
grade of cancer
7.1.2.3
X


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Protocol 
Section
Screening 
Phase
Treatment Phase 
Canakinumab / placebo (18 cycles / 54 weeks)
Post treatment 
surveillance (PTS)
Follow up 
phase
Visit Name
Screening
Cycle 1
Cycles 
2 to 17
C18/ 
EOT
Safety follow up (every 28d 
for 130d)
Post treatment 
surveillance
Survival 
follow up
Study/treatment cycle 
day
-28 to -1
C1D1
C1D8
C1D15
C2D1, 
C3D1, 
etc.
C18/EOT
Safety 1
Safety 2
Safety 3
Safety 4
Safety 5
Years 2 
and 3
Years 4 
and 5
Every 12 
weeks
Visit Number
1
110
140
150
210, 
310, 
etc.
1999
2010
2020
2
0
3
0
2
0
4
0
2
0
5
0
3010, 
3020,
3030, 
3040 etc.
3050
3060
SS
Collection of 
concomitant
molecular alteration 
data
7.1.2.3
X
Prior anti-neoplastic 
therapies (medication, 
surgery, radiotherapy)
7.1.2.3
X
Prior/concomitant 
medications
7.1.2.3
Continuous, up to 130 days after the EOT visit. (X)


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Protocol 
Section
Screening 
Phase
Treatment Phase 
Canakinumab / placebo (18 cycles / 54 weeks)
Post treatment 
surveillance (PTS)
Follow up 
phase
Visit Name
Screening
Cycle 1
Cycles 
2 to 17
C18/ 
EOT
Safety follow up (every 28d 
for 130d)
Post treatment 
surveillance
Survival 
follow up
Study/treatment cycle 
day
-28 to -1
C1D1
C1D8
C1D15
C2D1, 
C3D1, 
etc.
C18/EOT
Safety 1
Safety 2
Safety 3
Safety 4
Safety 5
Years 2 
and 3
Years 4 
and 5
Every 12 
weeks
Visit Number
1
110
140
150
210, 
310, 
etc.
1999
2010
2020
2
0
3
0
2
0
4
0
2
0
5
0
3010, 
3020,
3030, 
3040 etc.
3050
3060
SS
Eligibility checklist 
(within IRT)
7.1.2.1
S
IRT Randomization
6.5.2
X
IRT study drug 
dispensation
6.6
S
S 
(every 
cycle)
S
Physical examination
7.2.2.2
S
S
S
S
S
S
S
S
S
Every 26 
weeks 
(S)
Annually 
(S)
ECOG Performance 
status
7.2.2.5
X
X
X
X
X
X
X
X
X
Every 26 
weeks 
(X)
Annually 
(X)
Vital signs
7.2.2.3
X
X
X
X
X
X
X
X
X
Every 26 
weeks 
(X)
Annually 
(X)
Weight
7.2.2.4
X
X
X
X
X
X
X
X
X
Every 26 
weeks 
(X)
Annually 
(X)
Height
7.2.2.4
X


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Protocol 
Section
Screening 
Phase
Treatment Phase 
Canakinumab / placebo (18 cycles / 54 weeks)
Post treatment 
surveillance (PTS)
Follow up 
phase
Visit Name
Screening
Cycle 1
Cycles 
2 to 17
C18/ 
EOT
Safety follow up (every 28d 
for 130d)
Post treatment 
surveillance
Survival 
follow up
Study/treatment cycle 
day
-28 to -1
C1D1
C1D8
C1D15
C2D1, 
C3D1, 
etc.
C18/EOT
Safety 1
Safety 2
Safety 3
Safety 4
Safety 5
Years 2 
and 3
Years 4 
and 5
Every 12 
weeks
Visit Number
1
110
140
150
210, 
310, 
etc.
1999
2010
2020
2
0
3
0
2
0
4
0
2
0
5
0
3010, 
3020,
3030, 
3040 etc.
3050
3060
SS
EORTC QLQ-C30 with 
lung module QLQ-
LC13 incorporated
7.2.6
X
(Prior to administration of investigational product or any other procedures). After randomization 
every 3 weeks for 18 cycles, at EOT, every 4 weeks during the 130-day safety follow up, every visit 
before any radiological study is done, before any unscheduled imaging assessments and two 
follow up visits after documented NSCLC disease recurrence (one within 7 days and one within 28 
days after discussing disease recurrence with the subjects). (X)
EQ-5D-5L
7.2.6
X
Determination of 
tuberculosis status
7.2.2.1
X
HIV screen, HBsAg 
and HCV Antibody
(For Japan only- in 
Japan, HBc antibody 
and HBs antibody are 
additionally included)
7.2.2.6
X
Hematology
7.2.2.6.1
X
X
X
X
X
X
X
X
X


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Protocol 
Section
Screening 
Phase
Treatment Phase 
Canakinumab / placebo (18 cycles / 54 weeks)
Post treatment 
surveillance (PTS)
Follow up 
phase
Visit Name
Screening
Cycle 1
Cycles 
2 to 17
C18/ 
EOT
Safety follow up (every 28d 
for 130d)
Post treatment 
surveillance
Survival 
follow up
Study/treatment cycle 
day
-28 to -1
C1D1
C1D8
C1D15
C2D1, 
C3D1, 
etc.
C18/EOT
Safety 1
Safety 2
Safety 3
Safety 4
Safety 5
Years 2 
and 3
Years 4 
and 5
Every 12 
weeks
Visit Number
1
110
140
150
210, 
310, 
etc.
1999
2010
2020
2
0
3
0
2
0
4
0
2
0
5
0
3010, 
3020,
3030, 
3040 etc.
3050
3060
SS
Biochemistry
7.2.2.6.2
X
X
X
X
X
X
X
X
X
Coagulation
7.2.2.6.4
X
As clinically indicated (X)
Urinalysis
7.2.2.6.5
X
X
X
X
X
X
X
X
X
Serum pregnancy test 
7.2.2.6.6
X
X
Urine pregnancy test 
(for women of child 
bearing potential only)
7.2.2.6.6
S
S
S
S
S
S
S
CT scan or MRI with 
contrast of chest,  
abdomen and  pelvis
7.2.1
X
Every 12 weeks (every 4 cycles) for the first year, every 26 weeks years 2 and 3, and 
then annually years 4 and 5 (X)
CT or MRI chest and 
abdomen (including full 
liver and bilateral 
adrenal imaging) low-
dose non-contrast 
(contrast may be 
added at investigator’s 
discretion)
7.2.1
Annually 
(X)
Whole body bone scan
7.2.1
As clinically indicated (X)


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Protocol 
Section
Screening 
Phase
Treatment Phase 
Canakinumab / placebo (18 cycles / 54 weeks)
Post treatment 
surveillance (PTS)
Follow up 
phase
Visit Name
Screening
Cycle 1
Cycles 
2 to 17
C18/ 
EOT
Safety follow up (every 28d 
for 130d)
Post treatment 
surveillance
Survival 
follow up
Study/treatment cycle 
day
-28 to -1
C1D1
C1D8
C1D15
C2D1, 
C3D1, 
etc.
C18/EOT
Safety 1
Safety 2
Safety 3
Safety 4
Safety 5
Years 2 
and 3
Years 4 
and 5
Every 12 
weeks
Visit Number
1
110
140
150
210, 
310, 
etc.
1999
2010
2020
2
0
3
0
2
0
4
0
2
0
5
0
3010, 
3020,
3030, 
3040 etc.
3050
3060
SS
MRI of brain
7.2.1
X
As clinically indicated (X)
Newly obtained biopsy 
for confirmation of 
disease recurrence
7.2.4.1.2
At the time of initial disease recurrence if radiological evidence is not conclusive (X)
Single ECG (standard 
12-lead)
7.2.2.7
X
As clinically indicated (X)
Adverse events
8.1
X
Continuous, up to 130 days after EOT (X)
SAEs related to study treatment 
(X)
Immunogenicity (IG) 
(Anti-canakinumab Ab)
7.2.3.1
X
X –
C2D1 
C4D1 
C6D1 
C9D1
C12D1
X
X
X
X


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Protocol 
Section
Screening 
Phase
Treatment Phase 
Canakinumab / placebo (18 cycles / 54 weeks)
Post treatment 
surveillance (PTS)
Follow up 
phase
Visit Name
Screening
Cycle 1
Cycles 
2 to 17
C18/ 
EOT
Safety follow up (every 28d 
for 130d)
Post treatment 
surveillance
Survival 
follow up
Study/treatment cycle 
day
-28 to -1
C1D1
C1D8
C1D15
C2D1, 
C3D1, 
etc.
C18/EOT
Safety 1
Safety 2
Safety 3
Safety 4
Safety 5
Years 2 
and 3
Years 4 
and 5
Every 12 
weeks
Visit Number
1
110
140
150
210, 
310, 
etc.
1999
2010
2020
2
0
3
0
2
0
4
0
2
0
5
0
3010, 
3020,
3030, 
3040 etc.
3050
3060
SS
PK
7.2.3.1
X
X
X
X –
C2D1
C4D1 
C6D1
C9D1
C12D1
X
X
X
X
X
X
IL-1β (PD)
7.2.3.1
X
X
X –
C4D1
C12D1
X
X
X
X


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Protocol No. CACZ885T2301
Protocol 
Section
Screening 
Phase
Treatment Phase 
Canakinumab / placebo (18 cycles / 54 weeks)
Post treatment 
surveillance (PTS)
Follow up 
phase
Visit Name
Screening
Cycle 1
Cycles 
2 to 17
C18/ 
EOT
Safety follow up (every 28d 
for 130d)
Post treatment 
surveillance
Survival 
follow up
Study/treatment cycle 
day
-28 to -1
C1D1
C1D8
C1D15
C2D1, 
C3D1, 
etc.
C18/EOT
Safety 1
Safety 2
Safety 3
Safety 4
Safety 5
Years 2 
and 3
Years 4 
and 5
Every 12 
weeks
Visit Number
1
110
140
150
210, 
310, 
etc.
1999
2010
2020
2
0
3
0
2
0
4
0
2
0
5
0
3010, 
3020,
3030, 
3040 etc.
3050
3060
SS
canakinumab/ placebo
6.6
Every 3 weeks for 18 cycles (54 weeks) (X)
Non-drug therapies 
and procedures
8.1.1
10.3
Continuous (X)
IRT Discontinuation 
canakinumab / placebo
7.1.4
S
Subsequent anti-
neoplastic therapies 
(medication, surgery, 
radiotherapy)
7.1.6
X
X
X
X
X
X
X
X
X


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Protocol 
Section
Screening 
Phase
Treatment Phase 
Canakinumab / placebo (18 cycles / 54 weeks)
Post treatment 
surveillance (PTS)
Follow up 
phase
Visit Name
Screening
Cycle 1
Cycles 
2 to 17
C18/ 
EOT
Safety follow up (every 28d 
for 130d)
Post treatment 
surveillance
Survival 
follow up
Study/treatment cycle 
day
-28 to -1
C1D1
C1D8
C1D15
C2D1, 
C3D1, 
etc.
C18/EOT
Safety 1
Safety 2
Safety 3
Safety 4
Safety 5
Years 2 
and 3
Years 4 
and 5
Every 12 
weeks
Visit Number
1
110
140
150
210, 
310, 
etc.
1999
2010
2020
2
0
3
0
2
0
4
0
2
0
5
0
3010, 
3020,
3030, 
3040 etc.
3050
3060
SS
Survival Follow-up
7.1.6.2
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
SS = Survival Status


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Table 7-2
Sub-study visit evaluation schedule (CACZ885T2301A)****
Visit
Volume
Protocol 
Section
Confirm 
eligibility*
Pre- resection 
surgery collection**
Post resection 
surgery collection***
Obtain Sub-study Informed Consent
N/A
7.1.2.4
X
Inclusion criteria for sub-study
N/A
5.2.1
X
Serious Adverse Events related to sub-study blood 
collection
N/A
8.2.2
X
X
Biomarker sub-study collections:
Blood (serum) for hs-CRP testing at central laboratory 
5 mL
7.2.4.2
X
X
Blood (plasma) for cytokine panel testing
10 mL
7.2.4.2
X
X
Blood (plasma) for ctDNA
20 mL
7.2.4.2
X
X = assessment to be recorded in the clinical database or received electronically from a vendor
*Eligibility confirmation can occur on the same day as the pre- resection surgery sample collection.
**Either one day prior to, or on the day of resection surgery.
***Prior to first administration of chemotherapy, not before 30 days after surgery but within 70 days after surgery.  For pathological stages not requiring chemotherapy, 
these samples must be drawn prior to their first imaging performed since resection surgery, still within 70 days after surgery.
****For China only: biomarker collection is conditional upon approval from HA, EC and additional authorities (i.e. HGRAC).


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7.1.1
Molecular pre-screening 
Not applicable
7.1.2
Screening
Written informed consent must be obtained before any study specific procedure is performed.
Subjects may be screened after undergoing complete surgical resection of their NSCLC and 
having R0 status confirmed (negative margins on pathologic review), after completing adjuvant 
cisplatin-based doublet chemotherapy if applicable, (and, if applicable, radiation therapy is 
allowed if indicated as per local guidelines or practice) and after all entry criteria are met. 
Subjects must not have had preoperative neo-adjuvant chemotherapy or radiotherapy to achieve 
the R0 status. 
After signing the study ICF, the screening assessments will be done within 1 to 28 days prior 
to randomization (see Table 7-1 for list of assessments to be performed). Laboratory parameters 
may be retested within the 28-day screening window (day -28 to day -1) period for an individual 
subject if such parameters meet an exclusion criterion when initially tested. Laboratory 
assessments performed as part of the screening evaluations will not be required to be repeated 
prior to dosing (except urine pregnancy test) unless deemed clinically necessary by investigator 
and/or required as per local institutional policies. Tumor imaging assessments will be performed 
at screening between Day -28 and Day -1. For details of assessments, see Table 7-1.
Assessments of patient reported outcomes during the screening period should be collected prior 
to any clinical assessments, drug dosing or diagnostic testing.
Imaging assessments will be performed at screening between Day -28 and Day -1. 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 as the 
baseline images for this study. Any imaging assessments obtained after randomization cannot 
be considered baseline images.
A new ICF will need to be signed if the investigator chooses to re-screen the subject after a 
subject has screen failed. In case of re-screening, the same subject ID will be used. All required 
screening activities must be performed when the subject is rescreened for participation in the 
study. An individual subject may only be re-screened once for the study. Details on capturing 
re-screening will be outlined in the eCRF Completion Guidelines.
Sub-study participants:
Written informed consent must be obtained prior to participation in the sub-study.
Subjects may be assessed for eligibility into the sub-study if they have NSCLC Stage IIA-IIIA, 
IIIB (T>5cm, N2 disease only) and who are candidates for complete resection surgery (and 
therefore prospective candidates for the main study, CACZ885T2301). After signing the sub-
study ICF, and sub-study eligibility criteria are met, biomarker samples will be collected as per 
Table 7-2.


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7.1.2.1
Eligibility screening 
Following registering in the IRT for screening, subject eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IRT system. 
Allocation to one of the two study arms will also be registered via IRT. Please refer and comply 
with detailed guidelines in the IRT manual.
7.1.2.2
Information to be collected on screening failures
A subject who signs the main informed consent but fails to satisfy all eligibility criteria for any 
reason will be considered a screen failure. The reason for not satisfying eligibility criteria and 
not being enrolled will be entered on the disposition eCRF. The following eCRFs must be 
completed for screen failure subjects:

Date of visit

Demographics

Informed Consent

Study Disposition Form

Inclusion/ Exclusion criteria

Death (if applicable)

Withdrawal of consent (if applicable)

SAEs (if related to reasons for screen failure)
No 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 (see 
Section 8 for SAE reporting details). If the subject fails to be enrolled, the IRT must be notified 
within 2 days of the screen fail that the subject was not enrolled.
7.1.2.3
Subject demographics and other baseline characteristics
Data to be collected on subject characteristics at screening include:

Demography (including: age, gender, race and ethnicity, or as allowed by local 
regulations)

Relevant medical history

History of smoking

NSCLC diagnosis and extent of disease, including:

Date of diagnosis of NSCLC 

Site of disease

Characteristics of disease including stage and histology 

Concomitant molecular alteration when available (and results of all the tests performed 
even if wild type)

Surgical and pathology reports confirming negative margins

Prior antineoplastic therapies (medications, radiation, surgeries)

Prior and Concomitant Medications, surgical and medical procedures


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7.1.2.4
Information to be collected on sub-study participants
The following eCRFs must be completed for sub-study subjects:

Date of visit

Demography (including: age, gender, race and ethnicity, or as allowed by local regulations)

Informed Consent

Study Disposition Form

Inclusion criteria 

Sub-study sample collection 

Death (if applicable)

Withdrawal of consent (if applicable)

SAEs (only if related to reasons for sub-study blood collection)
7.1.3
Treatment period
The study treatment phase begins on Cycle 1 Day 1 with the first administration of 
canakinumab/placebo. Subjects will continue their assigned treatment until they complete 18 
cycles or experience any one of the following: disease recurrence as determined by the 
investigator, unacceptable toxicity that precludes further treatment, treatment discontinuation 
at the discretion of the Investigator or subject, or start of a new antineoplastic therapy, or death, 
or lost to follow-up, whichever occurs first. Subjects will be assessed as per visit schedule in
Table 7-1. All subjects will be followed for AEs and SAEs for at least 130 days following the 
EOT visit. Subjects will present to the clinical site every 28 days, for a total of five follow-up 
visits. If disease recurrence is not observed during the treatment phase, subjects will be followed 
for recurrence during the post treatment surveillance phase for up to five years (see 
Section 7.2.1).
Visit windows of ± 1 calendar day will be applicable to scheduled study assessments during 
Cycle 1. Visit windows of ± 3 days from scheduled study assessments during the treatment 
phase will apply during and beyond Cycle 2 through EOT and Safety follow up visits. For 
Survival follow up and Post treatment surveillance, visit windows of ± 7 days will apply in 
years 2 and 3, and visit windows of ± 21 days will apply for years 4 and 5. Imaging assessments 
will have a ± 14 day window during years 1-3, and ± 21 days in years 4 and 5. For details of 
assessments, refer to Table 7-1. 
7.1.4
Discontinuation of study treatment
Subjects who discontinue study treatment should NOT automatically be considered withdrawn 
from the study. See Table 7-1 for the required assessments of these subjects after 
discontinuation of study treatment. Subjects who discontinue study treatment during the 
treatment phase should be scheduled for a visit within 7 days or as soon as possible after the 
last dose of study treatment, at which time all of the assessments listed for the EOT visit will 
be performed. If a subject withdraws from treatment at a study visit, EOT assessments that are 
already part of that scheduled study visit do not need to be repeated. The disposition page should 
be completed, giving the date and reason for stopping treatment.


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For subjects who discontinue treatment for reasons other than documented disease recurrence, 
initiation of new antineoplastic therapies, death, lost to follow-up, or withdrawal of consent, 
assessments must continue to be performed according to Table 7-1 until disease recurrence, 
withdrawal of consent by the subject, subject is lost to follow up, death or the sponsor terminates 
the study for up to five years.
Subjects may voluntarily discontinue from the study for any reason at any time. If a subject 
decides to discontinue from the study, the investigator should make a reasonable effort (e.g. 
telephone, e-mail, letter) to understand the primary reason for this decision and record this 
information in the subject’s chart and on the appropriate eCRF pages. They may be considered 
withdrawn if they state an intention to withdraw, fail to return for visits, or become lost to 
follow-up for any other reason. The investigator must also contact the IRT to register the 
subject’s discontinuation from study treatment.
At a minimum, all subjects who discontinue study treatment, including those who refuse to 
return for a final visit, will be contacted for safety evaluations during the 130 days following 
the EOT visit (see Section 7.1.6.1).
The investigator may discontinue study treatment for a given subject if, he/she believes that
continuation would be detrimental to the subject’s well-being.
In addition to mandatory study drug discontinuation criteria listed in Table 6-2, treatment must
also be discontinued under the following circumstances:

Pregnancy

Study Terminated by Sponsor

Subject/guardian decision

Physician decision

Non-compliance, as defined by missing any single dose greater than 42 days from the 
intended day of the next scheduled dose.

Initiation of a new antineoplastic therapy
Subjects who become pregnant during the trial must be withdrawn (Section 8.4). Subjects who 
become pregnant must cease all tumor assessments regardless of whether or not they developed 
recurrence. 
The appropriate personnel from the site and Novartis will assess whether study treatment
should be discontinued for any subject whose treatment code has been broken inadvertently for 
any reason.
Discontinuation from study is when the subject permanently stops receiving the study treatment, 
and further protocol-required assessments or follow-up, for any reason. 
If the subject agrees, a final evaluation at the time of the subject’s study discontinuation should 
be made as detailed in the assessment table (refer to Table 7-1).
7.1.4.1
Replacement policy
Not applicable


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7.1.5
Withdrawal of consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information. Where consent to the use of Personal and Coded Data is not required 
in a certain country's legal framework, the subject therefore cannot withdraw consent. However, 
they still retain the right to object to the further collection or use of their Personal Data.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to keep and use collected study informational research research results 
(data) that have already been collected for the study evaluation, (including processing of 
biological samples that has already started at time of consent any data resulting from the 
analysis of a subject’s samples until their time of withdrawal/opposition.) according to 
applicable law. No new Personal Data (including biological samples) will be collected 
following withdrawal of consent/opposition.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form. 
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements.
Applicable for sub-study:
Subjects may voluntarily withdraw consent/ to participate in the sub-study for any reason at
any time. Withdrawal of consent occurs only when a subject does not want to participate in the 
study any longer, and does not want any further visits or assessments, and does not want any 
further study related contact.
Novartis will continue to retain and use all research results that have already been collected 
for the study evaluation,All biological samples that have already been collected may be retained
and analyzed at a later date (or as required by local regulations).
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form. 


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For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements
7.1.6
Follow up evaluations
7.1.6.1
Safety follow up
All subjects will be followed for AEs and SAEs for at least 130 days following the EOT visit. 
Subjects will present to the clinical site every 28 days, for a total of five follow-up visits (see 
Table 7-1). At the end of this period, the investigator should assess and discuss with the subject 
any AEs observed and concomitant medications taken since discontinuation of study treatment. 
Subjects whose treatment is permanently discontinued due to an AE (clinical or based on 
abnormal laboratory value) must be followed until resolution or stabilization of the event, 
whichever comes first. In case of an abnormal laboratory value, blood tests should be repeated 
until resolution or stabilization.
If a new antineoplastic therapy is initiated after discontinuation of study treatment, only SAEs 
suspected to be related to study treatment will be collected in the Adverse Events eCRF.
7.1.6.2
Survival
All subjects who discontinue from the study treatment will be followed up every 12 weeks for 
survival until the final overall survival (OS) analysis or death, lost to follow-up or withdrawal 
of consent for survival follow-up (see Table 7-1). 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. The investigator or his designee will 
collect this survival information and any new anti-neoplastic therapies for all subjects until the 
final survival analysis. Follow-up can be done via a phone contact.
7.1.7
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 subject’s data 
privacy rights), the investigator 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. A subject should not be considered lost to follow-up until due diligence has been
completed. Subjects lost to follow up should be recorded as such on the appropriate disposition
eCRF.
7.2
Assessment types
7.2.1
Recurrence assessments
Detection of first disease recurrence will be done by clinical evaluation that includes physical 
examination and radiological tumor measurements as determined by the investigator.  In case 
of non-conclusive radiological evidence, a biopsy should be performed to confirm recurrence.  


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If a biopsy is performed, the fresh tissue sample and the pathology report should be submitted 
to the central lab.
The following assessments are required at screening/baseline:

Chest, abdomen and pelvis CT or MRI

Brain MRI

Whole body bone scan, if clinically indicated
Subsequent imaging assessments will be done every 12 weeks for the first year (treatment 
phase) following Cycle 1 Day 1, then every 26 weeks during years two and three, and annually 
during years four and five (post-treatment surveillance phase) (see Table 7-1). The intervals 
between imaging assessments across all study phases should be respected as described 
above regardless of whether study treatment is temporarily withheld or permanently 
discontinued before the last scheduled dose administration on Cycle 18 Day 1, or if 
unscheduled assessments are performed. A window of ±14 days in years 1-3, then ±21 days 
in years 4 and 5 is permitted to take into account scheduling over holidays.
First disease recurrence must be radiologically confirmed by the investigator. In case of non-
conclusive radiological evidence, a biopsy should be performed to confirm recurrence.  If a 
biopsy is not feasible, the subject will be followed up until recurrence can be confirmed as per 
protocol (radiologically conclusive and/or biopsy). 
For any antineoplastic therapy, surgery, or radiotherapy initiated after the start of study 
treatment, the reason for its use must be clearly documented and recurrence of cancer must be 
assessed and documented. Imaging assessments are to continue regardless of start of new 
antineoplastic therapies. 
If a subject discontinues study treatment for reasons other than recurrence, recurrence 
assessments should continue as per the scheduled visits per Table 7-1 and Table 7-2 until 
disease recurrence, withdrawal of consent by the subject, subject is lost to follow up, death or 
the sponsor terminates the study.
A whole body bone scan (e.g. Tc-99m bone scan, sodium fluoride PET [NaF-PET] bone scan) 
can be done to identify location of recurrence in bone tissue. If bone metastases were identified 
by a bone scan, it has to be confirmed histologically (preferred) or radiographically (by CT, 
MRI or FDG-PET-CT) if biopsy confirmation is unsafe.
All MRI and CT should be done with contrast unless contraindicated. If a subject is known to 
have a contraindication to CT intravenous (IV) contrast media or develops a contraindication 
during the trial, a non-contrast CT of the chest (Chest MRI is not recommended due to 
respiratory artifacts, however if CT is not feasible per local regulations, MRI can be performed 
instead) plus a contrast-enhanced MRI (if possible) of the abdomen and pelvis should be 
performed.
Brain MRI with contrast is required. If a subject has known contraindication or develops 
contraindication to MRI contrast media, MRI without contrast may be acceptable as long as the 
image quality and the slice thickness (5mm or less is recommended) is high enough to confirm 
disease-free status, and after discussion and approval by a Novartis study physician.


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Findings from radiological evaluations (evaluation of suspicion of recurrence or unconfirmed 
findings) will be recorded in the eCRF.
Table 7-3
Imaging Assessment Collection Plan
Procedure
Screening/Baseline
During Treatment/Follow-up
Chest, abdomen and pelvis CT or 
MRI (with intravenous contrast 
enhancement) 
Mandated
Mandated, every 12 weeks for 
the first year and every 26 weeks 
for years two and three
Brain MRI
Mandated
If clinically indicated (upon signs 
or symptoms of CNS metastases)
Whole body bone scan
If clinically indicated
If clinically indicated (new bone 
pain or other symptoms of bone 
metastases)
Chest and abdomen (including 
full liver and bilateral adrenal 
imaging) low-dose non-contrast 
CT or MRI (contrast may be 
added at investigator’s discretion)
Not done
Mandated, every 12 months for 
years four and five
Unscheduled CT or MRI of 
involved area, upon any signs or 
symptoms of recurrence
Not applicable
Upon suspected recurrence
7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing Eastern Cooperative Oncology Group (ECOG) 
Performance Status, vital signs, weight, ECG (at select visits), Patient Reported Outcomes, 
laboratory assessments including hematology, chemistry, coagulation, and urinalysis, as well 
as collecting adverse events and performing physical exams at every visit. For details on AE 
collection and reporting, refer to Section 8.
As per Section 2.7 Rationale for public health emergency mitigation procedures during a public 
health emergency as declared by local or regional authorities i.e. pandemic, epidemic or natural 
disaster, that limits or prevents on-site study visits, regular phone or virtual calls can occur for 
safety monitoring and discussion of the subject´s health status until it is safe for the subject to 
visit the site again. Notification of the public health emergency should be discussed with 
Novartis prior to implementation of mitigation procedures.
7.2.2.1
Determination of tuberculosis status
Determination of tuberculosis status, is required before administration of study drug and must 
be performed according to the locally approved evaluation methods as per local clinical practice 
or guidelines. In subjects without active tuberculosis, if the results of the evaluation require 
treatment, then the treatment should be initiated before randomization (unless otherwise 
required by Health Authorities or IRB in which case curative treatment must be completed prior 
to screening). TB In countries with no local tuberculosis guidelines, CDC guidelines may be 
used (httpswwwcdcgov/tb/default.htm). The QuantiFERON-TB Gold Plus (QFT-Plus) assay, 
is offered through central lab, as an option.  


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7.2.2.2
Physical examination
The physical examination comprises a total body examination that should include: general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, 
lymph nodes, extremities, vascular and neurological review. If indicated, rectal, external 
genitalia, breast and pelvis exams will be performed. Information about the physical 
examination must be present in the source documentation at the study site. Physical examination 
is to be performed according to the visit schedule as outlined in Table 7-1.
Significant findings that were present prior to the signing of informed consent must be included 
in the medical history eCRF. Significant new findings that begin or worsen after informed 
consent must be recorded on the adverse event eCRF.
7.2.2.3
Vital signs
Vital signs include blood pressure (supine position preferred when ECG is collected), pulse 
measurement, and body temperature.
7.2.2.4
Height and weight
Height will be measured at screening (without shoes).
Body weight (in indoor clothing, but without shoes) will be measured at screening and at 
subsequent time points as specified in Table 7-1.
7.2.2.5
Performance status
The performance status will be assessed according to the Eastern Cooperative Oncology Group 
(ECOG) Performance Status Scale as specified in Table 7-4 (Oken 1982) following the schedule 
given in Table 7-1.
Table 7-4
ECOG Performance Status
Grade
ECOG status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
7.2.2.6
Laboratory evaluations
Central and/or local laboratories (with normal range provided) will be used for the analysis of 
scheduled hematology, biochemistry, and coagulation specimens collected as part of safety 
monitoring (as detailed in Table 7-1). Other blood specimens collected as part of safety 
monitoring (e.g., HIV screen, HBsAg, HCV antibody) will be analyzed by central laboratories. 
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). Laboratory values 


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obtained during the Screening phase will be used to assess subject’s eligibility. The time 
windows granted for laboratory evaluations are identical to the corresponding visit time 
windows for each visit (refer to Section 7.1).
When using central laboratory analysis, 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) and locally 
unscheduled results may be used. Details on the collection, shipment of samples and reporting 
of results by the central laboratory are provided to investigators separately.
Details on the collection, shipment of samples and reporting of results by the central laboratory 
are provided to investigators in the Central Laboratory Manual/Flowchart. Visit windows of ± 
3 days are allowed for all visits beyond Cycle 1 during the treatment phase.
If at any time a subject has laboratory parameters obtained from a different (outside) laboratory, 
Novartis must be provided with a copy of the certification and a tabulation of the normal ranges 
and units for this laboratory. The investigator is responsible for reviewing all laboratory reports 
for subjects in the study and evaluating any abnormalities for clinical significance.
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.
At any time during the study up to safety follow-up, abnormal laboratory parameters which are 
clinically relevant and require an action to be taken with study treatment (e.g., require dose 
modification and/or interruption of study treatment, lead to clinical symptoms or signs, or 
require therapeutic intervention), whether specifically requested in the protocol or not, will be 
recorded on the AE eCRF page. The severity of laboratory data will be graded using the 
Common Terminology Criteria for Adverse events (CTCAE) version 5.0. Additional analyses 
are left to the discretion of the investigator.
Table 7-5
Clinical laboratory parameters collection plan
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, calcium (at screening, calcium corrected for albumin will be tested 
in addition to calcium), creatinine, creatinine clearance, total bilirubin, direct bilirubin 
(only if total bilirubin is ≥ grade 2), blood urea nitrogen (BUN) or urea, magnesium, 
potassium, sodium, fasting glucose, phosphate (inorganic phosphorus), alkaline 
phosphatase, total serum amylase, pancreatic amylase (as needed), lipase, GGT
hs-CRP*
Biomarker assessment to be performed in Central Laboratory Testing
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) 




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7.2.2.6.6 Pregnancy and assessments of fertility
During screening, a serum pregnancy test will be completed (Day -28 to Day -1). On Cycle 1 
Day 1 prior to dosing and at subsequent cycles, a urinary pregnancy test (dipstick) will be 
performed. 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. Refer 
to Table 7-1. If local requirements dictate otherwise, local regulations should be followed.
As per Section 2.7, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, if 
participants cannot visit the site to have serum pregnancy tests, 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 participants are instructed to perform the urine pregnancy test 
first and only if the test result is negative proceed with the administration of the study treatment. 
A communication process should be established with the subject so that the Site is informed 
and can verify the pregnancy test results (e.g., following country specific measures).
Women who are determined not to be of child bearing potential before the study will only be 
tested 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), total 
hysterectomy, or bilateral tubal ligation at least six weeks prior to first dose of study drug. 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 performed in between study visits, the subject must immediately 
notify the investigator. 
7.2.2.7
Cardiac assessments 
7.2.2.7.1 Electrocardiogram (ECG)
Local single 12-lead ECGs should be recorded after the subject has been resting for 5-10 min 
prior to the timepoint indicated in Table 7-1.
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.


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7.2.3
Pharmacokinetics, immunogenicity and pharmacodynamics
7.2.3.1
Pharmacokinetic, immunogenicity and pharmacodynamics blood 
collection and handling
Time points of blood sample collection for canakinumab PK, IG and PD are outlined in 
Table 7-6. If a subject starts new antineoplastic therapy after discontinuing study treatment, no 
further PK/PD/IG samples need to be collected. Blood samples will be taken by either direct 
venipuncture or an indwelling cannula inserted in a forearm vein.
For each scheduled PK sample, 2.5 mL of blood will be collected into SST tubes. The blood 
sample will be allowed to clot over a minimum of 30 minutes at room temperature prior to 
harvesting of the serum. The serum will be obtained by centrifugation at approximately 2500 g 
for 10 minutes. Serum PK samples will be split into 2 aliquots of approximately 0.5 mL serum 
(polypropylene tubes) and then stored (within 30 min of preparation) at -24˚C (approximately) 
prior to shipment to the Sponsor or central lab (see sample storage information below for 
detailed stability information). One aliquot will be shipped on dry ice to the analytical 
laboratory. The remaining aliquot must be kept at the central lab as a backup sample. Remaining 
samples will only be disposed of after approval by Novartis. 
For each scheduled IG sample, 2.5 mL of blood will be collected into SST tubes. The blood 
sample will be allowed to clot over a minimum of 30 minutes at room temperature prior to 
harvesting of the serum. The serum will be obtained by centrifugation at approximately 2500 g 
for 10 minutes. Serum IG samples will be split into 3 aliquots of approximately 0.3 mL serum 
(polypropylene tubes) and then stored (within 30 min of preparation) at -70˚C (approximately) 
prior to shipment to the Sponsor or central lab (see sample storage information below for 
detailed stability information). Two aliquots will be shipped on dry ice to the analytical 
laboratory. The remaining aliquot must be kept at the central lab as a backup sample. Remaining 
samples will only be disposed of after approval by Novartis. If anaphylactoid reactions occur 
after injection, two more samples (at the time of the event and 8 weeks later) need to be taken.
For each scheduled PD (IL-1β) sample, 3.5 mL of blood will be drawn into SST tubes, to obtain 
1.5 mL serum. The sample will be allowed to clot during 45 minutes at room temperature. The 
serum will be obtained by centrifugation at approximately 2500 g for 10 minutes. The sample 
will be split into two aliquots of 0.7 mL to be transferred into freezer-proof polypropylene 
screw-cap tubes. Serum tubes will be frozen within 90 min of venipuncture and kept at -24°C 
pending shipment on dry ice. One aliquot will be shipped on dry ice to the analytical 
laboratory. The remaining aliquot must be kept at the central lab as a backup sample.
On days and time points where blood IG and PD samples are to be drawn, the PK sample must 
be drawn first. The exact collection date and time of all samples must be documented on the 
PK, IG and PD blood collection eCRF pages. The date and exact time of dosing, as well as the 
date and actual time of blood sampling must be recorded on the eCRF.
All samples will be given a unique sample number and a dose reference ID. 
Further details on labeling of the PK, IG and PD samples, instructions for the collection, 
handling and shipment of samples can be found in the [CACZ885T2301 laboratory manual]. If 
subjects experience a SAE or an AE leading to the discontinuation of the study treatment, an 
unscheduled PK and IG blood sample should be obtained as close as possible to the event 




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Dose Reference 
Identification (ID)
PK 
sample 
number
IG 
sample 
numberb
Total IL-
1β (PD) 
sample 
numberb
Scheduled time points (hours)
Dose ID 
following 
sampling
Dose ID 
prior to 
sampling*
Cycle
Day
Scheduled 
time (hours)
Description
* These dose reference IDs refer to the dose administered and dosing time of the last dose prior to collection of 
the corresponding PK, IG and PD sample.
** This collection is mandatory for all subjects that end or complete study treatment. If the subject completes 
treatment, this sample will be collected pre dose for cycle 18. If the subject presents for EOT visit as a result of 
discontinuation, then this will be a post-dose collection relative to the last dose administered. 
a Sample should be taken immediately prior to the next administration of canakinumab.
b IG and PD samples are to be collected together with PK samples at the same time.
c PK sample numbers for any unscheduled PK collection will start with 1001.
d IG sample numbers for any unscheduled IG collection will start with 2001.
e PD sample numbers for any unscheduled PD collection will start with 3001.
7.2.3.2
Analytical method
An ELISA method will be used for bioanalytical analysis of ACZ885 in serum, with an 
anticipated lower limit of quantification (LLOQ) of 100 ng/mL for samples analyzed in China 
and 300 ng/mL for all other samples. The detailed method description to assess ACZ885 
concentration will be described in the bioanalytical raw data of the study and in the respective 
Bioanalytical Data Report (BDR).
A Meso Scale Discovery (MSD) electrochemiluminescence assay based method will be used 
for the detection of potential anti-ACZ885 antibody formation. The detailed method description 
to assess immunogenicity will be described in the bioanalytical raw data of the study and in the 
respective BDR.
An ELISA method will be used for bioanalytical analysis of total IL-1β 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. 


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7.2.4.2 Biomarker sample collection sub-study (CACZ885T2301A) in non-small 
cell lung cancer subjects that are candidates for curative surgery*
NSCLC subjects who are candidates for complete resection surgery (and therefore, prospective 
candidates for the main study, CACZ885T2301) will be asked to participate in a biomarker sub-
study (CACZ885T2301A).  In this sub-study, pre- and post-surgery blood samples will be 
collected to evaluate biomarkers involved in the IL-1β inflammatory pathway as well as 
mutations present in blood prior to surgery (see Table 7-2).
The sub-study will be identified as CACZ885T2301A. Signature of a separate informed consent 
form will be required before any samples are collected. Lack of participation in the sub-study 
does not exclude subject’s ability to participate in the main study, CACZ885T2301.
Enrollment into the sub-study will end when the enrollment into the main study has been 
completed.
The scope of this sub-study is limited to the collection of samples as described in Table 7-2. 
Data for this sub-study will be collected in a separate database with unique subject IDs (Refer 
to Section 6.5.1). 
*For China only: biomarker collection is conditional upon approval from HA, EC and 
additional authorities (i.e. HGRAC).
7.2.5
Other assessments
7.2.5.1
Anti-ACZ885 antibodies (immunogenicity assessment)
To assess potential immunogenicity, serum samples for determination of anti-canakinumab 
antibodies will be collected during the study according to the visit schedule outlined in 
Table 7-1.
7.2.6
Patient reported outcomes
7.2.6.1
PRO Questionnaires
The European Organization for Research and Treatment of Cancer’s core quality of life 
questionnaire EORTC-QLQC30 (version 3.0) and it’s lung cancer specific module QLQ-LC13 
(version 1.0) will be used to collect data on the subject’s functioning, disease-related symptoms, 
health-related quality of life, and health status. The EQ-5D-5L will be used for the purpose of 
the computation of utilities that can be used in health economic studies. The EORTC QLQ-
C30/LC13 as well as the EQ-5D-5L are reliable and valid measures frequently used in clinical 


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trials of subjects with lung cancer and previously used in the adjuvant setting 
(Bezjak et al 2008).
The EORTC-QLQC30 is a self-reporting 30-item generic instrument for use in cancer subjects 
across tumor types including lung cancer. It assesses 15 domains consisting of 5 functional 
domains (physical, role, emotional, cognitive, social) and 9 symptom domains (fatigue, nausea 
and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, financial 
difficulties) and a global health status or HRQoL scale (Aaronson et al 1993).The EORTC 
QLQ-LC13 complements the QLQ-C30, and measures disease symptoms and treatment-related 
adverse effects. The lung cancer module incorporates one multi-item scale to assess dyspnea, 
and 9 single items assessing pain, coughing, sore mouth, dysphagia, peripheral neuropathy, 
alopecia, and hemoptysis (Bergman et al 1994).
All of the domain scores of the EORTC-QLQC30 and QLQ-LC13 range from 0 to 100.  A high 
score indicates a higher response level.  Hence, a high score for a functional scale indicates a 
high and healthy level of functioning but a high score for a symptom scale indicates a high level 
of symptoms/problems.
The EQ-5D-5L is a standardized measure of health status developed by the EuroQol Group in 
order to provide a simple, generic measure of health for clinical and economic appraisal 
(EuroQol Group 1990). The EQ-5D-5L is designed for self-completion by respondents and 
takes only a few minutes to complete. Instructions to respondents are included in the 
questionnaire. The EQ-5D-5L consists of 2 pages – the descriptive system and the EQ visual 
analogue scale (EQ VAS) (Herdman M et al 2011). The descriptive system comprises 5 
dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each 
with 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme 
problems. The EQ VAS records the respondent’s self-rated health on a 20 cm vertical, visual 
analogue scale with endpoints labeled ‘the best health you can imagine’ and ‘the worst health 
you can imagine’.


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7.2.6.2
PRO assessments
PRO questionnaires (EORTC QLQ-C30/LC13 and EQ-5D-5L) will be provided at the visits 
indicated in Table 7-1, i.e. at screening, after randomization every 3 weeks for 18 cycles, at 
EOT, every 4 weeks during the 130-day safety follow up, every visit before any radiological 
assessment is done for recurrence, before any unscheduled imaging assessments and two follow 
up visits after documented disease recurrence (one within 7 days and one within 28 days after 
discussing disease recurrence with the subject). 
All questionnaires should be provided in the subject’s local language at the beginning of the 
study visit prior to any interaction with the study investigator including any tests, treatments or 
receipt of results from any tests to avoid biasing the subject’s perspective. This is to avoid 
potentially biasing subjects or their responses to study questionnaires.
PRO data will be recorded by subjects onto an electronic tablet device maintained at the study 
site. Investigators or study personnel should provide technical assistance but should not 
encourage the subjects to change responses reported in questionnaires.
Subjects should be given sufficient space and time to complete all study questionnaires. 
Subjects should be encouraged to complete any missing responses. Attempts should be made 
to collect responses to all questionnaires for all subjects, including from those who discontinue 
prior to the study evaluation completion visit, however, if subjects refuse to complete 
questionnaires, this should be documented in study source records. Subjects’ refusal to 
complete study questionnaires are not protocol deviations.
Questionnaires should be completed before any other clinical assessments planned for the study 
visit. 
8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after a subject’s signed informed 
consent has been obtained.
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
Adverse events that begin or worsen after informed consent should be recorded in the AE eCRF. 
Conditions that were already present at the time of informed consent should be recorded in the 
medical history eCRF. Adverse event monitoring should be continued for at least 130 days 
following the EOT visit. 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.


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If a new antineoplastic therapy is initiated after discontinuation of study treatment, only SAEs 
suspected to be related to study treatment will be collected in the Adverse Events eCRF.
Adverse events will be assessed and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0.
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, death related to the AE corresponding respectively to Grades 1 - 5, will be 
used. Information about any deaths (related to an adverse event or not) will also be collected 
though a death form.
The occurrence of adverse events should be sought by non-directive questioning of the subject 
during the screening process after signing informed consent and at each visit during the study. 
Adverse events also may be detected when they are volunteered by the subject during the 
screening process or between visits, or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine:

The severity grade (CTCAE v5.0 Grades 1-5)

Its duration (Start and end dates)

Its relationship to the study treatment. Reasonable possibility that AE is related:

No (i.e. not treatment-related);

Yes, investigational treatment (i.e. related to treatment with canakinumab/placebo);

Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)

Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)

Whether it is serious, where an SAE is defined as in Section 8.2.1 and which seriousness 
criteria have been met

Outcome 
(not 
recovered/not 
resolved, 
recovering/resolving, 
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.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the AE eCRF.
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome.


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8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the AE eCRF. Whenever possible, a 
diagnosis, rather than a symptom should be provided (e.g. anemia instead of low hemoglobin). 
Laboratory abnormalities that meet the criteria for adverse events should be followed until they 
have returned to normal or an adequate explanation of the abnormality is found. When an 
abnormal laboratory or test result corresponds to a sign/symptom of an already reported adverse 
event, it is not necessary to separately record the lab/test result as an additional event.
Laboratory abnormalities that do not meet the definition of an adverse event should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such.
8.1.3
Adverse events of special interest
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may be 
appropriate. Such events may require further investigation in order to characterize and 
understand them.
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data and include:

infections/opportunistic infections,  

neutropenia, 

abnormal liver parameters, 

thrombocytopenia, 

immunogenicity/allergenicity, 

autoimmunity reactions, 

new 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.
Canakinumab is associated with an increased incidence of serious infections during and after 
treatment. Therefore subjects should be carefully monitored for signs and symptoms of 


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infections during and after treatment with canakinumab. Physicians should exercise caution 
when administering canakinumab to subjects with infections, a history of recurring infections, 
or underlying conditions which may predispose them to infection.
Neutropenia has been observed with medicinal products that inhibit IL-1β, including 
canakinumab.Treatment should not be initiated in subjects with neutropenia. It is recommended 
that neutrophil counts be assessed before and during treatment.
8.2
Serious adverse events
8.2.1
Definitions
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:

Is 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, fetal death or a congenital abnormality or 
birth defect

Requires in subject hospitalization or prolongation of existing hospitalization,

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the 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, i.e., 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 (please refer to the ICH-
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Confirmed COVID-19 infection should be considered as medically significant and should 
therefore be reported as an 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.
8.2.2
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 Serious 
Adverse Event Report Form; all applicable sections of the form must be completed in order to 
provide a clinically thorough report. In case of technical issue to report SAE information via 
eSAE, the site must complete paper SAE form to meet 24-hour reporting timeline; once the 
issue is resolved, the site must enter the SAE information in eSAE database.
If a new antineoplastic therapy is initiated after discontinuation of study treatment, only SAEs 
suspected to be related to study treatment will be collected in the Adverse Events eCRF.
For SAE reporting in case of malignancies during the study, the following applies: 

Recurrence of NSCLC 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 recurrence of 
NSCLC malignancy (example, deep vein thrombosis at the time of recurrence or hemoptysis 
concurrent with finding of disease recurrence) will be reported as per usual guidelines used 
for such events with proper attribution regarding relatedness to the drug.

New primary lung cancer malignancies should always be reported as SAEs.

New primary malignancies in organs other than lung should always be reported as SAEs.
Any additional information for the SAE including complications, progression of the initial SAE, 
and recurrent episodes must be reported as follow-up to the original episode immediately, 
without undue delay, but under no circumstances later than within 24 hours of the investigator 
receiving the follow-up information (Note: If more stringent, local regulations regarding
reporting timelines prevail). An SAE occurring at a different time interval or otherwise 
considered completely unrelated to a previously reported one should be reported separately as 
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Any SAEs experienced after the 130-day safety follow-up period should only be reported to 
Novartis if the investigator suspects a causal relationship to the study treatment.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. 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.
Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the subject continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis 
Chief Medical Office and Patient Safety (CMO&PS) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN), to inform all investigators involved in any study with 
the same drug that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Applicable for sub-study:
Only SAEs related to the blood sample collection in the sub-study will be collected. 
8.3
Emergency unblinding of treatment assignment
Emergency unblinding should only be undertaken when it is essential for effective treatment of 
the subject. 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. Unblinding is also permitted under exceptional circumstances if treatment 
assignment is critical to determine the optional subsequent treatment for the subject and only if 
post-progression therapy with an IL-1β inhibitor is being considered. In case of unblinding for 
determination of subsequent treatment, approval by a Novartis study physician is required. 
Emergency code breaks are performed using the IRT. When the investigator contacts the IRT 
to unblind a subject, he/she must provide the requested subject identifying information and 
confirm the necessity to unblind the subject. The investigator will then receive details of the 
drug treatment for the specified subject and a fax confirming this information. The system will 
automatically inform the Novartis monitor for the site and the Study Lead that the code has 
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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

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 EOT visit completed and will continue to be followed for recurrence as specified 
in the protocol. Subject will remain in follow-up unless withdrawn from study.
8.4
Pregnancies
If a female subject becomes pregnant, the study treatment should be stopped, and the pregnancy 
consent form should be presented to the trial subject. The subject must be given adequate time 
to read, review and sign the pregnancy consent form. This consent form is necessary to allow 
the investigator to collect and report information regarding the pregnancy. To ensure subject 
safety, each pregnancy occurring while the subject is on study treatment must be reported to 
Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed up to 
determine outcome, including spontaneous or voluntary termination, details of the birth, and 
the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Chief Medical Office and Patient Safety (CMO&PS). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment and any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. If a subject becomes 
pregnant while on study treatment, the newborn will be followed for up to 12 months.
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided [canakinumab 
Investigator Brochure]. Additional safety information collected between IB updates will be
communicated in the form of Investigator Notifications. This information will be included in 
the subject informed consent and should be discussed with the subject during the study as 
needed.
8.6
Data Monitoring Committee
This study will institute 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 
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for the first 18 months after the first randomized subject has started study treatment (first 
meeting will be conducted when approximately 50 subjects have been treated) and 
approximately every 1 year thereafter until all subjects have completed 18 cycles 
(approximately 54 weeks) of treatment or final DFS analysis (whichever occurs earlier). The 
DMC will also be responsible to review efficacy and safety data in the conduct of the interim 
DFS analyses as defined in the protocol. This includes but does not limit the role of the DMC 
to evaluate these data and to provide recommendations to the sponsor to continue, modify or 
stop the study early.
It is expected that the DMC will consist at a minimum of two physicians with appropriate 
disease area qualifications and one statistician. There will be a meeting with the DMC 
describing their roles and responsibilities and discussing potential data format and process 
issues prior to the finalization of DMC charter and the interim analysis plan.
8.7
Steering Committee
The steering committee will be established comprising investigators participating in the trial, 
i.e. not being members of the DMC or Novartis representatives from the Clinical Trial Team.
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the Steering Committee will be defined in a Steering Committee charter.
9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the subject 
experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
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9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and eCRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of subject records, the accuracy of entries on the eCRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on eCRFs must be traceable to source documents in the 
subject's file. The investigator must also keep the original signed informed consent form (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 eCRF entries. Novartis monitoring standards require full verification for 
the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the eCRFs 
are performed according to the study-specific monitoring plan.
9.3
Data collection
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the eCRF. The eCRFs have been built using fully validated 
secure web-enabled software that conforms to 21 CFR Part 11 requirements, Investigator site 
staff will not be given access to the EDC system until they have been trained. Automatic 
validation programs check for data discrepancies in the eCRFs and, allow modification or 
verification of the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into the eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner.
Blood, plasma/serum and tumor samples for laboratory data and biomarkers assessments will 
be collected by sites and sent to the Novartis designated central laboratory for processing. The 
laboratory results and IRT data will be sent electronically to Novartis. PRO data will be 
recorded by subjects onto an electronic tablet device maintained at the study site. The device 
will be programmed to ensure that all relevant observations are recorded.
9.4
Database management and quality control
For studies using eCRFs, Novartis personnel (or designated CRO) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system. Designated investigator site staff are 
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Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Samples and/or data (e.g. biomarkers, safety samples) will be processed centrally and the results 
will be sent electronically to Novartis (or a designated CRO). PRO data collected using an 
electronic tablet device will be documented into a separate study-specific database supplied and 
managed by a designated vendor. The PRO database will be accessible to study sites and 
Novartis personnel (or a designated CRO) for data management. All PRO data will be sent 
electronically to Novartis personnel (or a designated CRO).
Randomization codes and data about all study treatments dispensed to the subject and all IRT 
assigned dosage changes will be tracked using an Interactive Response Technology. The system 
will be supplied by a vendor(s), who will also manage the database. The data will be sent 
electronically to Novartis personnel (or designated CRO).
At the conclusion of the study, the occurrence of any emergency code breaks will be determined 
after return of all code break reports and unused drug supplies to Novartis personnel (or 
designated CRO). The occurrence of any protocol violations will be determined. After these 
actions have been completed and the data has been verified to be complete and accurate, the 
database will be declared locked and the treatment codes will be unblinded and made available 
for data analysis. Authorization is required prior to making any database changes to locked data, 
by joint written agreement between the Global Head of Biostatistics and Data Management and 
the Global Head of Clinical Development.
For EDC studies, after database lock, the investigator/ designee will generate Patient Data 
Report from EDC and archive  at the investigational site.
10
Statistical methods and data analysis
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (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 (AJCC/UICC v. 8 stage: IIA versus IIB versus IIIA versus 
IIIB with T>5cm N2 disease; Histology: squamous versus non-squamous; and Region: Western 
Europe and North America vs. eastern Asia vs. Rest of the world (RoW)) to which they have 
been assigned during the randomization procedure.
10.1.2
Safety set
The Safety Set includes all subjects who received at least one dose of study drug. Subjects will 
be analyzed according to the study treatment they received, either canakinumab or placebo. The 
treatment received is defined as the randomized treatment if the subject took at least one dose 
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10.1.3
Dose-determining analysis set
Not applicable
10.1.4
Pharmacokinetic analysis set
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 SAP.
10.1.5
Other analysis sets 
Other analysis sets, if needed, will be specified in the SAP.
10.2
Subject demographics/other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and
summarized descriptively by treatment arm for the FAS. In light of COVID-19 pandemic 
impacting the study during the enrollment phase, it will be summarized by pandemic phases: 
pre-pandemic period and pandemic period.
Participant race and ethnicity are collected to identify variations in safety or efficacy due to 
these factors as well as to assess the diversity of the study population as required by Health 
Authorities.
Categorical data will be presented as frequencies and percentages. For continuous data, 
summary statistics (mean, standard deviation, median, minimum, and maximum) will be 
presented.
Relevant medical histories and current medical condition at baseline will be summarized  by 
system organ class , preferred term, and treatment arm.
10.3
Treatments (study treatment, concomitant therapies, 
compliance)
The safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, summary statistics (mean, standard 
deviation, median, 25th and 75th percentiles, minimum, and maximum) will be presented.
The duration of exposure to canakinumab and placebo, as well as the dose intensity (computed 
as the ratio of actual cumulative dose received and actual duration of exposure) and the relative 
dose intensity (computed as the ratio of dose intensity and planned dose intensity) will be 
summarized by treatment arm by means of descriptive statistics using the safety set.
The number of subjects with dose adjustments (interruption, or permanent discontinuation) and 
the reasons will be summarized by treatment arm. All dosing data will be listed.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by treatment arm.


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10.4
Primary objective
The primary objective is to compare the DFS in the canakinumab versus placebo arms as 
determined by local investigator assessment.
10.4.1
Variable
The primary efficacy variable of the study is DFS, defined as the time from the date of 
randomization to the date of the first documented NSCLC disease recurrence as assessed by 
local investigator radiologically or death due to any cause. Disease recurrence includes 
diagnoses of new primary lung malignancies. Clinical deterioration is not considered as a 
recurrence of disease. In case of non-conclusive radiological evidence, a biopsy assessment will 
be performed to confirm NSCLC recurrence; radiological assessment date will be used as DFS 
event date. DFS events will be assessed locally. Censoring conventions are provided below in 
Section 10.4.3.
10.4.2
Statistical hypothesis, model, and method of analysis
Assuming proportional hazards model for DFS, the following statistical hypotheses will be 
tested to address the primary efficacy objective:
H01 (null hypotheses): Θ1≥ 0 vs. Ha1 (alternative hypotheses): Θ1 < 0
Where Θ1 is the log hazard ratio of DFS in the canakinumab (investigational) arm vs. placebo 
(control) arm.
The primary efficacy analysis to test this hypothesis and compare the two treatment groups will 
consist of a stratified log-rank test at an overall one-sided 2.5% level of significance. The 
stratification will be based on the following randomization stratification factors: AJCC/UICC 
v. 8 stage IIA versus IIB versus IIIA versus IIIB with T>5cm N2 disease; Histology: squamous 
versus non-squamous; and Region: Western Europe and North America vs. eastern Asia vs. 
Rest of the world (RoW). The primary efficacy variable, DFS, will be analyzed at one interim 
analysis enabling the study to stop due to futility and final analysis of a group sequential design, 
using a Lan-DeMets (O’Brien-Fleming) α-spending function and a non-binding user-defined β-
spending function (gamma function with γ=-3). Analyses will be based on the FAS population 
according to the treatment group and strata assigned at randomization. The DFS distribution 
will be estimated using the Kaplan-Meier method, and Kaplan-Meier curves will be presented 
for each treatment group. The DFS Kaplan- Meier estimate along with 95% confidence intervals 
will be presented at different time points (e.g. 1 year, 2 years, 3 years, 4 years, 5 years) for each 
of the two treatment arms. The hazard ratio for DFS will be calculated, along with its 95% 
confidence interval, from a stratified Cox model using the same stratification factors as for the 
log-rank test. 
10.4.3
Handling of missing values/censoring/discontinuations
DFS will be censored if no DFS event is observed prior to the analysis cut-off date or subjects 
who received any subsequent anti-neoplastic therapy for NSCLC. The censoring date will be 
the date of last assessment before the cut-off date or NSCLC related anti-neoplastic therapy 
date.


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10.4.4
Supportive and Sensitivity analyses
As sensitivity analyses performed in the FAS, the hazard ratio and 95% confidence interval for 
DFS will be obtained from:

an unstratified and covariate unadjusted Cox model.

stratified Cox model using a modified definition of DFS event with the inclusion of the start 
of anti-neoplastic therapy as a DFS event in addition to NSCLC disease recurrence defined 
for primary analysis.

stratified Cox model without censoring NSCLC related anti-neoplastic therapy

stratified Cox model with censoring two or more missing assessments

stratified Cox model with censoring subjects when discontinuing treatment or death due to 
COVID-19, or receiving COVID-19 medications

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.
If the primary analysis is statistically significant, subgroup analyses to assess the homogeneity 
of the treatment effect across demographic and baseline disease characteristics will be 
performed including AJCC/UICC v.8 stage, histology and region. Other subgroups to be 
considered will be defined in the SAP. 
The number of subjects censored and reasons for censoring for DFS will be summarized by 
treatment group using descriptive statistics. 
10.5
Secondary objectives 
Secondary objectives of the study are as specified in Table 3-1. The secondary objectives in this 
study are to compare the two treatment groups with respect to overall survival (OS), lung cancer 
specific survival (LCSS), DFS and OS in PD-L1 and CD8 subgroups, time to 10 point definitive 
deterioration and first 10 point definitive deterioration in patient-reported outcomes, including 
key symptom scores, and safety. OS is identified as the key secondary endpoint. A hierarchical 
testing strategy will be used to control the overall type I error rate, where OS will only be 
formally tested and interpreted if the primary analysis of DFS is statistically significant. 
10.5.1
Key secondary objective(s)
The key secondary objective is to determine whether treatment with canakinumab prolongs OS 
compared with placebo arm. OS is defined as the time from the date of randomization to the 
date of death due to any cause. If a subject is not known to have died, then OS will be censored 
at the latest date the subject was known to be alive (on or before the cut-off date).
Assuming proportional hazards model for OS, the following statistical hypotheses will be tested 
only if DFS is statistically significant:
H02 (null hypotheses): Θ2≥ 0 vs. Ha2 (alternative hypotheses): Θ2 < 0
Where Θ2 is the log hazard ratio of OS in the canakinumab (investigational) arm vs. placebo 
(control) arm. The analysis to test these hypotheses will consist of a stratified log-rank test at 
an overall one-sided 2.5% level of significance. The stratification will be based on the following 


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randomization stratification factors: AJCC/UICC v. 8 stage IIA versus IIB versus IIIA versus 
IIIB T>5cm N2 disease; Histology: squamous versus non-squamous; and Region: Western 
Europe and North America vs. eastern Asia vs. Rest of the world (RoW).
OS analyses will be conducted as part of a group sequential design using a 
Lan-DeMets (O’Brien-Fleming) α spending function (a separate function to that used for DFS). 
Analyses will be based on the FAS population according to the randomized treatment group 
and strata assigned at randomization. The OS distribution will be estimated using the Kaplan-
Meier method, and Kaplan-Meier curves, medians and 95% confidence intervals of the medians 
will be presented for each treatment group. The hazard ratio for OS will be calculated, along 
with its 95% confidence interval, using a stratified Cox model.
OS will be tested hierarchically:

If DFS is statistically significant at the final analysis, OS will be tested. If OS is not 

statistically significant at this stage, an additional IA for OS and a final OS analysis will be 
planned at approximately 418 deaths and 504 deaths respectively. 

If DFS is not statistically significant at the final analysis for DFS, OS will not be tested.
The number of subjects censored and reasons for censoring for OS will be summarized by 
treatment group using descriptive statistics.
10.5.2
Other secondary efficacy objectives
In order to evaluate the effect of canakinumab within PD-L1 subgroups, DFS and OS analyses 
will be performed by PD-L1 subgroups with 1% cut-off on tumor cells (TC) to define positive 
or negative status as determined by IHC. Additionally, PD-L1 subgroups will also be assessed 
using ≥ 50% cut-off. Therefore, a comparison between <1%, ≥1-49%, and ≥ 50% PD-L1 
expression level subgroups will be done.
In order to evaluate the effect of canakinumab within CD8 subgroups, DFS and OS analyses 
will be performed by CD8 subgroups with the median and quartiles (including quartile-
complements, e.g. below lower quartile and above lower quartile) of baseline CD8 as cut-offs.
In addition, the relation between CD8 expression in resected tumor sample and clinical outcome 
will be evaluated using CD8 as continuous, potentially log-transformed, co-variate as well as 
categorical covariates in a Cox model. These analyses will support the establishment of CD8 as 
a prognostic/predictive factor if there is an expressions level correlating to clinical outcome.
Lung cancer specific survival (LCSS) is defined as the time from the date of randomization to
the date of death due to lung cancer. Analyses will be based on the FAS population according 
to the randomized treatment group and strata assigned at randomization. The LCSS distribution 
will be estimated using the Kaplan-Meier method, and Kaplan-Meier curves, medians and 95% 
confidence intervals of the medians will be presented for each treatment group. The hazard ratio 
for LCSS will be calculated, along with its 95% confidence interval, using a stratified Cox 
model. 


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10.5.3
Safety objectives
10.5.3.1 Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment arm.
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 
study medication
2. on-treatment period: from day of first dose of study treatment to 130 days after last dose of 
study treatment 
3. post-treatment period: starting at day 131 after last dose of study treatment.
10.5.3.2 Adverse events (AEs)
Summary tables for adverse events (AEs) will include only AEs with onset date during the on-
treatment period, the treatment-emergent AEs.
The incidence of treatment-emergent adverse events will be summarized by system organ class 
and or preferred term, severity (based on CTCAE grades), type of adverse event, and relation 
to study treatment.
Serious adverse events, non-serious adverse events and adverse events of special interest
(AESI) during the on-treatment period will be tabulated. AESIs will be defined based on the 
current case retrieval strategy (CRS).
All reported deaths (on-treatment and post-treatment) will be summarized.
All AEs, deaths and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those starting during the pre-treatment and post-treatment period will 
be flagged.
10.5.3.3 Laboratory abnormalities
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account.
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
For laboratory tests where grades are not defined by CTCAE 5.0, results will be categorized as 
low/normal/high based on laboratory normal ranges. If required, for certain laboratory 
parameter, values lower than lower limit of normal (LLN) or higher than upper limit of normal 
(ULN) may further be summarized into categories based on multiples of LLN or ULN 
respectively.  
The following listings/summaries will be generated separately for hematology, and 
biochemistry tests:


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
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 analyses if needed, 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.
10.5.3.4 Other safety data
ECG
Notable ECG data will be summarized by treatment. In addition, a listing of these subjects will 
be produced by treatment arm with notable values flagged.
Vital signs
Notable vital signs will be summarized by treatment. In addition, a listing of these subjects will 
be produced by treatment arm with notable values flagged.
10.5.3.5 Supportive analyses for secondary objectives 
If the primary analysis on OS is statistically significant, subgroup analyses to assess the 
homogeneity of the treatment effect across demographic and baseline disease characteristics 
will be performed. The subgroups to be considered will be defined in the SAP.
10.5.3.6 Tolerability
Not applicable
10.5.4
Pharmacokinetics, 
 and immunogenicity
PAS will be used in the pharmacokinetic data analysis. Descriptive statistics (n, m (number of 
non-zero concentrations), mean, CV%, SD, median, geometric mean, geometric CV%, 
minimum and maximum) for canakinumab concentrations will be presented at each scheduled 
timepoint. For canakinumab, pre-dose concentrations collected before dose administration on 
Day 1 of Cycle 2 and beyond are Ctrough.
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The FAS will be used for analyzing PRO data. Time to definitive 10 point deterioration 
symptom scores of pain, cough and dyspnea per QLQ-LC13 questionnaire are primary PRO
variables of interest. Time to first 10 point deterioration symptom scores of pain, cough and 
dyspnea per QLQ-LC13 questionnaire, time to first 10 point deterioration of global health 
status/QoL, shortness of breath and pain per QLQ-C30 questionnaire, time to 10 point definitive 
deterioration of global health status/QoL, shortness of breath and pain per QLQ-C30 together 
with the utilities derived from EQ-5D-5L are secondary PRO variables of interest.
Time to deterioration in symptoms and in global health status/QoL are defined as follows:

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, whichever occurs earlier. If a subject has not had 
an event, time to definitive deterioration will be censored at the date of the last adequate 
assessment. The distribution will be presented descriptively 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 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.

Thetime to first 10 point deterioration is defined as the time from the date of randomization 
to the first onset of at least 10 points absolute increase from baseline (worsening) in 
symptoms scores or at least 10 points absolute decrease from baseline (worsening) in global 
health status/QoL, or death due to any cause, whichever occurs earlier. If a subject has not 
had an event, time to deterioration will be censored at the date of the last adequate 
assessment. The distribution will be presented descriptively using Kaplan-Meier curves. 
Summary statistics from Kaplan-Meier distributions will be determined, including the 
median time to 10 point deterioration along with two-sided 95% confidence interval. 
Additionally, time to first deterioration with different definitions 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 QLQC30/ QLQ-LC13 and EQ-5D-5L at each scheduled assessment time point 
for each treatment group. Additionally, change from baseline in the scale and subscale values 
at the time of each assessment will be summarized. 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 time point. 
No formal statistical tests will be performed for PRO data and hence no multiplicity adjustment 
will be applied. The FAS will be used for analyzing PRO data.


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In addition, a repeated measurement analysis model will be used to compare the treatment 
groups with respect to changes in all domain scores of the EORTC QLQ-C30/QLQ-LC13 as 
well as the thermometer and utility scores of the EQ-5D-5L, longitudinally over time. The 
differences in least square means between the treatment arms and corresponding 95% 
confidence interval at selected time points will be presented. Details, including handling of 
missing data, will be specified in the SAP.
 


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10.7
Interim analysis
10.7.1
Disease free survival (DFS)
One interim analysis is  planned after approximately 196  of the approximately 392 targeted 
DFS events (i.e., at approximately 50%  information fraction) have been documented.  The 
primary intent of the  interim analysis is to stop early for lack of efficacy (futility). There is no 
intent to carry out an analysis to declare superior efficacy at the time of the  interim analysis. 
An α-spending function according to a two-look (Lan-DeMets) group sequential design with 
(O’Brien-Fleming) type stopping boundary (as implemented in East 6.4) will be used to 
construct the efficacy stopping boundaries (Lan and DeMets 1983). A user-defined gamma 
function with γ=-3 stopping boundary as implemented in East 6.4 will be used as a β-spending 
function to determine the non-binding futility boundary. The choice of non-binding nature of 
the futility stopping boundary ensures that the efficacy stopping boundaries are not affected. 
Based on the choice of α-spending and β-spending function described above and if the  interim 
analysis is performed exactly at 196 DFS events, the futility boundary expressed on the p-value 


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scale (or the Z-statistic scale) at the first interim is calculated as p = 0.411 (or Z =  0.226). The 
observed (i.e., nominal) p-value has to be greater than p-value scale futility boundary = 0.411 
(or the observed Z-statistic has to be < Z-statistic scale boundary =   0.226) to conclude futility. 
Since the observed number of events at the interim analysis may not be exactly equal to the 
planned 196  DFS events, the futility boundary will need to be recalculated using the pre-
specified α and β-spending functions and based on the actual number of observed events at 
interim and the total number of targeted events to calculate the exact information fraction. The 
observed p-value (or Z-test statistic) at the interim analyses will then be compared against the 
re-calculated  futility boundary.
If the study continues to the final DFS analysis, the final DFS analysis will be performed when 
approximately 392 DFS events have been documented. If exactly 196 events are observed at 
the interim analysis, the study continued and exactly 392 events are obtained at the final 
analysis, the observed p-value will have to be less than   0.024 (or the observed Z statistics has 
to be  > 1.969) to declare statistical significance. In practice, the final analysis will be based on 
the actual number of DFS events documented at the cut-off date for the final DFS analysis and 
α already spent at the interim analysis. 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 0.025.
The statistical properties of the group sequential design are summarized for DFS in Table 10-1
below.
Table 10-1
Simulated probabilities to stop for futility or efficacy at the interim or 
final DFS analysis
Scenario
Look
# DFS 
events
Simulated cumulative 
probabilities (%)
Simulated incremental 
probabilities (%)
Stop for 
efficacy
Stop for
futility
Stop for 
efficacy
Stop for 
futility
Under H01 (HR=1)
1st IA (futility)
196
-
59.34
-
59.34
Final
392
2.36
-
2.18
-
Under Ha1
(HR=0.716)
1st IA (futility)
196
-
1.83
-
1.83
Final
392
89.56
-
63.7
-
Under HR=0.8
1st IA (futility)
196
-
9.28
-
9.28
Final
392
58.65
-
50.49
-
Note: Simulation is performed in East 6.4 with number of simulations = 10,000 and 
randomization seed = 1234
The interim analysis will be performed by an independent statistician (not involved with the 
conduct of the study). Further details will be described in the DMC charter. The results of the 
interim analysis will be provided to the DMC by the independent statistician.
10.7.2
Key secondary endpoint: Overall survival (OS)
A hierarchical testing procedure will be adopted and the statistical tests for OS will be 
performed only if the primary efficacy endpoint DFS is statistically significant. 


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A maximum of three analyses are planned for OS; at the time of the final analysis for DFS 
(provided DFS is statistically significant), at which point a total of approximately  318 (63%) 
deaths are expected, an additional IA for OS when a total of approximately 418 (83%) deaths 
are expected (expected 52 months from the date of the first subject being randomized), and a 
final analysis for OS when approximately 504 deaths are expected (expected 63 months from 
the date of the first subject being randomized). 
An α-spending function according to Lan-DeMets (O’Brien-Fleming) as implemented in East 
6.4 (Lan and DeMets 1983), independent of the one used for the DFS,  along with the testing 
strategy outlined below will be used to maintain the overall type I error probability. This 
guarantees the protection of the 2.5% overall level of significance across the two hypotheses 
and the repeated testing of the OS hypotheses in the interims and the final analysis 
(Glimm 2010). 
The trial allows for the stopping of the study for a superior OS result, provided the primary 
endpoint DFS has already been shown to be statistically significant favoring the test treatment 
arm. Further, the exact nominal p-values that will need to be observed to declare statistical 
significance at the time of these analyses for OS will depend on the number of OS events that 
have been observed at the time of these analyses and the α for OS already spent at the time of 
earlier analyses.
The projected timing of interim analysis is summarized in Table 10-2. 
At the time of final DFS analysis, both DFS and interim OS analysis will be performed by the 
Sponsor's clinical team. Investigators and subjects will remain blinded to study treatment and 
all subjects will continue to be followed for OS until the final OS analysis (or earlier if OS 
reaches statistical significance at any of the interim analyses).
The statistical properties of the group sequential design are summarized for OS in Table 10-2
below.
Table 10-2
Simulated cumulative power to stop for efficacy on overall survival at 
final DFS analysis or final OS analysis
Look
Months after 
randomization of 
the first subject 
(approximation)
# DFS 
Events
Cumulative 
power against 
a hazard ratio 
of  0.716
# OS
Events
Cumulative 
powerb
against a 
hazard ratio 
of 0.776
1st DFS IA 
(futility)
27
196 (50.0%)
-
-
-
Final DFS
42
392 (100%)
89.56%
318 (63.1%)a
36.26%
OS IA
52
-
-
418 (82.9%)a
64.09%
Final OS
63
-
-
504 (100%)a
79.25%
a: To be performed only if the final DFS analysis is significant
b: Power conditional on DFS being significant
Simulations performed in East 6.4 with number of simulations = 10,000 and randomization seed =1234.


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10.8
Sample size calculation
The sample size calculation is based on the primary variable DFS. The hypotheses to be tested 
and details of the testing strategy are described in Sections 10.4.2 and Section 10.7.1. 
Based on available data, the median DFS in the placebo arm is expected to be around 48 months 
(Kelly 2015). It is expected that treatment with canakinumab will result in a 28.4% reduction 
in the hazard rate for DFS (corresponding to an increase in median DFS from 48 months to 67 
months under the exponential model assumption). 
Then, in order to ensure 90.4% power to test the null hypothesis: DFS hazard ratio = 1, versus 
the specific alternative hypothesis: DFS hazard ratio = 0.716, it is calculated that a total of 392 
DFS events need to be observed. This calculation assumes analysis by a one-sided log-rank test 
at the overall 2.5% level of significance, subjects randomized to the two treatment groups in a 
1:1 ratio, and a 2-look group sequential design with a Lan-DeMets (O’Brien-Fleming) α-
spending function and a user-defined gamma function (with γ=-3) β-spending function to 
define a non-binding futility rule at the interim analyses, using an information fraction of 50% 
for the interim analysis (futility only) . Assuming that enrolment will continue for 
approximately 30 months at a rate of 50 subjects per month and a 5% yearly dropout rate by the 
time of the final DFS analysis,  approximately 1500 subjects may  be randomized to observe 
the targeted 392 DFS events at about 12 months after the randomization date of the last subject, 
i.e., 42 months after the randomization date of the first subject. It is required that all enrolled 
subjects have a minimal efficacy follow-up of 3 months to ensure all subjects have at least one 
post-baseline recurrence assessment. These calculations were made using the software package 
East 6.4.
10.9
Power for analysis of key secondary variables
OS, as the key secondary variable, will be formally statistically tested, provided that the primary 
variable DFS is statistically significant. The hypotheses to be tested and details of the testing 
strategy are provided in Section 10.5.1 and Section 10.7.2. Based on available data, the median 
OS in the placebo arm is expected to be approximately 5 years (Pignon 2008). In addition, the 
OS result presented in Kelly (2015) was not mature as the median was not reached at 5 years, 
but the overall trend indicates a median OS greater than 5 years. After taking these into 
consideration, the median OS for the placebo arm is assumed to be approximately 66 months.
It is hypothesized that treatment with canakinumab will result in a 22.4% reduction in the hazard 
rate for OS, i.e., an expected hazard ratio of 0.776 (which corresponds to an increase in median 
66 to 85 months under the exponential model assumption). Then, in order to ensure 80% power 
to test the null hypothesis: OS hazard ratio = 1, versus the specific alternative hypothesis: OS 
hazard ratio = 0.776, it is calculated that a total of 504 deaths need to be observed. This 
calculation assumes analysis by a one-sided log-rank test at the overall 2.5% level of 
significance, subjects randomized to the two treatment arms in a 1:1 ratio, and a 3-look group
sequential design with a Lan-DeMets (O’Brien-Fleming) α-spending function using 
information fractions of 63%, 83% and 100%. Based on the same number of subjects that are 
planned to be enrolled in this study to provide sufficient power for the primary endpoint (i.e., 
1500 subjects), and assuming losses to follow-up for OS of 3% yearly, it is estimated that these 
504 deaths will be observed approximately 63 months after the randomization date of the first 
subject. Therefore the cut-off date for the final analysis of OS will be approximately 21 months 


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after the cut-off date for the final analysis of DFS. These calculations were made using the 
software package East 6.4.
10.10
Sample size consideration in the sub-study
Enrollment into the sub-study will end when the enrollment into the main study has been 
completed. This section explores the impact of different sample sizes on testing DFS hypotheses 
in biomarker subgroups.
It is assumed that canakinumab will result in a 28.4% reduction in hazard rate for DFS (hazard 
ratio of 0.716) in the biomarker subgroup of interest assessed at pre/post-surgery and 
approximately 50% enrolled subjects in the sub-study are expected to be randomized in the 
main study. Assuming an equal distribution of subjects across the biomarker subgroups of 
interest and a similar DFS event rate (~26%) from all randomized subjects is expected to be 
observed in the biomarker subgroup of interest, Table 10-3 shows the power to reject the null 
hypothesis H0: DFS hazard ratio = 1, versus the specific alternative hypothesis H1: DFS hazard 
ratio = 0.716 in the biomarker subgroup of interest for different sample sizes in the sub-study 
at a one-sided 2.5% level of significance without any multiplicity consideration for control of 
overall type 1 error.
Table 10-3
Power to reject the null hypotheses in the biomarker subgroup of 
interest for different sample sizes in the sub-study
Sample size in the 
sub-study
Number of 
subjects from sub-
study randomized 
in the main study
Biomarker 
subgroup sample 
size
Number of DFS 
events in the 
biomarker subgroup
Power to reject the 
null hypothesis for 
DFS in the 
biomarker group
2000
1000
500
131
48%
1800
900
450
118
44%
1500
750
375
98
38%
1200
600
300
79
32%
1000
500
250
65
27%
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 


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protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
subject. In cases where the subject’s representative gives consent, the subject should be 
informed about the study to the extent possible given his/her understanding. If the subject is 
capable of doing so, he/she should indicate assent by personally signing and dating the written 
informed consent document or a separate assent form.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the subject source documents. The date when a subject’s Informed Consent was 
actually obtained will be captured in their eCRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH E6 GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication 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 requirement for the 
duration of the study. If there is any question that the subject will not reliably comply, they 
should not be entered in the study.
As per Section 2.7, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster, that 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 heath 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.).  
Additional consent form
Sub-studies and studies with an optional Exploratory Biomarker component will have a separate 
consent form covering those studies. This form will be adapted for each study based on a 
standard template used globally for all studies. These informed consent forms will be submitted 
for ethical approval together with the Study Protocol and the main informed consent form of 
the study. If a subject opts not to participate in the optional assessments, this in no way affects 
the subject’s ability to participate in the main research study.


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11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 4.4.
11.5
Publication of study protocol and results
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g. wwwclinicaltrials.gov before study start. 
In addition, results of interventional clinical trials in adult subjects are posted on 
wwwnovartisclinicaltrials.com, a publicly accessible database of clinical study results within 1 
year of study completion (i.e., LPLV), those for interventional clinical trials involving pediatric 
subjects within 6 months of study completion.
Novartis follows the ICMJE authorship guidelines (wwwicmje.org) and other specific 
guidelines of the journal or congress to which the publication will be submitted
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no honorarium 
provided for such presentations.
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable.
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to wwwnovartis.com.
Any data analysis carried out independently by the Investigator should be submitted to Novartis 
before publication or presentation.
Summary results of primary and secondary endpoints will be disclosed based upon the global 
Last Patient Last Visit (LPLV) date, since multinational studies are locked and reported based 
upon the global LPLV.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 


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of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (eCRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the eCRFs and all other required reports. Data reported 
on the eCRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the eCRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper eCRF 
should be dated, initialed, and explained (if necessary) and should not obscure the original entry. 
For electronic eCRFs an audit trail will be maintained by the system. The investigator should 
retain records of the changes and corrections to paper CRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
11.7
Confidentiality of study documents and subject records
The investigator must ensure anonymity of the subjects; subjects must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and subject 
enrollment log must be kept strictly confidential to enable subject identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of subjects at the site - prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 


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to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for subject safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any subject included in this study, even if this action represents a deviation from the protocol. 
In such cases, Novartis should be notified of this action and the IRB/IEC at the study site should 
be informed according to local regulations (e.g. UK requires the notification of urgent safety 
measures within 3 days) but not later than 10 working days.


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13
References (available upon request)
Aaronson N.K. et al. The European organization for research and treatment of cancer QLQ-
C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl 
Cancer Inst 1993;85(5):365-76.
AJCC Cancer Staging Manual. 8th ed. New York: Springer; 2017.
Alifano M, Falcoz P, Seeger V, Roche N, Schusska O et al. Pre-Resection serum C-Reactive 
Protein Measurement and Survival of Subjects with Resectable NCSLC. J Thorac Cardiovasc 
Surg. 2011;142:1161-7.
Antonia SJ et al. Duvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. 
N Engl J Med DOI: 2017;10.1056/NEJMoa1709937
Apte R.N. et al. Effects of micro-environment and malignant cell-derived interleukin-1 in 
carcinogenesis, tumor invasiveness and tumor-host interactions. European Journal of Cancer 
2006;42:751-759.
Arriagada R. et al. Long-term results of the international adjuvant lung cancer trial evaluation 
adjuvant cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol 2009;28:35-42.
Becker Y. Molecular immunological approaches to biotherapy of human cancers – a review, 
hypothesis and implications. Anticancer research 2006;26:1113-1134.
Bergman B. et al. The EORTC QLC-LC13: a modular supplement to the EORTC core quality 
of life questionnaire (QLQ-C30) for use in lung cancer clinical trials. EORTC study group on 
quality of life. Eur J Cancer 1994;30A(5):635-42.
Bracke  KR, D’Hulst AI, Maes T et al. Cigarette smoke-induced pulmonary inflammation and 
emphysema are attenuated in CCR-6 deficient mice. J Immunol 2006; 177: 4350-4359.
Cancer Facts and Figures 2012 American Cancer Society at wwwACS.org
Chaturvedi A.K. et al. C-reactive protein and risk of lung cancer. J Clin Oncol 
2010;28(16):2719-26.
Dalgliesh AG and O’Byrne KJ. Cancer Treat Res 2006; 130:1-38.
Dinarello C.A. Anti-inflammatory agents: present and future. Cell 2010;140(6):935-950.
Douillard J.Y. et al. Adjuvant vinorelbine plus cisplatin versus observation in subjects with 
completely resected stage IB–IIIA non-small celllung cancer (Adjuvant Navelbine 
International Trialist Association [ANITA]): a randomised controlled trial. Lancet oncology 
2006;7:719-27.
Duewell P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by 
cholesterol crystals. Nature 2010;464(7293):1357-61.
El-Refai S.M. et al. Epidemiologic analysis along the mevalonate pathway reveals improved 
cancer survival in subjects who receive statins alone and in combination with 
bisphosphonates. Clin Cancer Inform 2017 DOI: 10.1200/CCI.17.00010.
EuroQol Group. EuroQol – a new facility for the measurement of health-related quality of 
life. Health Policy. 1990;16(3):199-208.


Novartis
Confidential
Page 137 of 144
Amended Protocol Version 03 (Clean)
Protocol No. CACZ885T2301
Fayers P.M. et al. on behalf of the EORTC Quality of Life Group. The EORTC QLQ-C30 
Scoring Manual (3rd edition). Published by: European Organization for Research and 
Treatment of Cancer, Brussels 2001.
Fearon W.F. et al. Inflammation and cardiovascular disease : role of the interleukin-1 receptor 
antagonist. Circulation 2008;117:2577-79.
Felip E, Altorki N, Zhou C, et al (2021) Adjuvant atezolizumab after adjuvant chemotherapy 
in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, 
multicentre, open-label, phase 3 trial.  Lancet; 398: 1344–57.
Fleming TR, Harrington DP and O’Brien PC, Designs for group sequential tests. Controlled 
Clinical Trials, 5, 1984; 348-361.
Fumet J-D, Richard C, Ledys F, et al (2018) Prognostic and predictive role of CD8 and PD-
L1 determination in lung tumor tissue of patients under anti-PD-1 therapy. British Journal of 
Cancer; 119: 950–60.
Glimm, E., Maurer, W. and Bretz, F. (2010) Hierarchical testing of multiple endpoints in group-
sequential trials, Statist. Med. 2010, 29, 219-228
Globocan 2012 Cancer Statistics at wwwGlobocan.iarc.fr
Goldstraw P. et al. The IASLC lung cancer staging project: proposals for revision of the TNM 
stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer. 
Journal of Thoracic Oncology 2016;11(1):39-51.
Hara M, Yonei A, Ayabe T, Tomita M, Nakamura K, and Onitsuka T. Post-Operative Serum 
C-Reactive Protein Levels in Non-Small Cell Lung cancer Subjects. Thorac. Cardiovasc. 
Surg. 2010; 16:85-91.
Herdman M. el al. Development and preliminary testing of the new five-level version of EQ-
5D (EQ-5D-5L).  Qual Life Res 2011;20(10):1727-36.
International adjuvant lung cancer trial collaborative group. Cisplatin-based adjuvant 
chemotherapy in subjects with completely resected non-small-cell lung cancer. N Engl J Med 
2004;350:351-60.
Jemal A. et al. Global cancer statistics. CA Cancer J Clin 2011;61:69-909.
Jenkins BJ. Potential Benefit of IL-1β Inhibition in Lung Cancer. Lancet. 2017 in comments  
published on line 27 Aug 2017. httpdxdoiorg/10.1016/S0140-6726(17)32289-4.
Kasza A. IL-1 and EGF regulate expression of genes important in inflammation and cancer. 
Cytokine 2013;62:22-33.
Kelly, K. et al. Adjuvant Erlotinib Versus Placebo in Subjects With Stage IB-IIIA Non–Small-
Cell Lung Cancer (RADIANT): A Randomized, Double-Blind, Phase III Trial, Journal of Clinical 
Oncology 2015; 33, no. 34 4007-4014.
Khuder S.A. et al. Nonsteroidal antiinflammatory drug use and lung cancer : a meta-analysis. 
Chest 2005;127(3):748-754.
Krelin Y. et al. Interleukin-1β–driven inflammation promotes the development and 
invasiveness of chemical carcinogen–induced tumors. Cancer Res 2007;67:1062-1071.


Novartis
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Krysan K, Lee JM, Dohadwala M et al. Inflammation, Epilthelial to Mesenchymal Transition, 
and Epidermal Growth Factor Receptor Tyroskinase Inhibitor Resistance. J Thoracic Oncol. 
2008; 3(2):107-110.
Lan, K., and DeMets, D. Discrete sequential boundaries for clinical trials. Biometrika; 1983, 
70:659–663. 
Li, C. & Wang, C. Current evidences on IL1β polymorphisms and lung cancer susceptibility: 
a meta-analysis. Tumour Biol. 2013; 34: 3477–3482.
Li F, Li C, Cai X, et al (2021) The association between CD8+ tumor-infiltrating lymphocytes 
and the clinical outcome of cancer immunotherapy: A systematic review and meta-analysis.
EClinicalMedicine; 41:101134. Mantovani A. Et al. Cancer-related inflammation. Nature 
2008;454:436-444.
NCCN Clinical Practice Guidelines in Oncology for NSCLC version 8 14 July 2017.  
Available at wwwnccn.org/subjects
O’Byrne KJ and Dalgleish AG. Chronic Immune Activation and Inflammation as the Cause of 
Malignancy. Br J Cancer. 2001;85:473-483.
O’Byrne KJ, Dalgleish AG, Browning MJ et al. The Relationship between angiogenesis and 
the immune response in carcinogenesis and the progression of malignant disease. Eur J 
Cancer 2000: 36:151-169.
O’Callaghan DS, O’Donnell D, O’Connell F and O’Byrne KJ. The Role of Inflammation in 
the Pathogenesis of NSCLC. J Thoracic Oncol. 2010; 5(12): 2024-2036.
Oken M.M. et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. 
Am J Clin Oncol 1982;5:649-55.
Pignon, J.P. et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE 
Collaborative Group. J Clin Oncol 2008; Jul 20; 26(21):3552-9.
Postmus, P.E. et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO 
Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 
2017; 28(4):iv1-iv21.
Rajamaki K. et al. Cholesterol crystals activate the NLRP3 inflammasome in human 
macrophages: a novel link between cholesterol metabolism and inflammation. PLoS ONE 
5(7): e11765. doi:10.1371/journal.pone.0011765.
Ridker P.M. et al. Anti-Inflammatory Therapy with Canakinumab for Atherosclerotic Disease. 
N Engl J Med. 2017a;377:1119-1131.
Ridker P.M. et al. Effect of interleukin-1β inhibition with canakinumab on incident lung 
cancer in subjects with atherosclerosis: exploratory results from a randomized, double-blind, 
placebo-controlled trial. 2017b Lancet: published online 27-Aug-2017 httpdx.doi.org/ 
10.1016/S0140-6736(17)32247-X)
Scagliotti G.V. et al. Randomized study of adjuvant chemotherapy for completely resected 
stage I, II, or IIIA non-small-cell lung cancer. Journal of the National Cancer Institute 2003; 
95(19):1453-1461.


Novartis
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Su, S.F. et al. The survival outcomes and prognosis of stage IV non-small-cell lung cancer 
treated with thoracic three-dimensional radiotherapy combined with chemotherapy. Radiation 
Oncology (2014) 9:290.
Vagulien N, Zemaitus M, Miliauskas S, Urboniene D, Sikauskiene B, Sikauskas R 
Comparison of C-Reactive Protein Levels in Cancer and Chronic Obstructive Pulmonary 
Disease. Medicina (Kaunas) 2011; 47(8): 421-7.
Van Reenen M. et al. EQ-5D-5L User Guide – Basic information on how to use the EQ-5D-
5L instrument. httpwww.euroqolorg/fileadmin/user_upload/Documenten/PDF/Folders_ 
Flyers/EQ-5D-5L_UserGuide_2015.pdf.  Accessed Oct 2017.
Vansteenkiste, J.F. et al. Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant 
therapy in subjects with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): 
a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2016; 17: 822–
35.
Voronov E. et al. Effects of IL-1 molecules on growth patterns of 3-MCA-induced cell lines: 
an interplay between immunogenicity and invasive potential. Journal of Immunotoxicology. 
2009;7:1, 27-38.
Wall RJ, Shyr Y and Smalley W. Nonsteroidal anti-inflammatory drugs and lung cancer risk: 
a population-based case control study. J Thoracic Oncol  2007;2: 109-114
WHO Cancer Fact Sheet Feb 2017 at wwwwho.int/mediacentre/factsheets/fs297/en/
Winton T. et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung 
cancer. N Engl J Med 2005;352:2589-97.
Wu T. et al. Modulation of IL-1β re-programs the tumor microenvironment to interrupt oral 
carcinogenesis. Scientific Reports 2016;6, 20208; doi: 10.1038/srep20208.
Yano, S. et al. Multifunctional interleukin-1beta promotes metastasis of human lung cancer 
cells in SCID mice via enhanced expression of adhesion-, invasion- and angiogenesis-related 
molecules. Cancer Sci. 2003; 94: 244–252.




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Storage of the safety syringe
1. Store the safety syringe sealed in its outer box in the refrigerator between 2°C and 8°C (36°F 
and 46°F). DO NOT STORE IT IN THE FREEZER AND PROTECT FROM LIGHT.
2. Remember to take the safety syringe out of the refrigerator and allow it to reach room
temperature before preparing it for injection (15 to 30 minutes).
3. Do not use the safety syringe after the expiration date shown on the outer box or syringe
label. If it has expired, return the entire pack to the pharmacy.
The injection site
The injection site is the place on the body where you are going to use the safety syringe.
Canakinumab can be injected in either the upper outer thigh, abdomen or the upper outer
arm. If you need more than one injection at a time, repeat the injection in the opposite thigh or 
arm.
Preparing the safety syringe ready for use
1. Take the box containing the safety syringe out of the refrigerator and leave it unopened for
about 15 to 30 minutes so that it reaches room temperature.
2. When you are ready to use the safety syringe, wash your hands thoroughly with soap and
water.
3. Clean the injection site with an alcohol swab.
4. Remove the safety syringe from the outer box and take it out of the plastic wrapper.
5. Inspect the safety syringe. DO NOT USE if it is broken or if the liquid has a distinctly brown 
discoloration or contains particles. In all these cases, return the entire product pack to the 
pharmacy.
How to use the safety syringe
Carefully remove the needle
guard from the safety syringe. 
Discard the needle guard
Gently pinch the skin at the
injection site and insert the needle.




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14.2
Appendix 2: AJCC v.8 Prognostic Stage Groups (adapted from 
the AJCC Cancer Staging Manual 2017)
When T is...
And N is...
And M is...
Then the stage group 
is...
TX
N0
M0
Occult carcinoma
Tis
N0
M0
0
T1mi
N0
M0
IA1
T1a
N0
M0
IA1
T1a
N1
M0
IIB
T1a
N2
M0
IIIA
T1a
N3
M0
IIIB
T1b
N0
M0
IA2
T1b
N1
M0
IIB
T1b
N2
M0
IIIA
T1b
N3
M0
IIIB
T1c
N0
M0
IA3
T1c
N1
M0
IIB
T1c
N2
M0
IIIA
T1c
N3
M0
IIIB
T2a
N0
M0
IB
T2a
N1
M0
IIB
T2a
N2
M0
IIIA
T2a
N3
M0
IIIB
T2b
N0
M0
IIA
T2b
N1
M0
IIB
T2b
N2
M0
IIIA
T2b
N3
M0
IIIB
T3
N0
M0
IIB
T3
N1
M0
IIIA
T3
N2
M0
IIIB
T3
N3
M0
IIIC
T4
N0
M0
IIIA


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Amended Protocol Version 03 (Clean)
Protocol No. CACZ885T2301
T4
N1
M0
IIIA
T4
N2
M0
IIIB
T4
N3
M0
IIIC
Any T
Any N
M1
IV
Any T
Any N
M1a
IVA
Any T
Any N
M1b
IVA
Any T
Any N
M1c
IVB

SAP_001.pdf: 
Clinical Development
ACZ885 (Canakinumab)
CACZ885T2301 / NCT03447769
A phase III, multicenter, randomized, double blind, placebo-
controlled study evaluating the efficacy and safety of 
canakinumab versus placebo as adjuvant therapy in adult 
subjects with stages AJCC/UICC v. 8 II-IIIA and IIIB (T>5cm 
N2) completely resected (R0) non-small cell lung cancer 
(NSCLC)
Statistical Analysis Plan (SAP) for close-out CSR
Author: 
Trial Statistician
Document type:
SAP Documentation
Document status:
Final
Release date:
03-Mar-2023
Number of pages:
10
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Template Document History – Changes compared to previous version
Date
Version 
number
Summary of changes
03-Mar-2023
1.0
N/A


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Table of contents
Template Document History – Changes compared to previous version .............................2
Table of contents .................................................................................................................3
1
Introduction .........................................................................................................................4
2
Planned tables, figures and listings .....................................................................................4


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1
Introduction
This statistical analysis plan (SAP) describes all planned analyses for the close-out clinical 
study report (CSR) of study CACZ885T2301, a phase III, multicenter, randomized, double 
blind, placebo-controlled study evaluating the efficacy and safety of canakinumab versus 
placebo as adjuvant therapy in adult subjects with stages American Joint Committee on Cancer 
(AJCC)/Union for International Cancer Control (UICC) v8 II-IIIA and IIIB (T > 5cm N2) 
completely resected (R0) non-small cell lung cancer (NSCLC).
The statistical methods for the study are documented in full in the SAP for the primary analysis 
CSR [CACZ885T2301 SAP Amendment 3 dated 21-Mar-2022]. The results of the primary and 
secondary endpoint data collected at the primary analysis cut-off date are described in the 
[CACZ885T2301 Primary Analysis CSR]. 
The close-out CSR will present the results of cumulative study data for secondary endpoints for 
which additional data were collected between the primary analysis cut-off date and the LPLV 
date. Thus the outputs planned for the close-out CSR will be a subset of the outputs planned for 
the primary analysis CSR that need to be updated after the primary analysis data cut-off date. 
The list of outputs planned for the close-out CSR is specified in Section 2. 
The primary endpoint was not met for this study as described in the [CACZ885T2301 Primary 
Analysis CSR]; therefore, no formal statistical analysis will be performed for this close-out 
CSR. The outputs for the close-out CSR consist mainly of summary tables prepared using 
descriptive statistics as well as data listings.
2
Planned tables, figures and listings
The table below provides the list of outputs that need to be generated, with additional guidelines 
added under ‘Notes’. Please follow the in-text layout given below, post-text output has been 
added for reference. 
Add footnote: CACZ885T2301- Cut-off date: 07Feb2023                                                                          
Output 
Number in 
close-out CSR
Output title in close-out CSR
Output 
number in 
primary CSR
Output title in primary CSR
Notes
Table 2-1
Subject disposition (Full analysis 
set)
Table 10-1
Subject disposition (Full 
analysis set)
Table 2-2
Protocol deviation (≥0.4% for 
any treatment arm) (Full analysis 
set)
Table 10-2
Protocol deviation (≥0.4% for 
any treatment arm) (Full 
analysis set)
Table 2-3
Duration of exposure to study 
drug (Safety set)
Table 10-7
Duration of exposure to study 
drug (Safety set)
Table 2-4
Dose of study drug received 
(Safety set)
Table 10-8
Dose of study drug received 
(Safety set)
Table 2-5
Dose interruptions and 
discontinuation of study drug 
(Safety set)
Table 10-9
Dose interruptions and 
discontinuation of study drug 
(Safety set)
Table 2-6
Summary of overall survival by 
study arm (Full analysis set)
Table 11-3
Summary of overall survival by 
study arm (Full analysis set)


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Table 2-6a
Summary of overall survival by 
study arm and baseline PD-L1 
subgroup (Baseline PD-L1: < 
1% vs. >= 1%) (Full analysis
set)
Table 11-3a
Summary of overall survival by 
study arm and baseline PD-L1 
subgroup (Baseline PD-L1: < 
1% vs. >= 1%) (Full analysis 
set)
Table 2-6b
Summary of overall survival by 
study arm and baseline PD-L1 
subgroup (Baseline PD-L1: < 
1% vs. >= 1% and < 49% vs. >= 
50%) (Full analysis set)
Table 11-3b
Summary of overall survival by 
study arm and baseline PD-L1 
subgroup (Baseline PD-L1: < 
1% vs. >= 1% and < 49% vs. 
>= 50%) (Full analysis set)
Table 2-6c
Summary of overall survival by 
study arm and baseline PD-L1 
subgroup (Baseline PD-L1: < 
50 % vs. >= 50%) (Full analysis 
set)
Table 11-3c
Summary of overall survival by 
study arm and baseline PD-L1 
subgroup (Baseline PD-L1: < 
50 % vs. >= 50%) (Full 
analysis set)
Table 2-6d
Summary of overall survival by 
study arm and median of 
baseline CD8 subgroup (Full 
analysis set)
Table 11-3d
Summary of overall survival by 
study arm and median of 
baseline CD8 subgroup (Full 
analysis set)
Table 2-6e
Summary of overall survival by 
study arm and quartile of 
baseline CD8 subgroup (Full 
analysis set)
Table 11-3e
Summary of overall survival by 
study arm and quartile of 
baseline CD8 subgroup (Full 
analysis set)
Table 2-7
Overview of adverse events 
(Safety set)
Table 12-1
Overview of adverse events 
(Safety set)
Table 2-8
Adverse events by system organ 
class (Safety set)
Table 12-2
Adverse events by system 
organ class (Safety set)
Table 2-9
On-treatment deaths by system 
organ class and preferred term
(Safety set)
Table 12-3
On-treatment deaths by system 
organ class and preferred term
(Safety set)
Table 2-10
Most frequently reported serious 
adverse events by preferred term
(≥2.0% all grades, both 
treatment arms) (Safety set)
Table 12-4
Most frequently reported 
serious adverse events by 
preferred term (≥2.0% all 
grades, both treatment arms) 
(Safety set)
Table 2-11
Most frequently reported adverse 
events leading to dose 
interruption, by preferred term 
(≥2.0% all grades, both 
treatment arms) (Safety set)
Table 12-5
Most frequently reported 
adverse events leading to dose
interruption, by preferred term 
(≥2.0% all grades, both 
treatment arms) (Safety set)
Table 2-12
Overview of adverse events of 
special interest (Safety set)
Table 12-6
Overview of adverse events of 
special interest (Safety set)
Table 2-13
Incidence of adverse events of 
special interest – Infections 
(Safety set)
Table 12-7
Incidence of adverse events of 
special interest – Infections 
(Safety set)
Table 2-14
Incidence of adverse events of 
special interest – Opportunistic
infections (Safety set)
Table 12-8
Incidence of adverse events of 
special interest – Opportunistic
infections (Safety set)
Table 2-15
Incidence of adverse events of 
special interest – Abnormal liver
parameters (Safety set)
Table 12-9
Incidence of adverse events of 
special interest – Abnormal 
liver parameters (Safety set)
Table 2-16
Incidence of adverse events of 
special interest – Neutropenia
(Safety set)
Table 12-10
Incidence of adverse events of 
special interest – Neutropenia
(Safety set)


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CACZ885T2301
Table 2-17
Incidence of adverse events of 
special interest –
Thrombocytopenia (Safety set)
Table 12-11
Incidence of adverse events of 
special interest –
Thrombocytopenia (Safety set)
Table 2-18
Incidence of adverse events of 
special interest – Pulmonary
complications, pulmonary 
hypertension and interstitial lung 
disease (Safety set)
Table 12-12
Incidence of adverse events of 
special interest – Pulmonary
complications, pulmonary 
hypertension and interstitial 
lung disease (Safety set)
source: 
Table 
14.3.1-
5.2
Table 2-19
Worst post-baseline hematology 
abnormalities based on CTC
grades (Safety set)
Table 12-13
Worst post-baseline 
hematology abnormalities 
based on CTC grades (Safety 
set)
Table 2-20
Worst post-baseline clinical 
chemistry abnormalities based 
on CTC grades (Safety set)
Table 12-14
Worst post-baseline clinical 
chemistry abnormalities based 
on CTC grades (Safety set)
Table 2-21
Categorical analysis of hepatic 
laboratory values (Safety set)
Table 12-15
Categorical analysis of hepatic 
laboratory values (Safety set)
Table 2-22
Notable vital sign values (Safety 
set)
Table 12-16
Notable vital sign values 
(Safety set)
Table 2-23
Notable ECG values (Safety set)
Table 12-17
Notable ECG values (Safety 
set)
Table 2-24
Canakinumab ADA and NAB 
incidence (Safety set)
Table 12-18
Canakinumab ADA and NAB 
incidence (Safety set)
Figure 2-1
Arithmetic mean (SD) and 
geometric mean concentration-
time profiles
for canakinumab (linear view, 
Pharmacokinetic analysis set)
Figure 11-5
Arithmetic mean (SD) and 
geometric mean concentration-
time profiles for canakinumab 
(linear view, Pharmacokinetic 
analysis set)
Table 14.1-
1.1
Subject disposition (Full analysis 
set)
Table 14.1-
1.1
Subject disposition (Full 
analysis set)
Table 14.1-
1.5
Protocol deviations (Full 
analysis set)
Table 14.1-
1.5
Protocol deviations (Full 
analysis set)
Table 14.2-
2.1
Summary of overall survival by 
study arm (Full analysis set)
Table 14.2-
2.1
Summary of overall survival by 
study arm (Full analysis set)
Table 14.2-
2.1a
Summary of overall survival by 
study arm and baseline PD-L1 
subgroup (Baseline PD-L1: < 
1% vs. >= 1%) (Full analysis 
set)
Table 14.2-
2.1a
Summary of overall survival by 
study arm and baseline PD-L1 
subgroup (Baseline PD-L1: < 
1% vs. >= 1%) (Full analysis 
set)
Table 14.2-
2.1b
Summary of overall survival by 
study arm and baseline PD-L1 
subgroup (Baseline PD-L1: < 
1% vs. >= 1% and < 49% vs. >= 
50%) (Full analysis set)
Table 14.2-
2.1b
Summary of overall survival by 
study arm and baseline PD-L1 
subgroup (Baseline PD-L1: < 
1% vs. >= 1% and < 49% vs. 
>= 50%) (Full analysis set)
Table 14.2-
2.1c
Summary of overall survival by 
study arm and baseline PD-L1 
subgroup (Baseline PD-L1: < 
50 % vs. >= 50%) (Full analysis 
set)
Table 14.2-
2.1c
Summary of overall survival by 
study arm and baseline PD-L1 
subgroup (Baseline PD-L1: < 
50 % vs. >= 50%) (Full 
analysis set)
Table 14.2-
2.1d
Summary of overall survival by 
study arm and median of 
baseline CD8 subgroup (Full 
analysis set)
Table 14.2-
2.1d
Summary of overall survival by 
study arm and median of 
baseline CD8 subgroup (Full 
analysis set)


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Table 14.2-
2.1e
Summary of overall survival by 
study arm and quartile of 
baseline CD8 subgroup (Full 
analysis set)
Table 14.2-
2.1e
Summary of overall survival by 
study arm and quartile of 
baseline CD8 subgroup (Full 
analysis set)
Table 14.2-
3.1
Summary of lung cancer specific 
survival by study arm (Full 
analysis set)
Table 14.2-
3.1
Summary of lung cancer 
specific survival by study arm 
(Full analysis set)
Table 14.2-
4.1
Canakinumab serum
concentrations (Pharmacokinetic 
analysis set)
Table 14.2-
4.1
Canakinumab serum
concentrations 
(Pharmacokinetic analysis set)
Table 14.2-
4.1a
Canakinumab serum 
concentrations by baseline ADA
(Pharmacokinetic analysis set)
Table 14.2-
4.1a
Canakinumab serum 
concentrations by baseline 
ADA
(Pharmacokinetic analysis set)
Table 14.2-
4.1b
Canakinumab serum 
concentrations by on-treatment 
ADA
(Pharmacokinetic analysis set)
Table 14.2-
4.1b
Canakinumab serum 
concentrations by on-treatment 
ADA
(Pharmacokinetic analysis set)
Table 14.2-
4.1c
Canakinumab serum 
concentrations by treatment-
induced ADA
(Pharmacokinetic analysis set)
Table 14.2-
4.1c
Canakinumab serum 
concentrations by treatment-
induced ADA
(Pharmacokinetic analysis set)
Table 14.2-
4.1d
Canakinumab serum 
concentrations by treatment 
boosted ADA (Pharmacokinetic 
analysis set)
Table 14.2-
4.1d
Canakinumab serum 
concentrations by treatment 
boosted ADA (Pharmacokinetic 
analysis set)
Table 14.2-
4.2b
Summary of overall survival by 
the quartile of average steady 
state evaluable Ctrough 
concentration (Pharmacokinetic 
analysis set)
Table 14.2-
4.2b
Summary of overall survival by 
the quartile of average steady 
state evaluable Ctrough 
concentration (Pharmacokinetic 
analysis set)
Table 14.2-
5.1
Summary of EORTC QLQ-C30 
Scores by time point and 
treatment arm (Full analysis set)
Table 14.2-
5.1
Summary of EORTC QLQ-C30 
Scores by time point and 
treatment arm (Full analysis 
set)
Table 14.2-
5.2
Summary of EORTC QLQ-
LC13 Scores by time point and 
treatment arm (Full analysis set)
Table 14.2-
5.2
Summary of EORTC QLQ-
LC13 Scores by time point and 
treatment arm (Full analysis 
set)
Table 14.2-
5.3
Summary of EQ-5D-5L Scores 
by time point and treatment arm 
(Full analysis set)
Table 14.2-
5.3
Summary of EQ-5D-5L Scores 
by time point and treatment 
arm (Full analysis set)
Table 14.2-
6.2
Canakinumab ADA and NAB 
incidence (Safety set)
Table 14.2-
6.2
Canakinumab ADA and NAB 
incidence (Safety set)
Table 14.2-
7.1
Shift table of subjects with 
positive or negative anti-
canakinumab antibodies overall 
and by visit (Full analysis set)
Table 14.2-
7.1
Shift table of subjects with 
positive or negative anti-
canakinumab antibodies overall 
and by visit (Full analysis set)
Table 14.3-
1.1
Duration of exposure to study 
drug (Safety set)
Table 14.3-
1.1
Duration of exposure to study 
drug (Safety set)
Table 14.3-
1.2
Dose of study drug received 
(Safety set)
Table 14.3-
1.2
Dose of study drug received 
(Safety set)


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Table 14.3-
1.3
Interruptions and discontinuation 
of study drug (Safety set)
Table 14.3-
1.3
Interruptions and 
discontinuation of study drug 
(Safety set)
Table 14.3-
3.5
Hematology laboratory results 
by time point (Safety set)
Table 14.3-
3.5
Hematology laboratory results 
by time point (Safety set)
Table 14.3-
3.6
Biochemistry laboratory results 
by time point (Safety set)
Table 14.3-
3.6
Biochemistry laboratory results 
by time point (Safety set)
Table 14.3-
3.7
Categorical analysis of hepatic 
laboratory values (Safety set)
Table 14.3-
3.7
Categorical analysis of hepatic 
laboratory values (Safety set)
Table 14.3-
4.1
Notable vital sign values (Safety 
set)
Table 14.3-
4.1
Notable vital sign values 
(Safety set)
Table 14.3-
5.1
Notable ECG values (Safety set)
Table 14.3-
5.1
Notable ECG values (Safety 
set)
Table 14.3.1-
1.1
Adverse events by system organ 
class and preferred term (Safety 
set)
Table 
14.3.1-1.1
Adverse events by system 
organ class and preferred term
(Safety set)
Table 14.3.1-
1.2
Treatment-related adverse events 
by system organ class and 
preferred term
(Safety set)
Table 
14.3.1-1.2
Treatment-related adverse 
events by system organ class 
and preferred term
(Safety set)
Table 14.3.1-
1.3
Adverse events leading to 
treatment discontinuation, by 
system organ class and preferred 
term (Safety set)
Table 
14.3.1-1.3
Adverse events leading to 
treatment discontinuation, by 
system organ class and 
preferred term (Safety set)
Table 14.3.1-
1.4
Adverse events leading to dose 
interruption, by system organ 
class and preferred term (Safety 
set)
Table 
14.3.1-1.4
Adverse events leading to dose 
interruption, by system organ 
class and preferred term (Safety 
set)
Table 14.3.1-
1.5
Adverse events requiring 
additional therapies, by system 
organ class and preferred term
(Safety set)
Table 
14.3.1-1.5
Adverse events requiring 
additional therapies, by system 
organ class and preferred term
(Safety set)
Table 14.3.1-
1.6
Adverse events leading to fatal 
outcome, by system organ class 
and preferred term (Safety set)
Table 
14.3.1-1.6
Adverse events leading to fatal 
outcome, by system organ class 
and preferred term (Safety set)
Table 14.3.1-
2.1
Non-serious adverse events 
(threshold=5%) by system organ 
class and preferred term (Safety 
set)
Table 
14.3.1-2.1
Non-serious adverse events 
(threshold=5%) by system 
organ class and preferred term 
(Safety set)
Table 14.3.1-
3.1
On-treatment deaths and serious 
adverse events by system organ 
class and preferred term (Safety 
set)
Table 
14.3.1-3.1
On-treatment deaths and 
serious adverse events by 
system organ class and 
preferred term (Safety set)
Table 14.3.1-
3.2
On-treatment deaths, by system 
organ class and preferred term
(Safety set)
Table 
14.3.1-3.2
On-treatment deaths, by system 
organ class and preferred term
(Safety set)
Table 14.3.1-
3.3
All deaths, by system organ 
class and preferred term (Safety 
set)
Table 
14.3.1-3.3
All deaths, by system organ 
class and preferred term (Safety 
set)
Table 14.3.1-
4.1
Serious adverse events by 
system organ class and preferred 
term (Safety set)
Table 
14.3.1-4.1
Serious adverse events by 
system organ class and 
preferred term (Safety set)
Table 14.3.1-
4.1a
Serious adverse events by
system organ class, preferred 
Table 
14.3.1-4.1a
Serious adverse events by
system organ class, preferred 


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term and maximum grade
(Safety set)
term and maximum grade
(Safety set)
Table 14.3.1-
4.2
Treatment-related serious 
adverse events by system organ 
class and preferred term (Safety 
set)
Table 
14.3.1-4.2
Treatment-related serious 
adverse events by system organ 
class and preferred term (Safety 
set)
Table 14.3.1-
4.2a
Treatment-related serious 
adverse events by system organ 
class, preferred term and 
maximum grade (Safety set)
Table 
14.3.1-4.2a
Treatment-related serious 
adverse events by system organ 
class, preferred term and 
maximum grade (Safety set)
Table 14.3.1-
5.1
Overview of adverse events of 
special interest (Safety set)
Table 
14.3.1-5.1
Overview of adverse events of 
special interest (Safety set)
Table 14.3.1-
5.2
Incidence of adverse event of 
special interest (Safety set)
Table 
14.3.1-5.2
Incidence of adverse event of 
special interest (Safety set)
Table 14.3.1-
5.3
Incidence of adverse event of 
special interest including 
preferred term level (Safety set)
Table 
14.3.1-5.3
Incidence of adverse event of 
special interest including 
preferred term level (Safety set)
Figure 2-1
Kaplan-Meier plot of overall 
survival by treatment arm (Full
Analysis Set)
Figure 11-2
Kaplan-Meier plot of overall 
survival by treatment arm (Full
Analysis Set)
Figure 2-2
Forest plot of hazard ratio with 
95% confidence interval for 
overall survival from subgroup 
analysis (Full analysis set)
Figure 11-3
Forest plot of hazard ratio with 
95% confidence interval for 
overall
survival from subgroup 
analysis (Full analysis set)
Figure 14.2-
2.1
Kaplan-Meier plot of overall 
survival by treatment arm (Full
analysis set)
Figure 14.2-
2.1
Kaplan-Meier plot of overall 
survival by treatment arm (Full 
analysis set)
Figure 14.2-
2.2
Forest plot of hazard ratio with 
95% confidence interval for 
overall survival from subgroup 
analysis (Full analysis set)
Figure 14.2-
2.2
Forest plot of hazard ratio with 
95% confidence interval for 
overall survival from subgroup 
analysis (Full analysis set)
Figure 14.2-
4.2
Arithmetic mean (SD) and 
geometric mean concentration-
time
profiles for canakinumab 
(Pharmacokinetic analysis set)
Figure 14.2-
4.2
Arithmetic mean (SD) and 
geometric mean concentration-
time
profiles for canakinumab 
(Pharmacokinetic analysis set)
Listing 
16.2.1-1.2
Subject disposition (Full analysis 
set)
Listing 
16.2.1-1.2
Subject disposition (Full 
analysis set)
Listing 
16.2.2-1.1
Protocol deviations (Full 
analysis set)
Listing 
16.2.2-1.1
Protocol deviations (Full 
analysis set)
Listing 
16.2.7-1.1
Adverse events (Safety set)
Listing 
16.2.7-1.1
Adverse events (Safety set)
Listing 
16.2.8-1.1
Subject laboratory profile: 
Hematology (Safety set)
Listing 
16.2.8-1.1
Subject laboratory profile: 
Hematology (Safety set)
Listing 
16.2.8-1.2
Subject laboratory profile: 
Biochemistry - Liver (Safety set)
Listing 
16.2.8-1.2
Subject laboratory profile: 
Biochemistry - Liver (Safety 
set)
Listing 
16.2.8-1.3
Subject laboratory profile: 
Biochemistry - Renal (Safety 
set)
Listing 
16.2.8-1.3
Subject laboratory profile: 
Biochemistry - Renal (Safety 
set)
Listing 
16.2.8-1.4
Subject laboratory profile: 
Biochemistry - Other (Safety set)
Listing 
16.2.8-1.4
Subject laboratory profile: 
Biochemistry - Other (Safety 
set)


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Listing 
16.2.8-2.1
Canakinumab ADA sample 
status – subjects treated with 
Canakinumab (Safety set)
Listing 
16.2.8-2.1
Canakinumab ADA sample 
status – subjects treated with 
Canakinumab (Safety set)
Listing 
16.2.8-2.2
Canakinumab ADA samples 
status for subjects with 
neutralizing antibodies (NAB) 
testing results – subjects treated 
with Canakinumab (Safety set)
Listing 
16.2.8-2.2
Canakinumab ADA samples 
status for subjects with 
neutralizing antibodies (NAB) 
testing results – subjects treated 
with Canakinumab (Safety set)
Listing 
16.2.9-1.1
Vital signs (Safety set)
Listing 
16.2.9-1.1
Vital signs (Safety set)
Listing 
16.2.9-1.2
ECG values (Safety set)
Listing 
16.2.9-1.2
ECG values (Safety set)
Listing 14.2-
1.2
Overall survival (Full analysis 
set)
Listing 14.2-
1.2
Overall survival (Full analysis 
set)
Listing 14.2-
1.3
Lung cancer specific survival 
(Full analysis set)
Listing 14.2-
1.3
Lung cancer specific survival 
(Full analysis set)
Listing 14.2-
1.4
Serum PK concentrations for 
canakinumab (Full analysis set)
Listing 14.2-
1.4
Serum PK concentrations for 
canakinumab (Full analysis set)
Listing 
14.3.2-1.1
Deaths (Safety set)
Listing 
14.3.2-1.1
Deaths (Safety set)
Listing 
14.3.2-1.3
Serious adverse events (Safety 
set)
Listing 
14.3.2-1.3
Serious adverse events (Safety 
set)
Listing 
14.3.2-1.4
Adverse events leading to 
discontinuation (Safety set)
Listing 
14.3.2-1.4
Adverse events leading to 
discontinuation (Safety set)
Listing 
14.3.2-1.5
Adverse events leading to dose 
interruptions (Safety set)
Listing 
14.3.2-1.5
Adverse events leading to dose 
interruptions (Safety set)
Listing 
14.3.2-1.6
Adverse events of special 
interest (Safety set)
Listing 
14.3.2-1.6
Adverse events of special 
interest (Safety set)
Listing 
14.3.4-1.1
CTC grade 3 or 4 laboratory 
values (Safety set)
Listing 
14.3.4-1.1
CTC grade 3 or 4 laboratory
values (Safety set)
Listing 
14.3.4-1.2
Patients with a post-baseline 
TBILI > 2xULN, or ALT> 
3xULN or AST > 3xULN
(Safety set)
Listing 
14.3.4-1.2
Patients with a post-baseline 
TBILI > 2xULN, or ALT> 
3xULN or AST > 3xULN
(Safety set)




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Document History – Changes compared to previous final version of SAP
Date
Section
Changes
14-Mar-2018
N/A- First version
10-Mar-2021
Section 1
Updated according to the latest protocol amendment version 02 prior to DFS futility 
analysis
Section 1.1
Added ‘The interim analysis for efficacy will only be carried out after all subjects 
have been randomized and have at least one post-baseline efficacy assessment if 
not withdrawn early’.
Updated standard care: ‘ at a minimum of two cycles of cisplatin are required’ and 
‘radiation therapy is allowed if indicated as per local guidance or practice’ 
Section 1.2
Removed approximate timings of DFS and OS analysis as they were no longer 
accurate given slower than expected enrollment rate. This update applied 
throughout the document
Section 2.1.1
Removed ‘End of treatment date’ from table 2-2 
Section 2.2
Removed Per protocol set (PPS) in line with ICH E9 (R1) 
Updated the PAS definition: ‘PAS includes all subjects who receive at least one 
dose of canakinumab’
Section 2.3
Added summary table of demographic and baseline characteristics by pandemic 
phase
Added table 2-4: COVID-19 start and end dates by region/country
Updated wording ‘Medical history and current medical conditions, including 
cancer-related conditions and symptoms entered on (e) CRF will be summarized 
and listed by treatment arm’
Section 2.3.1
Updated wording of ‘discontinued post treatment follow-up’ to ‘discontinued
study’
Section 2.3.2
In light of COVID-19 pandemic, added COVID-19 related protocol deviations
Section 2.4.1
To clarify the dose interruption: a dose interruption reported in the eCRF after the 
last dose of study drug, won’t be considered as a dose interruption
Added ‘First new NSCLC anti-neoplastic medication after discontinuation of study 
treatment will also be summarized’
Section 2.5.1
Added ‘New primary lung malignancies are treated as recurrence, clinical 
deterioration is not considered as recurrence’
Added ‘For subjects having the event confirmed by biopsy results, radiology date 
will be used as DFS event date’
In light of ICH E9 addendum, added Primary estimand (DFS) 
Section 2.5.3
Rewrote section 2.5.3 by adding a censoring table 2-5 and new censoring rules: i) 
subjects having new antineoplastic therapy (ANP) for NSCLC will be censored at 


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Date
Section
Changes
the last assessment date prior to initiation of ANP;  ii) subjects having ‘evidence of 
unresected NSCLC or distant metastatic NSCLC disease on screening evaluation’ 
will be censored at randomization date
Included  ‘New primary lung malignancies’ as recurrence
Added ‘Clinical review will be performed to determine if anti-neoplastic therapy is 
related to NSCLC in case of multiple malignancies’
Section 2.5.4
Restructured supportive analyses into two subsections: sensitivity analyses and 
supplementary analyses
Section 2.5.4.1
Removed PPS sensitivity analysis in line with recommendations from ICH E9 (R1)
Moved ANP related sensitivity analyses to supplementary analyses 
Added DFS sensitivity analysis with stratification factors from eCRF
Added sensitivity analysis of censoring subjects with two or more times TAs 
missing
Section 2.5.4.2
Clarified supplementary analyses related NSCLC ANP: i) DFS event after initiating 
new NSCLC anti-neoplastic therapy will be counted as event; ii) new NSCLC anti-
neoplastic therapy prior to disease recurrence will be considered as DFS event
Added supplementary analysis for DFS to assess the treatment effect had the 
pandemic not occurred. Hypothetical strategy was used to handle intercurrent 
events due to COVID-19.
Section 
2.5.4.2.1
Added subsection 2.5.4.2.1 ‘Medications treating suspected or confirmed COVID-
19’
Analysis of protocol deviations related to COVID-19 pandemic were added.
Supplementary analyses were added for DFS and OS to assess the treatment effect 
had the pandemic not occurred. Hypothetical strategy was used to handle 
intercurrent events due to COVID-19.
Section 2.6.1
In light of ICH E9 addendum, added key secondary estimand (OS)
Added justification for key-secondary estimand
Section 2.6.4
Restructured supportive analyses into two subsections: sensitivity analyses and 
supplementary analyses
Added justification for the key second estimand
Section 2.6.4.1
Removed PPS sensitivity analysis in line with recommendations from ICH E9 (R1)
Section 2.6.4.2
Added supplementary analysis for OS to assess the treatment effect had the 
pandemic not occurred. Hypothetical strategy was used to handle intercurrent 
events due to COVID-19.
Section 2.8.1.1
AESI groups in table 2-6 updated according to current eCRS. 








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Date
Section
Changes
functioning and fatigue per QLQ-C30 questionnaire; time to 10 point definitive 
deterioration of role functioning, physical functioning and fatigue per QLQ-C30
Added the plots of change from baseline by visit for all scores per QLQ-LC13, 
QLQ-C30 and EQ-5D-5L
Added tables of compliance and completion rate over time for QLQ-LC13, QLQ-
C30 and EQ-5D-5L by treatment arm 
Added first deterioration analysis at 5 point cut off in sensitivity analysis
Added a reference (Osoba 1998)
Section 2.13.1
Updated the interim analysis plan for DFS and modified all boundary values; 
updated table 2-9 with the new interim analysis plan
Section 2.13.2
Updated the interim analysis plan for OS; updated table 2-10 with the new interim 
analysis plan
Section 2.13.3
Updated DMC analysis plan with only futility interim analysis of DFS; removed 
efficacy interim analysis DFS responsibility from DMC 
Section 3.1
Updated interim analysis plan for DFS


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Table of contents
Table of contents..................................................................................................................8
1
Introduction........................................................................................................................11
1.1
Study design...........................................................................................................11
1.2
Study objectives and endpoints..............................................................................12
2
Statistical methods.............................................................................................................14
2.1
Data analysis general information..........................................................................14
General definitions ................................................................................15
2.2
Analysis sets...........................................................................................................18
Subgroup of interest ..............................................................................19
2.3
Subject disposition, demographics and other baseline characteristics...................21
Subject disposition.................................................................................22
Protocol deviations................................................................................23
Analysis sets ..........................................................................................24
2.4
Treatments (study treatment, rescue medication, concomitant therapies, compliance)
................................................................................................................................24
Study treatment / compliance................................................................24
Prior, concomitant and post therapies ...................................................25
2.5
Analysis of the primary objective..........................................................................26
Primary estimand...................................................................................26
Statistical hypothesis, model, and method of analysis ..........................28
Handling of missing values/censoring/discontinuations .......................28
Supportive analyses for primary estimand ............................................29
Subgroup analyses for the primary estimand ........................................31
2.6
Analysis of the key secondary objective................................................................31
Key secondary estimand........................................................................32
Statistical hypothesis, model, and method of analysis ..........................32
Handling of missing values/censoring/discontinuations .......................33
Supportive Analyses for key secondary estimand.................................33
2.7
Analysis of secondary efficacy objectives.............................................................34
Secondary endpoints..............................................................................34
Duration of follow-up............................................................................35
New primary cancer other than lung cancer..........................................35
2.8
Safety analyses.......................................................................................................35
Adverse events (AEs)............................................................................36
Deaths....................................................................................................37
Laboratory data......................................................................................37
Other safety data....................................................................................40




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List of abbreviations
AE
AESI
Adverse event
Adverse events of special interest
ATC
Anatomical Therapeutic Classification
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
DFS
Common Terminology Criteria for Adverse Events
Disease Free Survival
DMC
Data Monitoring Committee 
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
OS
PAS
Overall Survival
Pharmacokinetic analysis set
PK
Pharmacokinetics
PRO
PT
Patient-reported Outcomes
Preferred Term
QoL
Quality of Life
RAP
Report and Analysis Process
SAP
Statistical Analysis Plan
SOC
System Organ Class
TFLs
Tables, Figures, Listings
WHO
World Health Organization


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1
Introduction
This statistical analysis plan (SAP) describes all planned analyses for the primary Clinical Study 
Report (CSR) of study CACZ885T2301, a phase III, multicenter, randomized, double blind, placebo-
controlled study evaluating the efficacy and safety of canakinumab versus placebo as adjuvant therapy 
in adult subjects with stages AJCC/UICC v8 II-IIIA and IIIB (T>5cm N2) completely resected (R0) 
non-small cell lung cancer (NSCLC). As specified in Section 4.3 of the study protocol version 03
(dated 03-Feb-2022), the final analysis of DFS will occur when approximately 392 DFS events are 
reached and the primary CSR will be based on the final DFS analysis. 
1.1
Study design
This phase III study CACZ885T2301 will enroll adult subjects with completely resected (R0) NSCLC 
AJCC/UICC v. 8 stages II-IIIA and IIIB (T>5cm N2) disease. Subjects may be screened after 
undergoing complete surgical resection of their NSCLC and having R0 status confirmed (negative 
margins on pathologic review), after completing adjuvant cisplatin-based doublet chemotherapy if 
applicable, (and, if applicable, radiation therapy for stage IIIA N2 or IIIB N2 disease) and after all 
entry criteria are met. Subjects must not have had preoperative neo-adjuvant chemotherapy or 
radiotherapy to achieve the R0 status. Approximately 1500 subjects will be randomized in 1:1 ratio to 
canakinumab 200 mg subcutaneously (s.c.) every 3 weeks or matching placebo s.c. every 3 weeks 
(Figure 1-1). Randomization will be stratified by AJCC/UICC v. 8 stage (IIA versus IIB versus IIIA 
versus IIIB with T>5cm, N2 disease), histology (squamous versus non-squamous), and region
(Western Europe and North America vs. eastern Asia vs. Rest of the world (RoW)). Subjects will 
continue their assigned treatment until they complete 18 cycles or experience any one of the following: 
disease recurrence as determined by the investigator, unacceptable toxicity that precludes further 
treatment, treatment discontinuation at the discretion of the investigator or subject, death, or lost to 
follow-up, whichever occurs first. It is postulated that the one year adjuvant treatment will provide an 
acceptable benefit for subjects who have intermediate or high risk of developing disease recurrence. If 
disease recurrence is not observed during the treatment phase, subjects will be followed up for five 
years until disease recurrence, withdrawal of consent by the subject, lost to follow up, death, or 
termination of the study by the sponsor. All subjects who discontinue from the study treatment will be 
followed up every 12 weeks for survival until death, lost to follow-up, or withdrawal of consent. 
The purpose of this multicenter, randomized, double-blind, placebo-controlled phase III study is to 
evaluate the efficacy and safety of canakinumab as adjuvant therapy, following standard of care for 
completely resected (R0) AJCC/UICC v. 8 stages II-IIIA and stage IIIB (T>5cm N2) NSCLC subjects.
Standard of care includes complete resection of the NSCLC with margins free of cancer. At a minimum, 
two cycles of cisplatin-based doublet chemotherapy are required for all stage IIB-IIIA and IIIB (T>5cm 
N2) disease subjects; chemotherapy is recommended but not mandatory for stage IIA with no nodal 
involvement. Radiation therapy is allowed if indicated as per local guidelines or practice. All subjects 
must have had complete surgical resection of their NSCLC to be eligible for study entry; and margins 
must be pathologically reviewed and documented as negative. Comparisons will be made between the 
arms for efficacy: DFS, OS, LCSS and Quality of Life measures (EQ-5D-5L and EORTC QLQ-
C30/LC13), and for safety.


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Figure 1-1   Study Design
Disease free survival (DFS) by local investigator assessment is the primary endpoint in this study. 
Overall survival (OS) is the key secondary endpoint.
One futility interim analysis (IA) is planned for DFS when approximately 196 (50%) of the 392 DFS 
events have been observed. The intent is to determine whether there is a need to stop the study early 
for lack of efficacy (futility), there is no plan to stop the study for efficacy at the futility IA. 
A hierarchical testing procedure will be adopted in this study. OS analysis will be performed only if 
the primary efficacy endpoint DFS is statistically significant. There are a maximum of three OS 
analyses planned, including two OS IAs and final OS analysis:  

At the time of final DFS analysis (provided DFS is statistically significant at final DFS 
analysis), at which point a total of approximately 318 (63%) deaths are expected 

An additional IA for OS when a total of approximately 418 (83%) deaths are expected 

A final analysis for OS when approximately 504 deaths are expected
This study has 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 this study. The DMC will be responsible to review safety data approximately 6 months 
after the first randomized subject has started study treatment, provided at least 50 subjects have been 
treated, and approximately every one year thereafter until all subjects have completed 18 cycles 
(approximately 54 weeks) of treatment or final DFS analysis, whichever occurs earlier. The DMC will 
also be responsible to review efficacy data at DFS futility IA. This includes but does not limit the role 
of the DMC to evaluate these data and to provide recommendations to the sponsor to continue, modify,
or stop the study early. The IA will be performed by an independent statistician external to Novartis 
and the results will be provided to the DMC by the independent statistician. A separate DMC SAP 
specifies the analyses to be performed for the DMC safety/efficacy reviews.
1.2
Study objectives and endpoints


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Objective
Endpoint
Primary
The primary objective is to compare the 
Disease-free survival (DFS) in the 
canakinumab versus placebo arms as 
determined by local investigator 
assessment.
DFS determined by local investigator assessment. See 
Section 2.5.1 for the primary estimand
Key secondary
To compare overall survival (OS) in the 
canakinumab arm versus placebo arm
OS. See Section 2.6.1 for the key secondary estimand
Other secondary
1.
To compare DFS by local investigator 
assessment 
and 
OS 
in 
the 
canakinumab versus placebo arms in 
subgroups defined respectively by PD-
L1 and CD8 expression levels
2.
To compare lung cancer specific 
survival in the canakinumab arm versus 
placebo arm
3. To characterize the safety profile of 
canakinumab
4. To characterize the pharmacokinetics of 
canakinumab therapy
5. To characterize the prevalence and 
incidence of immunogenicity (anti-drug 
antibodies, ADA) of canakinumab
6. To assess the effect of canakinumab 
versus placebo on PROs (EORTC 
QLQ-C30 with QLQ-LC13 incorporated 
and EQ-5D) including functioning and 
health-related quality of life
1.
DFS by local investigator assessment and OS in PD-
L1 and CD8 subgroups
2.
Lung cancer specific survival (LCSS)
3.
Frequency 
of 
AEs, 
ECGs 
and 
laboratory 
abnormalities
4.
Serum concentration-time profiles of canakinumab 
and appropriate individual PK parameters based on 
population PK model
5.
Serum 
concentrations 
of 
anti-canakinumab
antibodies
6.
Time to 10 point definitive deterioration of symptom 
scores of pain, cough and dyspnea per QLQ-LC13 
questionnaire are primary PRO variables of interest.
Time to 10 point definitive deterioration of global 
health status/QoL,shortness of breath, pain, role 
functioning, physical functioning and fatigue per 
QLQ-C30 questionnaire, time to first 10 point 
deterioration for symptom scores of pain, cough, 
dyspnea per QLQ-LC13 questionnaire, time to first 
10 point deterioration for global health status/QoL,
shortness of breath, pain, role functioning, physical 
functioning and fatigue per QLQ-C30 questionnaire 
together with the utilities derived from EQ-5D-5L are 
secondary PRO variables of interest


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2
Statistical methods
2.1
Data analysis general information
The futility IA of DFS will be performed by an independent statistician external to Novartis. The final 
DFS analysis will be the basis of the primary CSR. Novartis will perform the analyses specified in this
SAP. SAS version 9.4 or later will be used for analysis.
Data included in the analysis
There is one IA and a final analysis planned for the primary efficacy endpoint of DFS.  Up to two IAs
and a final analysis may be performed for the key secondary endpoint of OS if DFS is statistically 
significant. A unique cut-off date will be established after the targeted number of events for the 
planned interim and final analyses has been documented. For each of the analyses, all statistical 
analyses will be performed using all data collected in the database up to the data cut-off date. All data
with an assessment date or event start date, e.g. vital sign assessment date or start date of an adverse
event, prior to or on the cut-off date will be included in the analysis. Any data collected beyond the
cut-off date or after subjects withdraw their consent forms will not be included in the analysis and 
will not be used for any derivations.
All events with start date before or on the cut-off date and end date after the cut-off date will be reported 
as ‘ongoing’. The same rule will be applied to events starting before or on the cut-off date and not 
having documented end date. This approach applies, in particular, to adverse event and concomitant 
medication reports. For these cases, the end date will not be imputed and therefore will not appear in 
the listings.
For any CSR after the primary CSR, a separate set of TFL shells will detail the planned outputs. If 
futility is claimed at the first DFS IA, neither DFS and OS is statistically significant, or the study is 
terminated by the sponsor, it can result in an either close-out CSR or abbreviated CSR.
General analysis conventions
Pooling of centers: Unless specified otherwise, data from all study centers will be pooled for the 
analysis. Due to expected small number of subjects enrolled at centers, no center effect will be assessed. 
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables by 
treatment arm; a missing category will be included as applicable. Percentages will be calculated using 
the number of subjects in the relevant population or subgroup as the denominator.


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Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate descriptive 
statistics (e.g. mean, standard deviation, median, percentiles, minimum, and maximum) by treatment 
arm.
General definitions
Study treatment
Study treatment will refer to canakinumab or placebo.
Date of first administration of study treatment 
The date of first administration of study treatment is defined as the first date when a non-zero dose of 
canakinumab or placebo is administered and recorded on the Dosage Administration Record (DAR) 
(e) CRF. The date of first administration of study treatment will also be referred as start of study 
treatment.
Date of last administration of study treatment 
The date of last administration of study treatment is defined as is the last date when a nonzero dose of
canakinumab or placebo is administered and recorded on DAR eCRF. The date of last administration 
of study treatment will also be referred as end of study treatment.
Study day
The study day, describes the day of the event or assessment date, relative to the reference start date. 
The study day is defined as:
the date of the event (visit date, onset date of an event, assessment date etc.) − reference start 
date + 1 if event is on or after the reference start date;

the date of the event (visit date, onset date of an event, assessment date etc.) − reference start 
date if event precedes the reference start date.
The reference start date for safety assessments (e.g. adverse event onset, laboratory abnormality
occurrence, vital sign measurement, dose interruption, pk etc.) is the start of study treatment.
The reference start date for all other, non-safety assessments (i.e., disease recurrence, survival, LCSS, 
ECOG performance status, and patient reported outcomes (PRO)) is the date of randomization.
The study day will be displayed in the data listings. If an event starts before the reference start date,
the study day displayed on the listing will be negative.
Time unit
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If duration is 
reported in months, duration in days will be divided by 30.4375.  If duration is reported in years, 
duration in days will be divided by 365.25.
Baseline
For efficacy evaluations, the last non-missing assessment, including unscheduled assessments on or 
before the date of randomization is taken as “baseline” value or “baseline” assessment. In the context 
of baseline definition, the efficacy evaluations also include PRO and performance status.  


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For safety evaluations, the last available assessment on or before the date of start of study treatment is 
taken or ‘‘baseline” assessment.
If subjects have no value as defined above, the baseline result will be missing.
On-treatment assessment/event and observation periods
For adverse event reporting the overall observation period will be divided into three mutually exclusive 
segments: 

pre-treatment period: from day of subject’s informed consent to the day before first
administration of study treatment

on-treatment period: from date of first administration of study treatment to 130 days 
(approximately five terminal half-lives of canakinumab) after date of last actual administration 
of any study treatment (including start and stop date)

post-treatment period: starting at day 131 after last administration of study treatment.
Safety summaries (tables, figures) include only data from the on-treatment period with the exception 
of baseline data which will also be summarized where appropriate (e.g. change from baseline 
summaries). In addition, a separate summary for death including on treatment and post treatment 
deaths will be provided.  In particular, summary tables for adverse events (AEs) will summarize only 
on-treatment events, with a start date during the on-treatment period (treatment-emergent AEs).  
However, all safety data (including those from the post-treatment period) will be listed and those 
collected during the pre-treatment and post-treatment period will be flagged.
Windows for multiple assessments 
Time windows will be defined for descriptive summary of PRO and ECOG performance status data 
by visit and longitudinal data analysis (Table 2-1). If more than one assessment is available in the same 
time window, the assessment closest to the planned date will be considered. If two assessments are 
obtained with the same time difference compared to the scheduled visit day, the assessment obtained 
prior to visit will be considered. Data obtained at the end of treatment will be classified as other 
assessment in the corresponding time window.    
Table 2-1 Time windows for PRO and ECOG PS assessments
Time Window
Planned Visit Timing 
Time Window Definition
Treatment phase
Baseline 
On or before Study Day 1[a]
≤ Study Day 1
Week 3
Study Day 22
Study Days 2 to 32
Week 6
Study Day 43
Study Days 33 to 53
....... 
......
......
Week k
(with k = 9, 12…)
Study Day 21*(k/3)+1
Study Day 
21*(k/3)-9 to 21*(k/3)+11 
If last dose date is in the 
window, upper bound of this
time window will be EOT visit 
date +7


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“Note: EOT will be included if 
EOT is performed within 7 
days of permanent 
discontinuation of study 
treatment”
Safety follow-up phase
Safety follow-up 1
Safety follow-up 2
Safety follow-up 3
Safety follow-up 4
Safety follow-up 5
26 days after treatment 
discontinuation
52 days after treatment 
discontinuation
78 days after treatment 
discontinuation
104 days after treatment 
discontinuation
130 days after treatment 
discontinuation
[EOT visit date+8; EOT date
+39]
[EOT visit date+40; EOT date
+65]
[EOT visit date+66; EOT date
+91]
[EOT visit date+92; EOT date
+117]
[EOT visit date+118; EOT date
+143]
Post treatment efficacy 
follow-up phase
Post treatment follow-up  
(Efficacy follow up) 
Every 26 weeks in Year 2 and 3;
Every 52 weeks in Year 4 and 5
First time window:  [upper 
bound of the last previous time 
windows with assessment + 1; 
TA date + TA interval at next 
visit/2]
Otherwise : [TA date - TA 
interval at this visit/2; TA
date+TA interval at next visit/2] 
7 days post disease 
progression (PRO only)
Within 7 days post disease 
progression
[disease progression date+1;
disease progression date +21 ]
28 days post disease 
progression (PRO only)
28 days post disease 
progression
[disease progression date+22; 
disease progression date +42]
[a] Study Day 1 = randomization date and PRO assessment on Cycle 1 Day1 will be baseline for 
PRO if randomization date is not Cycle 1 Day1.
Last contact date 
The last contact date will be derived for subjects not known to have died at the analysis cut-off using 
the last complete date among the following (Table 2-2):
Table 2-1  Last contact date data sources
Source data
Conditions
Date of Randomization 
No condition


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Source data
Conditions
Last contact date/last date subject was known to 
be alive from Survival Follow-up page 
Subject status is reported to be alive, lost to 
follow-up or unknown.
Start/End dates from further antineoplastic 
therapy
Non-missing medication/procedure term.
Start/End dates from drug administration record 
Non-missing dose. Doses of 0 are allowed.
Date of disease recurrence
No condition
Laboratory/PK collection dates
Sample collection marked as ‘done’. 
Vital signs date
At least one non-missing parameter value
Performance Status date
Non-missing performance status
Start/End dates of AE 
Non-missing verbatim term
The last contact date is defined as the latest complete date from the above list on or before the data 
cut-off date. The cut-off date will not be used for last contact date, unless the subject was seen or 
contacted on that date. No date post cut-off date will be used. Completely imputed dates (e.g. the
analysis cut-off date programmatically imputed to replace the missing end date of a dose
administration record) will not be used to derive the last contact date. Partial date imputation is 
allowed for event (death)/censoring is coming from ‘Survival information’ eCRF. 
The last contact date will be used for censoring of subjects in the analysis of overall survival.
2.2
Analysis sets
Full Analysis Set
The Full Analysis Set (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 
(AJCC/UICC v8 stage: IIA versus IIB versus IIIA versus IIIB with T>5cm N2 disease; Histology: 
squamous versus non-squamous; and Region: Western Europe and North America vs. eastern Asia vs. 
Rest of the world (RoW)) to which they have been assigned during the randomization procedure.
Safety
The Safety Set includes all subjects who received at least one dose of study treatment. Subjects will 
be analyzed according to the study treatment they received, either canakinumab or placebo. The 
treatment received is defined as the randomized treatment if the subject took at least one dose of that 
treatment or the first treatment received if the randomized treatment was never received.
Pharmacokinetic analysis set (PAS)
The Pharmacokinetic analysis set (PAS) includes all subjects who receive at least one dose of 
canakinumab and provide at least one evaluable PK sample. A PK sample for canakinumab is 
considered evaluable when subjects have:


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
at least one dose of canakinumab prior to sampling, except C1D1 pre-dose sample

Pre-dose samples collected before the next dose administration 

Pre-dose samples (except for Cycle 1 Day 1) collected between 16 days (384 hours) and 26 
days (624 hours) after the last 200 mg canakinumab dose administration

Received 200 mg of canakinumab prior to post-dose PK sampling
Subject Classification: 
Subjects may be excluded from the analysis populations defined above based on the protocol 
deviations entered in the database and/or on specific subject classification rules defined in Table 2-3. 
Table 2-2  Subject classification based on protocol deviations and non-PD criteria
Analysis set
Protocol 
deviations 
leading 
to 
exclusion
Non 
protocol 
deviation 
leading to exclusion
FAS 
No written inform consent
Not applicable
Safety set
No written inform consent
No dose of study medication 
PAS
No written inform consent
See definition of PAS  
Withdrawal of Informed Consent
Any data collected in the clinical database after a subject withdraws informed consent from all further 
participation in the trial, will not be included in the analyses. The date on which a subject withdraws 
full consent is recorded in the eCRF. 
Death events may be used in the analysis if captured from public records, local law, and subject 
informed consent permitting.
Additional data for which there is a separate informed consent, e.g. PK, 
etc., collected in 
the clinical database without having obtained that consent, will not be included in the analyses. These 
data will be excluded by the presence of the appropriate protocol deviation criterion.
Subgroup of interest
Efficacy
The primary endpoint (DFS) and key secondary endpoint (OS) will be summarized by the following 
subgroups to examine homogeneity of treatment effect, provided that the corresponding primary 
efficacy analysis and key secondary efficacy analysis based on the FAS are statistically significant
respectively: 

AJCC/UICC v. 8 stage (IIA vs. IIB vs. IIIA vs. IIIB with T>5cm, N2 disease)  based on 
randomization data from IRT

AJCC/UICC v. 8 stage (IIA vs. IIB vs. IIIA vs. IIIB with T>5cm, N2 disease)  based on eCRF 
data 

Histology (squamous vs. non-squamous) based on randomization data from IRT




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
Prior radiotherapy (yes vs. no) in subjects with N2 disease based on eCRF data

BMI ≥ 35kg/m2 at baseline (yes vs. no)

PD-L1 categories (<1%, >= 1 %, < 50%, >= 50%, >= 1 % and < 49%)

CD8 categories by median or quartile (including its complements)
The objective for carrying out these subgroup analyses is to identify potential safety issues that
may be limited to a subgroup of subjects, or safety issues that are more commonly observed in a 
subgroup of subjects.
The following safety summaries will be performed by subgroup:

AEs, regardless of study treatment, by primary system organ class and preferred term

AEs with suspected relationship to study treatment by primary system organ class and preferred 
term

Adverse Event of Special Interest, irrespective of causality, by grouping, preferred term, 
maximum grade, and treatment
Country-specific subgroup analyses
Key efficacy and safety outputs, including baseline characteristics, PK and immunogenicity, will be 
repeated for Japanese subjects and Non-Japanese subgroup respectively. 
2.3
Subject disposition, demographics and other baseline characteristics
The Full Analysis Set (FAS) will be used for all baseline and demographic summaries and listings 
unless otherwise specified. Summaries will be reported by treatment arm and for all subjects. In 
addition, listings will be reported by treatment arm to assess baseline comparability. No inferential 
statistics will be provided.
Basic demographic and background data
All demographic and baseline disease characteristics data will be summarized and listed by treatment. 
Categorical data (e.g. gender, age groups: <50 years vs. (≥50 years and <65 years) vs. (≥65 years and 
< 75 years) vs. ≥75 years, race, WHO performance status, and smoking history), PD-L1 categories 
(<1%, >= 1 %, < 50%, >= 50%, >= 1 % and < 49%) and CD8 categories by median and quartile
(including its complements) will be summarized by frequency counts and percentages; the number and 
percentage of subjects with missing data will be provided. Continuous data (e.g. age, weight, height, 
and body mass index (BMI)) will be summarized by descriptive statistics (e.g. N, mean, median, 
standard deviation, percentiles, minimum, and maximum). BMI (kg/m2) will be calculated using 
weight and height at baseline.  
In light of COVID-19 pandemic impacting the study during the enrollment phase, summary of 
demographic and baseline characteristics  will be generated by groups of subjects who are enrolled in 
different pandemic phases to have an understanding of whether there is a shift in subject population 
characteristics. The pandemic phase will be divided into two phases: pre-pandemic period and 
pandemic period. Table 2-4 specifies COVID-19 start and end dates by region/country to determine 
the pandemic phase. 


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Table 2-4 COVID-19 start and end dates by region/country
Region/Country
Start Date
End Date
China
01Jan2020
Not defined yet
South Korea
20Feb2020
Not defined yet
Japan
21Feb2020
Not defined yet
Italy
23Feb2020
Not defined yet
Rest of the world
01Mar2020
Not defined yet
Baseline stratification factors
The number (%) of subjects in each randomization stratum based on data obtained from the IRT system 
will be summarized overall and by treatment for the FAS. Discordances between the stratum recorded 
in IRT at the time of randomization and the actual stratum recorded in the clinical database through 
the data collected on eCRF will be cross-tabulated and listed.
Diagnosis and extent of cancer 
Summary statistics will be tabulated for diagnosis and extent of cancer. This analysis will include the 
following: primary site of cancer, details of tumor histology/cytology, and TNM pathological staging 
after resection.  
Medical history
Medical history and current medical conditions at screening, including cancer-related conditions and 
symptoms entered on (e) CRF, will be summarized and listed by primary system organ class (SOC), 
preferred term (PT), and treatment. They will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) terminology. 
Other
All data collected at baseline, including source of subject referral and other informed consents than 
main study informed consent, will be listed.
Subject disposition
All screened and randomized subjects will be summarized by country and center. The number (%) of 
randomized subjects will be presented overall and by treatment. The number (%) of screened subjects
and not-randomized subjects, along with the reasons of screening failure, will be displayed. The 
number (%) of randomized subjects who are still on-treatment, who discontinued the treatment or study, 
along with the reasons for discontinuation, will be presented overall and by treatment.
The following summaries will be provided (with % based on the total number of FAS subjects):

Number (%) of subjects who were randomized (based on data from IRT system)

Number (%) of subjects who were randomized but not treated (based on ‘DAR’ eCRF page not 
completed for study treatment)

Primary reason for not being treated (based on “Treatment disposition” eCRF page) 


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
Number (%) of subjects who were treated (based on ‘DAR’ eCRF pages of study treatment 
completed with non-zero dose administered)

Number (%) of subjects who are still on-treatment (based on the ‘Treatment disposition’ page 
not completed); 

Number (%) of subjects who discontinued the study treatment (based on the ‘Treatment 
disposition’ page) 

Primary reason for treatment discontinuation (based on the ‘Treatment disposition’ page)

Number (%) of subjects who discontinued study (based on the ‘Study disposition’  page);

Reasons for study discontinuation (based on ‘Study disposition’page)
Protocol deviations
Protocol deviations, including COVID-19 pandemic related and not related, will be summarized in 
total by treatment. In addition to the pre-defined standard protocol deviation terms, the following 
protocol deviations related to COIVD-19 in line with “FDA Guidance on Conduct of Clinical Trials 
of Medical Products during COVID-19 Public Health Emergency” (March 2020) and “Guidance on 
the management of clinical trials during the COVID-19 (coronavirus) pandemic” (April 2020) from 
EMA will be summarized:

Missing visits

Changes in procedures and assessments

Planned visits not done at sites

Changes in drug supply method

Treatment not given

Subject discontinuation due to COVID-19 situation

Dose interruption greater than 84 days
The relationship of protocol deviation to COVID-19 will also be summarized using the following 
descriptions: 

COVID-19 Health Status: (i.e. subject’s COVID-19 infection led to this PD) 

COVID-19 *Site issue: (e.g. site closed, personnel not available) 

COVID-19 Lockdown: (e.g. site is active but subject not allowed to come) 

COVID-19 Subject/Subject concern: (e.g. site is active, subject/subject could come but 
refused to come / do assessment) 

COVID-19 Drug supply issue (e.g. drug was delivered to home) 

COVID-19 Other: (e.g. situation not already covered by the information above ) 
* For deviation with multiple relationships, ‘Site Issue’ was reported as the primary relationship to 
COVID-19 if another relationship was also applicable.
In addition, COVID-19 related outcomes (e.g., COVID-19 AEs, treatment discontinuation and study 
discontinuation due to COVID-19, death due to COVID-19) will be descriptively summarized by 
country, site, and treatment. 
All protocol deviations will be listed. 


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Analysis sets
The number (%) of subjects in each analysis set will be summarized by treatment and randomization 
stratum.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
Study treatment / compliance
Duration of exposure, actual cumulative dose, dose intensity (DI), and relative dose intensity (RDI) 
will be summarized by treatment. Duration of exposure will be categorized into time intervals; 
frequency counts and percentages will be presented for the number (%) of subjects in each interval. 
The number (%) of subjects who have dose interruptions, along with interruption reasons, will be 
summarized by treatment. No dose modification is allowed as per study protocol.
Subject level listings of all doses administered on-treatment, along with dose interruption reasons, will 
be produced.  
The safety set will be used for all summaries and listings of study treatment. 
Duration of exposure to study treatment
Last date of exposure and duration of exposure are defined as below:

Last date of exposure to study treatment = last dosing date of study treatment + 20 days 
(If the subject died or was lost to follow-up before the derived last date of exposure, the last 
date of exposure to study treatment is the date of death or the date of last contact before lost to 
follow-up, respectively. If the derived last date of exposure goes beyond the data cutoff date, 
it should be truncated to the date of data cutoff.)

Duration of exposure to study treatment (days):
last date of exposure to study treatment − first dosing date of study treatment + 1 (periods of 
interruption are not excluded)
Summary of duration of exposure of study treatment in months will include categorical summaries and 
continuous summaries (i.e. mean, standard deviation, etc.).
Cumulative dose
Cumulative dose of a study treatment is defined as the total dose given during the study treatment 
exposure. 
The planned cumulative dose for a study treatment refers to the total planned dose per the protocol 
up to the last date of study treatment. 

Cumulative planned dose for a study treatment:
planned dose per cycle as per protocol * number of complete cycles the subject should have 
been over the duration of exposure 

Number of complete cycles: (last dosing date of study treatment – first dosing date of study 
treatment + 21)/21

Planned dose per cycle as per protocol: 200 mg/cycle 


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The actual cumulative dose refers to the total actual dose administered, over the duration for which 
the subject is on the study treatment as documented in the Dose Administration eCRF. 
For subjects who did not take any drug, the cumulative dose is equal to zero.
The actual cumulative dose should be defined based on the days when the subject is assumed to have 
taken a non-zero dose during dosing periods. 

Actual cumulative dose (mg):
total dose of  study treatment taken by a subject in the study calculated as the sum of amount 
of dose administered 
Dose intensity and relative dose intensity
Dose intensity (DI) for subjects with non-zero duration of exposure is defined as follows: 

DI (mg/cycle) = Actual Cumulative dose (mg) / Duration of exposure to study treatment
(days)*21 (days/cycle)
For subjects who did not take any drug, the DI is equal to zero. 
Planned dose intensity (PDI) is defined as follows:

PDI (mg/cycle) = Planned Cumulative dose (mg) / Duration of exposure to study treatment 
(days)*21 (days/cycle)
Relative dose intensity (RDI) is defined as follows:

RDI = DI (mg/cycle) / PDI (mg/cycle)  
DI and RDI will be summarized by treatment arm. 
Dose interruptions or permanent discontinuations
The number of subjects who have dose permanent discontinuations or interruptions, and the reasons, 
will be summarized by treatment. Dose reduction is not allowed per study protocol.
‘Dose interrupted’ will be determined if the total “Dose Administered” equal to 0 from the Dosage 
Administration CRF pages (DAR). The corresponding reasons will be summarized as well. If multiple 
interruptions are entered on consecutive cycles with different reasons, they will be counted as separate 
interruptions, whereas they will be counted as one single interruption. Any dose interruption reported 
after the last dose of study drug followed by permanent discontinuation won’t be considered as a dose 
interruption.
Prior, concomitant and post therapies
Prior anti-cancer therapy
The number and percentage of subjects, who received prior anti-neoplastic medications, radiotherapies,
or surgeries, will be summarized by treatment. Prior anti-neoplastic medications will also be 
summarized by therapy type, setting, lowest ATC class, preferred term, and treatment. Summaries will 
include total number of regimens. For radiotherapies, time since last radiotherapy, locations, and 
setting of last therapy will be summarized by treatment. For prior surgeries, time since last surgery, 
procedure, and residual disease of last therapy will be summarized by treatment. In addition, the 
summaries for prior antineoplastic medications and radiotherapies will be repeated by AJCC/UICC v. 


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8 stage (including Stage IIA, T2b, N0 T (>4 - 5cm) vs.  IIB (T1abc-2ab) vs. IIB T3 >5cm & ≤7cm, N0 
vs. IIIA T3 or T4 Tis>5 cm vs. IIIA T≤5cm vs.  IIIB T>5cm).
Separate listings will be produced for prior anti-neoplastic medications, radiotherapies, and surgeries. 
Anti-neoplastic medications will be coded using the WHO Drug Dictionary (WHO-DD); anti-
neoplastic surgery will be coded using MedDRA. The above analyses will be performed using the 
FAS.
Post treatment anti-cancer therapy
Anti-neoplastic therapies since discontinuation of study treatment will be summarized and listed by 
ATC class, preferred term, and treatment by means of frequency counts and percentages using FAS.
First new Anti-neoplastic therapies related to NSCLC since discontinuation of study treatment will be 
summarized as well.
Concomitant medications
Concomitant therapies are defined as interventions (therapeutic treatment or procedure), other than the 
study treatment, administered to a subject in the study treatment period. They includes concomitant 
medications and therapies.
Concomitant medications will be coded using the World Health Organization (WHO) Drug Reference 
Listing (DRL) dictionary that employs the WHO Anatomical Therapeutic Chemical (ATC) 
classification system and summarized by lowest ATC class and preferred term using frequency counts 
and percentages. Summaries will include:

Medications starting on or after the start of study treatment but no later than 130 days after  last 
dose of study treatment and

Medications starting prior to start of study treatment and continuing after the start of study 
treatment
All concomitant therapies will be listed. Any concomitant therapies starting and ending prior to the
start of study treatment or starting more than 130 days after the last date of study treatment will be 
flagged. Surgical and medical procedures will be coded using MedDRA and summarized by SOC, 
preferred term, and treatment.
The safety set will be used for all tables and listings of concomitant medications and therapies.
2.5
Analysis of the primary objective
The primary objective is to compare the DFS in the canakinumab versus placebo arms as determined 
by local investigator assessment.
Primary estimand
The primary efficacy variable of the study is DFS, defined as the time from the date of randomization 
to the date of the first documented disease recurrence as assessed by local investigator radiologically 
or death due to any cause. Disease recurrence includes diagnoses of new primary lung malignancies. 
Clinical deterioration is not considered as a recurrence of disease. In case of non-conclusive 
radiological evidence, a biopsy should be performed to confirm recurrence. If a biopsy is not feasible, 
the subject will be followed up until recurrence can be confirmed as per protocol (radiologically 
conclusive and/or biopsy)”; radiological assessment date will be used as DFS event date. The primary 


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analysis will be based on FAS and will include all data observed up to the cut-off date. Censoring
conventions are provided in Section 2.5.3.
The scientific objective guiding the primary estimand is to estimate the treatment effect based on the 
primary endpoint of DFS for canakinumab compared to placebo, for the randomized subjects enrolled 
with inclusion/exclusion criteria, which were defined in the protocol, irrespective of any treatment 
discontinuation reasons, any new malignancy not related to lung cancer and had the post-treatment 
antineoplastic therapies for NSCLC not been administered. It is expected that new therapies such as 
PD-L1s for adjuvant NSCLC may be approved during the conduct of this trial. In case placebo subjects 
in this study were to switch to these new approved therapies prior to disease recurrence, it can have a 
potential impact on the treatment effect in the placebo arm. Hence, the primary estimand uses a 
hypothetical strategy to assess the treatment effect based on DFS had the post-treatment antineoplastic 
therapies for NSCLC not been administered. Additional intercurrent events such as discontinuation of 
study treatment, appearance of new primary malignancy not related to lung, post-treatment 
antineoplastic therapies not related to lung, and intercurrent events due to COVID-19 pandemic are 
expected in both treatment arms. Hence, the primary estimand of interest will be to assess the treatment 
effect based on DFS, irrespective of these intercurrent events.
The primary estimand is described by the following five attributes:
1. The target population includes all randomized subjects (FAS).
2. The primary variable is DFS defined as the time from the date of randomization to the date 
of the first documented disease recurrence, assessed by local investigator radiologically, or 
death due to any cause. Any new primary lung malignancy will be handled as disease 
recurrence.
3. The treatment of interest is the randomized treatment (canakinumab arm or placebo arm).
4. The remaining intercurrent events describe how events that may occur after randomization are 
considered when assessing the treatment effect.

Discontinuation of study treatment: DFS will take into account all DFS assessments,
irrespective of the study treatment discontinuation reasons (treatment policy)

Initiation of post-treatment anti-neoplastic therapies for NSCLC: DFS will be censored at 
the last adequate tumor assessment prior to the initiation of post-treatment antineoplastic 
therapy (hypothetical strategy) 

New primary malignancy not related to Lung cancer: DFS will take into account all DFS 
assessments, irrespective of the occurrence of any new malignancy not related to lung 
cancer (treatment policy)

Initiation of post-treatment anti-neoplastic therapies for malignancies not related to lung 
cancer: DFS will take into account all DFS assessments, irrespective of initiation of any 
post-treatment antineoplastic therapies for new malignancy not related to lung cancer 
(treatment policy)

Any unforeseen intercurrent events due to COVID-19 pandemic will be handled by 
treatment policy strategy
5. The summary measure is the hazard ratio (HR) for DFS between two treatment arms. It will 
be estimated using Cox proportional hazard model stratified by randomization stratification 
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Statistical hypothesis, model, and method of analysis
Assumed proportional hazards model for DFS, the following statistical hypotheses will be tested to 
address the primary efficacy objective:
H01 (null hypotheses): Θ1≥ 0 vs. Ha1 (alternative hypotheses): Θ1 < 0
Where Θ1 is the log hazard ratio of DFS in the canakinumab (investigational) vs. placebo (control).
The primary efficacy analysis to test this hypothesis and compare the two arms will involve a stratified 
log-rank test at an overall one-sided 2.5% level of significance. The stratification will be based on the 
following randomization stratification factors: AJCC/UICC v8 stage IIA versus IIB versus IIIA versus 
IIIB with T>5cm N2 disease; Histology: squamous versus non-squamous; and Region: Western 
Europe and North America vs. eastern Asia vs. Rest of the world (RoW). A group sequential design is 
employed for the primary efficacy variable DFS. One interim analysis, along with a final analysis, is 
planned, using a Lan-DeMets (O’Brien-Fleming) α-spending function for efficacy and a non-binding 
user-defined β-spending function (gamma function with γ=-3) for futility. There is only futility 
assessed at the  IA.
The DFS distribution will be estimated using the Kaplan-Meier method, and Kaplan-Meier curves will 
be plotted for each arm. The DFS Kaplan-Meier estimate along with 95% confidence intervals will be 
presented by year for each arm. The hazard ratio for DFS will be calculated, along with its 95% 
confidence interval, from a stratified Cox model using the same stratification factors as those for the 
log-rank test.
Handling of missing values/censoring/discontinuations
For subjects who received any subsequent anti-neoplastic therapy for NSCLC, the following rules will 
apply:

If new NSCLC anti-neoplastic therapy is started without evidence of documented disease 
recurrence, then DFS will be censored at the date of last tumor assessment before the date of 
initiation of anti-cancer therapy

If a subject does not have any tumor assessment before the date of initiation of new anti-
neoplastic therapy for NSCLC, DFS will be censored at the date of randomization.
Clinical review will be performed to determine if anti-neoplastic therapy is NSCLC related in case of 
multiple malignancies.
Any new primary malignancies not related to lung or clinical deterioration will not be considered as a 
disease recurrence. 
Event/censoring dates for the primary estimand will be determined by Table 2-5:
Table 2-5   Outcome and event/censoring dates for primary DFS analysis
Situation
Date
Outcome
Evidence of unresected NSCLC or distant 
metastatic NSCLC disease on screening 
evaluation
Date of randomization
Censored
Death before any tumor assessment
Date of death
Event


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Situation
Date
Outcome
Recurrence or death documented between 
scheduled visits
Date of tumor assessment (or death)
Event
No recurrence (or death) 
Date of last adequate tumor assessment 
Censored
New antineoplastic therapy (including surgery) 
for NSCLC given prior to recurrence or death
Date of last adequate assessment on or 
prior to starting new anti-cancer therapy
Censored
New antineoplastic therapy (including surgery) 
for NSCLC prior to any scheduled visit
Date of randomization
Censored
New primary lung malignancies
Date of tumor assessment
Event
The DFS censoring reasons are defined in the following way. If the date is the earliest of the following 
dates:

Analysis cut-off date 

Date of consent withdrawal

Date of new NSCLC antineoplastic therapy

Date of lost to follow-up 
Then the DFS censoring reason will be:

Ongoing without event

Withdrew consent 

New NSCLC antineoplastic therapy

Lost to follow-up
Supportive analyses for primary estimand
2.5.4.1
Sensitivity analyses for primary estimand
First sensitivity analysis estimand: The target population, the primary variable, the treatment of 
interest, intercurrent events, and the summary measure of this endpoint are the same as those for the 
primary estimand. To assess the impact of stratification, the two treatment arms will be compared using 
the unstratified log-rank test. In the summary tables, this approach is referred to as ‘unstratified DFS 
sensitivity analysis’.
Second sensitivity analysis estimand: the target population, the primary variable, the treatment of 
interest, intercurrent events, and the summary measure of this endpoint are the same as those for the 
primary estimand. The two treatment arms will be compared using the stratified log-rank test with 
stratification factors derived from the clinical database. In the summary tables, this approach is referred 
to as ‘DFS sensitivity analysis with stratification factors from eCRF’.


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Third sensitivity analysis estimand: the target population, the primary variable, the treatment of 
interest, intercurrent events, and the summary measure of this endpoint are the same as those for the 
primary estimand. Subjects with two or more times missing tumor assessments will be censored at the 
last adequate tumor assessment. Algorithm to identify missing tumor assessments are defined in
Appendix 5.6. In the summary tables, this approach is referred to as ‘DFS sensitivity analysis with 
censoring for two or more missing assessments’.
2.5.4.2
Supplementary analyses for primary estimand
First supplementary analysis estimand: the target population, the primary variable, the treatment of 
interest, and intercurrent events are the same as those for the primary estimand. A Cox regression 
model, stratified by randomization stratification factors, will be fitted to evaluate the effect of the 
baseline demographic and disease characteristics, which include age (< 50 years vs. ( ≥50 years and 
< 65 years) vs. ( ≥65 years and < 75 years) vs. ≥75 years), gender (Male vs. Female), race (White vs. 
Black vs. Asian vs. Others (includes “Native Hawaiian or Other Pacific Islander” and “American 
Indian or Alaska Native”), ECOG status (0 vs. ≥1), and smoking history (never vs. former smoker vs. 
current smoker). In the summary tables, this approach is referred to as ‘DFS supplementary analysis 
adjusted for baseline covariates’.
Second supplementary analysis estimand: the target population, intercurrent events, and the 
summary measure of this endpoint are the same as those for the primary estimand. The treatment of 
interest is the randomized treatment (canakinumab arm or placebo arm without any NSCLC 
antineoplastic therapy post randomization). The primary variable is defined as the time from the date 
of randomization to the date of the first documented disease recurrence, date of death due to any cause,
or date of new NSCLC antineoplastic therapy, whichever occurs first. Any new NSCLC antineoplastic 
therapy post randomization prior to recurrence/death will be considered as a DFS event (composite 
strategy). In the summary tables, this approach is referred to as ‘ANP leading to DFS event 
supplementary analysis’.
Third supplementary analysis estimand: the target population, treatment of interest, and the 
summary measure of this endpoint are the same as those for the primary estimand. The intercurrent 
event of initiation of post-treatment anti-neoplastic therapies for NSCLC will be handled by treatment 
policy, i.e., DFS assessments after initiation of post-treatment anti-neoplastic therapies for NSCLC 
will be taken into account in assessment of treatment effect. In the summary tables, this approach is 
referred to as ‘DFS supplementary analysis regardless of ANP’.
Fourth supplementary analysis estimand: In light of COVID-19 pandemic and its potential impact 
on treatment effect, an important scientific question of interest is to estimate the treatment effect based 
on DFS, had COVID-19 pandemic not occurred. The target population, treatment of interest, and the 
summary measure of this endpoint are the same as those for the primary estimand. The primary 
variable is defined as the time from the date of randomization to the date of the first documented 
recurrence or date of death due to non-COVID-19 pandemic reasons, whichever occurs first. The 
remaining intercurrent events will be handled as follows: 

Discontinuation of study treatment due to any non-COVID-19 pandemic reasons: DFS 
will take into account all DFS events, irrespective of the study treatment discontinuation 
reasons (treatment policy)

Discontinuation of study treatment due to COVID-19 pandemic reasons: DFS will be 
censored at the date of the last adequate tumor assessment prior to discontinuation of treatment 


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due to COVID-19 pandemic (hypothetical strategy). The discontinuation reason due to 
COVID-19 will be identified from the defined COVID-19 protocol deviations.

Medications used for treating suspected or confirmed COVID-19 cases: DFS will be 
censored at the date of the last adequate tumor assessment prior to the administration of 
COVID-19 medication (hypothetical strategy). Details to identify medications in Section 
2.5.4.2.1

Death due to COVID-19: DFS will be censored at the date of the last adequate tumor 
assessment prior to death due to COVID-19 (hypothetical strategy)
In the summary tables, this approach is referred to as ‘COVID-19 DFS supplementary analysis’.
2.5.4.2.1 Medications treating suspected or confirmed COVID-19
The identification of the drug used to treat COVID-19 depends on whether COVID-19 is confirmed 
or suspected.
For confirmed COVID-19, the drug treating COVID-19 is selected based on:

Drug indication that contains key word "COVID" or "SARS-COV" 

Drug class (CM ATC level 4) is aminoquinolines, protease inhibitors, glucocorticoids, 
macrolides, antiviral or antiretroviral; or drug name (CM standard medicine name) contains 
key word “hydroxychloroquine” or “chloroquine”
For suspected COVID-19, the drug treating COVID-19 is selected based on:

AEs with the preferred term of “SARS-CoV-2 test negative” or “suspected COVID-19”

Drug class (CM ATC level 4) is aminoquinolines, protease inhibitors, glucocorticoids, 
macrolides, antiviral or antiretroviral; drug name (CM standard medicine name) contains key 
word “hydroxychloroquine” or “chloroquine”; drug class (CM ATC level 4) is glucocorticoids 
and drug indication contains key word "PNEUM" or equals to "DYSPNEA"

Selecting the first drug with start date within a time window of +/- 7 days of AE start date
Subgroup analyses for the primary estimand
If the primary efficacy analysis is statistically significant, the primary endpoint of DFS will be 
summarized for the subgroups specified in Section 2.2.1:

Median DFS with its 95% CI from Kaplan-Meier estimation of the DFS distribution

Hazard ratio with its 95% CI using Cox proportional hazards model stratified by 
randomization stratification factors
Subgroup analyses are intended to explore the consistency (homogeneity) of treatment effect. A forest 
plot, including sample size, number of events, and HR with its 95% CI, will be produced for subgroups. 
p-values will not be generated.
2.6
Analysis of the key secondary objective
The key secondary objective is to determine whether canakinumab prolongs OS, compared with 
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Key secondary estimand
The key secondary endpoint is OS, defined as the time from the date of randomization to the date of 
death due to any cause. If a subject is not known to have died, then OS will be censored at the last date 
the subject was known to be alive (on or before the cut-off date). The OS analysis will be based on the 
FAS and will include all data up to the cut-off date.
The scientific objective guiding the key secondary estimand is to estimate the treatment effect based 
on the key secondary endpoint of OS for canakinumab compared to placebo for the randomized 
subjects with completely resected (R0) NSCLC AJCC/UICC v.8 stages II-IIIA and IIIB (T> 5 cm N2) 
disease, irrespective of any treatment discontinuation reasons and any post-treatment antineoplastic 
therapies administered. The justification for the primary estimand is driven by the rationale to assess 
treatment effect based on overall survival, irrespective of intercurrent events such as treatment 
discontinuation, new malignancy, and post treatment anti-neoplastic therapies using treatment policy 
strategy. 
The key secondary endpoint analysis will be described by the following five attributes:
1. The target population includes all randomized subjects (FAS). 
2. The primary variable is OS, defined as the time from the date of randomization to the date of 
death due to any cause.
3. The treatment of interest is the randomized treatment (canakinumab arm or the matching 
placebo arm) with or without any new anti-neoplastic therapy administered as needed.
4. The remaining intercurrent event describes how events that may occur after randomization 
are considered when assessing the treatment effect.

Discontinuation of study treatment: OS will take into account all deaths and assessments,
irrespective of the study treatment discontinuation reasons (treatment policy).

New primary malignancy: OS will take into account all deaths and assessments,
irrespective of the occurrence of any new malignancy (treatment policy)

Any unforeseen intercurrent events due to COVID-19 pandemic will be handled by 
treatment policy strategy.
5. The summary measure is the HR for OS between two treatment arms. It will be estimated 
using Cox proportional hazard model stratified by randomization stratification factors.
Statistical hypothesis, model, and method of analysis
Assumed proportional hazards model for OS, the following statistical hypotheses will be tested only if 
DFS is statistically significant:
H02 (null hypotheses): Θ2≥ 0 vs. Ha2 (alternative hypotheses): Θ2 < 0
Where Θ2 is the log hazard ratio of OS in the canakinumab (investigational) vs. placebo (control). The 
analysis to test these hypotheses will involve a stratified log-rank test at an overall one-sided 2.5% 
level of significance. The stratification will be based on the following randomization stratification 
factors: AJCC/UICC v. 8 stage IIA versus IIB versus IIIA versus IIIB T>5cm N2 disease; Histology: 
squamous versus non-squamous; and Region: Western Europe and North America vs. eastern Asia vs. 
Rest of the world (RoW).


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A group sequential design using a Lan-DeMets (O’Brien-Fleming) α-spending function is employed 
for OS analyses. OS will be tested hierarchically as follows:

If DFS is statistically significant at the final DFS analysis, OS will be tested. If OS is not 
statistically significant at this time, an additional IA and final OS analysis will be planned. 

If DFS is not statistically significant at the final DFS analysis, OS will not be tested.  
The OS distribution will be estimated using the Kaplan-Meier method. Kaplan-Meier curves, medians 
OS and its 95% CI will be presented for each arm. The OS Kaplan-Meier estimate along with its 95% 
CI will be presented by year as well. The HR and its 95% CI for OS will be calculated using a stratified 
Cox model. The number of subjects censored for OS and their reasons for censoring will be 
summarized and listed by treatment.
Handling of missing values/censoring/discontinuations
Subjects not known to have died will be censored for ‘Lost to follow-up’ if the time between their last 
contact date and the analysis cut-off date is longer than 14 weeks, i.e., the protocol specified interval 
between the survival follow-up assessments plus 2 weeks.
Supportive Analyses for key secondary estimand
2.6.4.1
Sensitivity analyses for key secondary estimand
First sensitivity analysis estimand: The target population, the primary variable, the treatment of 
interest, intercurrent events, and the summary measure of this endpoint are the same as those for the 
key secondary estimand. To assess the impact of stratification, the two treatment arms will be 
compared using the unstratified log-rank test. In the summary tables, this approach is referred to as 
‘unstratified OS sensitivity analysis’.
Second sensitivity analysis estimand: the target population, the primary variable, the treatment of 
interest, intercurrent events, and the summary measure of this endpoint are the same as those for the 
key secondary estimand. The two treatment arms will be compared using the stratified log-rank test 
with stratification factors derived from the clinical database. In the summary tables, this approach is 
referred to as ‘OS sensitivity analysis with stratification factors from eCRF’.
2.6.4.2
Supplementary analyses for key secondary estimand
First supplementary analysis estimand: the target population, the primary variable, the treatment of 
interest, and intercurrent events are the same as those for the key secondary estimand. A Cox regression 
model, stratified by randomization stratification factors, will be fitted to evaluate the effect of the 
baseline demographic and disease characteristics, which include age (< 50 years vs. ( ≥50 years and 
< 65 years) vs. ( ≥65 years and < 75 years) vs. ≥75 years), gender (Male vs. Female), race (White vs. 
Black vs. Asian vs. Others (includes “Native Hawaiian or Other Pacific Islander” and “American 
Indian or Alaska Native”), ECOG status (0 vs. ≥1), and smoking history (never vs. former smoker vs. 
current smoker). In the summary tables, this approach is referred to as ‘OS supplementary analysis 
adjusted for baseline covariates’.
Second supplementary analysis estimand: In addition, analysis to assess the treatment effect based 
on OS, had COVID-19 pandemic not occurred, will be conducted. The target population, treatment of 
interest, and the summary measure of this endpoint are the same as those for the key secondary 
estimand. The variable is defined as the time from the date of randomization to the date of death due 
to non-COVID-19 pandemic reasons. The remaining intercurrent events will be handled as follows: 


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
Discontinuation of study treatment due to any non-COVID-19 pandemic reasons: OS will 
take into account all deaths and assessments, irrespective of the study treatment discontinuation 
reasons (treatment policy)

Discontinuation of study treatment due to COVID-19 pandemic reasons: OS will be 
censored on the date of discontinuation of treatment due to COVID-19 pandemic (hypothetical 
strategy). The discontinuation reason due to COVID-19 pandemic will be identified from the 
defined COVID-19 protocol deviations.

Medications used for treating suspected or confirmed COVID-19 cases: OS will be 
censored on the date of administration of COVID-19 medication (hypothetical strategy). 
Details to identify medications are shown in Section 2.5.4.2.1

Death due to COVID-19: OS will be censored on the date of death due to COVID-19 
(hypothetical strategy)
In the summary tables, this approach is referred to as ‘COVID-19 OS supplementary analysis’. 
2.6.4.3
Subgroup analyses for key secondary estimand
If the key secondary efficacy analysis is statistically significant, OS will be summarized for the 
subgroups specified in Section 2.2.1:

Median OS with its 95% CI from Kaplan-Meier estimation of the OS distribution

Hazard ratio with its 95% CI using Cox proportional hazards model stratified by 
randomization stratification factors
A forest plot, including sample size, number of events, and HR with its 95% CI, will be produced for 
subgroups. p-values will not be generated. 
2.7
Analysis of secondary efficacy objectives
Along with the OS as the key secondary endpoints, three secondary efficacy objectives are also 
evaluated:

To compare DFS by local investigator assessment and OS in the canakinumab versus placebo 
arms in subgroups defined by PD-L1 expression levels

To compare DFS by local investigator assessment and OS in the canakinumab versus placebo 
arms in subgroups defined by CD8 expression levels

To compare lung cancer-specific survival (LCSS) in the canakinumab arm versus placebo arm 
is an important secondary efficacy objective.
Secondary endpoints
In order to evaluate the effect of canakinumab within PD-L1 subgroups, DFS and OS analyses will be 
performed by PD-L1 subgroups with 1% cut-off on tumor cells (TC) to define positive or negative 
status as determined by IHC (<1% and ≥1%). Additionally, PD-L1 subgroups will also be assessed 
using ≥ 50% cut-off (<50% and ≥50%).  A comparison between <1%, ≥1-49%, and ≥ 50% PD-L1 
expression level subgroups will also be done. 
In order to evaluate the effect of canakinumab within CD8 subgroups, DFS and OS analyses will be 
performed by CD8 subgroups with the median and quartiles (including quartile-complements, e.g. 


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below lower quartile and above lower quartile) of baseline CD8 as cut-offs. In addition, the relation 
between CD8 expression in resected tumor sample and clinical outcome will be evaluated using CD8 
as continuous, potentially log-transformed, co-variate as well as categorical covariates in a Cox model. 
These analyses will support the establishment of CD8 as a prognostic/predictive factor if there is an 
expression level correlating to clinical outcome regardless of treatment (prognostic) and/or associated 
with canakinumab treatment (predictive).
LCSS is a secondary efficacy endpoint, defined as the time from the date of randomization to the date 
of death due to lung cancer. For subjects who have died due to reasons other than lung cancer, LCSS 
will be censored at the death date. For subjects who is not known to have died, LCSS will be censored 
at the last date the subject was known to be alive (on or before the cut-off date); they will be censored 
for ‘Lost to follow-up’ if the time between their last contact date and the analysis cut-off date is longer 
than 14 weeks, i.e., the protocol specified interval between the survival follow-up assessments plus 2 
weeks.
The LCSS distribution will be estimated using the Kaplan-Meier method. Kaplan-Meier curves, 
medians and its 95% CI will be presented for each arm. The HR and its 95% CI for LCSS will be 
calculated using a stratified Cox model. The number of censored subjects will be summarized by 
treatment. Reasons for censoring (‘Alive’, ‘Lost to follow-up’, ‘Death due to reasons other than lung 
cancer’), along with death cause, will be summarized and listed by treatment. 
Duration of follow-up
Summary information regarding the follow-up of subjects in the FAS will be displayed by arm in order 
to describe the maturity of data and quality of follow-up.  
Randomization period, duration between randomization and cut-off date, and follow-up times for
DFS/OS are defined as follows:

Randomization (recruitment) period = (Date of last subject randomized - Date of first subject
randomized + 1)/30.4375 (months).

Duration between randomization date and data cut-off date = (Data cut-off date – Date of 
randomization + 1)/30.4375 (months).

Follow-up time elapsed from study start reference date= (Date of event or censoring –
randomization date + 1)/30.4375 (months) regardless of censoring. Date of event or censoring 
is the same as the one defined for the primary analyses.
The follow-up time for DFS/OS derived from KM method will also be summarized.
New primary cancer other than lung cancer
Summary statistics will be tabulated for subjects with new primary cancer other than lung cancer based 
on “Diagnosis and extent of new primary Cancer Other than Lung” eCRF page. This analysis will 
include the following: number of subjects with new primary cancer, primary site of cancer, the time 
from randomization to initial diagnosis, predominant histology/cytology, staging system and 
metastatic sites.
2.8
Safety analyses
All safety analyses will be based on the safety set. 


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Adverse events (AEs)
AE summaries will include all AEs occurring during on-treatment period. All AEs collected in the AE 
(e)CRF page will be listed along with the information collected on those AEs e.g. AE relationship to 
study treatment, AE outcome, etc. AEs with start date outside of on-treatment period will be flagged 
in the listings.
AEs will be summarized by number and percentage of subjects by primary system organ class (SOC), 
preferred term (PT), and treatment. A subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. A subject with multiple CTCAE grades for the same preferred 
term will be summarized under the maximum grade. AE with missing CTCAE grade will be included 
in the ‘All grades’ column of the summary tables.
In AE summaries, the primary system organ class will be presented alphabetically and the PTs will be 
sorted within primary SOC in descending frequency. The sort order for the PTs will be based on their 
frequency in the investigational treatment.
The following AE summaries will be produced by treatment; overview of AEs and deaths, AEs by 
SOC and PT, summarized by relationship, seriousness, leading to treatment discontinuation, leading 
to dose interruption, requiring additional therapy, and leading to fatal outcome. In addition, a summary 
of serious adverse events with number of occurrences will be produced (an occurrence is defined as >
1 day between start and prior end date of record of same PT).
2.8.1.1
Adverse events of special interest / grouping of AEs
Data analysis of AESIs
An AE of special interest (AESI) is a grouping of AEs that are of scientific and medical concern 
specific to canakinumab. These groupings are defined using MedDRA terms, SMQs (standardized 
MedDRA queries), HGLTs (high level group terms), HLT (high level terms) and PTs. Customized 
SMQs (Novartis MedDRA queries, NMQ) may also be used. A NMQ is a customized group of search 
terms which defines a medical concept for which there is no official SMQ available or the available 
SMQ does not completely fit the need. It may include a combination of single terms and/or an existing 
SMQ, narrow or broad. The groups are defined according to the MedDRA terms defined in the program 
Case Retrieval Strategy (CRS) document and will be summarized. The latest version of the CRS 
document available at the time of the analyses will be used. For each specified AESI, number and 
percentage of subjects with at least one event of the AESI occurring during on treatment period will 
be summarized.
Summaries of these AESIs will be provided by treatment (specifying grade, SAE, relationship, leading 
to treatment discontinuation, leading to dose interruption, hospitalization, death, etc.).
A listing of all grouping levels down to the MedDRA PTs used to define each AESI will be generated. 
Table 2-6 provides current AESI groupings. CRS at the time of database lock will govern how these 
groups will be summarized:
Table 2-6   AESI groupings
AESI grouping
Infections
Opportunistic infections
Opportunistic infections (based on SMQ Broad)


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Opportunistic infections (based on SMQ Narrow)
Neutropenia
Abnormal liver parameters
Thrombocytopenia
Immunogenicity/allergenicity
Autoimmunity reactions
Malignancy
Interactions with vaccines
Pulmonary complications: pulmonary hypertension and interstitial lung 
disease
Injection site reactions
Time to onset of AESI
Time to onset of CTC grade ≥2 AESI is defined as the time from the start of treatment to the start date 
of the first incidence of an event of CTC grade ≥2, i.e., time in days is calculated as (start date of first 
occurrence of the event) – (date of first dose of study treatment) +1. 
In the absence of an event during the on-treatment period, the censoring date applied will be the earliest 
of the following dates:

End date of on-treatment period (end of study treatment + 130 days).

death date

Start date of new antineoplastic therapy before experiencing any CTC grade ≥2 AESI. 

Data cut-off date.

withdrawal of informed consent date
Time to onset of CTC grade ≥2 AESI will be summarized using the Kaplan-Meier method by AESI 
grouping and treatment. Median time to onset and its 95% CI will be provided and ascending Kaplan-
Meier plots will be generated by treatment. The analysis of time to onset of AESI will be performed 
only for AESI groupings of infections, opportunistic infections, neutropenia, DILI (Hepatic 
transaminase and bilirubin elevations) and thrombocytopenia (if there are sufficient number of events).
The same analysis will be repeated for time to onset of CTC grade ≥3 AESI with similar censoring 
rules applied.
Deaths
Summaries for on-treatment and all deaths will be produced separately by SOC, PT, and treatment.
Deaths will be listed with post treatment deaths flagged. A listing of deaths prior to starting treatment 
will be provided for all screened subjects.
Laboratory data
On analyzing laboratory, data from all sources, including central and local laboratories, will be 
combined. The summaries will include all assessments available for the lab parameter collected no 
later than 130 days after the last study treatment administration date. Grading of laboratory values will 
be assigned programmatically per NCI CTCAE 5.0. The time windows for lab assessments are shown 
in Table 2-7:


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Table 2-7 Time windows for lab assessments
Time Window
Planned Visit Timing 
Time Window Definition
On treatment
Baseline 
On or before Study Day 1[a]
≤ Study Day 1
Week 3
Study Day 22
Study Days 2 to 32
Week 6
Study Day 43
Study Days 33 to 53
....... 
......
......
Week k
(with k = 9,12 …)
Study Day 21*(k/3)+1
Study Day 
21*(k/3)-9 to 21*(k/3)+11 
Safety follow-up 1
Safety follow-up 2
Safety follow-up 3
Safety follow-up 4
Safety follow-up 5
26 days after treatment 
discontinuation
52 days after treatment 
discontinuation
78 days after treatment 
discontinuation
104 days after treatment 
discontinuation
130 days after treatment 
discontinuation
[EOT visit date+8; EOT date +39]
[EOT visit date+40; EOT date
+65]
[EOT visit date+66; EOT date
+91]
[EOT visit date+92; EOT date
+117]
[EOT visit date+118; EOT date
+143]
[a] Study Day 1 = first treatment date
The following summaries will be produced for hematology and biochemistry laboratory data by 
laboratory parameter and treatment:

Worst post-baseline CTC grade, regardless of the baseline status. Each subject will be counted
only for the worst grade observed post-baseline

Shift tables using CTC grades to compare baseline with the worst on-treatment value. Hypo 
and hyper worst grade will be summarized separately if applicable

For laboratory tests where CTC grades are not defined, shift tables using the low/normal/high
classification to compare baseline with the worst on-treatment value

Trends of lab parameter values over time, including baseline and selected on-treatment time 
points, will be displayed via boxplots 
The following listings will be produced for the laboratory data:

Listings of all laboratory data, with CTC grades and classification relative to the laboratory 
normal range. Lab data collected during the post-treatment period will be flagged

Listing of all CTC grade 3 or 4 laboratory toxicities


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Liver function parameters 
Liver function parameters of interest are total bilirubin (TBL), ALT, AST, and alkaline phosphatase 
(ALP). The number (%) of subjects with worst post-baseline values per Novartis Liver Toxicity 
guidelines will be summarized by treatment:
The following summaries will be produced:

ALT > 3xULN 

ALT > 5xULN

ALT > 10xULN

ALT > 20xULN

AST > 3xULN 

AST > 5xULN

AST > 10xULN

AST > 20xULN

ALT or AST > 3xULN 

ALT or AST > 5xULN

ALT or AST > 8xULN

ALT or AST > 10xULN

ALT or AST > 20xULN

TBL > 2xULN

TBL > 3xULN
Combined elevations post-baseline:
For AST and ALT ≤ ULN at baseline

ALT or AST > 3xULN & TBL > 2xULN

ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN

ALT or AST > 3xULN & TBL > 2xULN & ALP ≥ 2xULN
For ALT or AST > ULN at baseline (Bsl)

Elevated ALT or AST (*) & TBL (> 2x Bsl and 2xULN)

Elevated ALT or AST (*) & TBL (> 2x Bsl and 2xULN) & ALP < 2xULN

Elevated ALT or AST (*) & TBL (> 2x Bsl and 2xULN) & ALP ≥ 2xULN
* Elevated AST or ALT defined as: >3x ULN if =< ULN at baseline, or (>3x Bsl or 8x ULN) if > 
ULN at baseline
In addition, a listing of all TBILI, ALT, AST, and ALP values for subjects with a post-baseline TBILI
> 2xULN, ALT> 3xULN or AST > 3xULN will be provided.  


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Time to onset of grade 2 or worse and time to onset of grade 3 or worse liver function test abnormalities 
will be summarized for the following liver function test parameters:

AST or ALT (whichever occurs first)

Total bilirubin
Time to onset will be summarized using Kaplan-Meier method. Median and its 95% CI will be 
summarized. 
Time to onset of LFT abnormalities is defined as the time from the start of treatment to the start date 
of the first incidence of grade 2 or worse LFTs post-baseline (or grade 3 or worse), i.e., time in days is 
calculated as (start date of first occurrence of LFT abnormalities) – (date of first dose of study 
treatment) +1. A subject will be censored for time to onset if:

the subject dies without experiencing the LFT abnormality 

the subject receives a new anticancer therapy without experiencing the LFT abnormality or 
before LFT abnormality has occurred 

the subject discontinues from the study treatment without experiencing the LFT abnormality 
(up to 130 days after study treatment discontinuation)

the subject is still ongoing at the analysis cut-off without experiencing the LFT abnormality
The censoring date will be the earliest date from the following dates: last date of study treatment in the 
treatment phase + 130 days, analysis cut-off, the day before new anticancer therapy start date, death 
date, and last on-treatment laboratory sampling date (for the particular parameter) during on-treatment 
period. For the time to onset of grade 2 or worse LFTs, subjects with grade 2 or worse at baseline will
be excluded from the analysis and the same for the time to onset of grade 3 or worse LFTs.
Time to onset of neutropenia and thrombocytopenia:
Time to onset of grade 2 or worse and time to onset of grade 3 or worse neutropenia and 
thrombocytopenia will be summarized respectively. The censoring rule will be the same as those used 
at time to onset of LFT abnormalities analysis.
Other safety data
2.8.4.1
ECG and cardiac imaging data
ECG abnormality for baseline and any post baseline assessments will be summarized by treatment. A 
listing of all ECG assessments will be produced by treatment with notable values flagged.
2.8.4.2
Vital signs
Vital sign assessments are performed in order to characterize the basic body function. The following 
parameters will be collected: height (cm), weight (kg), body temperature (°C), pulse rate (beats per 
minute), systolic and diastolic blood pressure (mmHg). 
Data handling
Vital signs collected on treatment will be summarized. Values measured outside of on-treatment period 
will be flagged in the listings.


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Data analysis
For analysis of vital signs, the clinically notable vital sign criteria are provided in Table 2-8:
Table 2-8   Clinically notable changes in vital signs
Vital sign 
(unit)
Clinically notable criteria
above normal value 
below normal value
Weight (kg)
increase > 10% from Baseline
decrease  > 10% from Baseline
Systolic blood 
pressure 
(mmHg)
>=180 with increase from baseline 
of >=20
<=90 with decrease from baseline 
of >=20
Diastolic blood 
pressure 
(mmHg)
>=105 with increase from baseline 
of >=15
<=50 with decrease from baseline 
of >=15
Pulse rate 
(bpm)
>=100 with increase from baseline 
of >25%
<=50 with decrease from baseline of 
> 25%
Body 
temperature
(°C)
>= 39.1 
-
The number and percentage of subjects with notable vital sign values (high/low) will be summarized 
by treatment.         
A listing of all vital sign assessments will be produced by treatment with notable values and 
assessments, collected outside of on-treatment, flagged. 
2.9
Pharmacokinetic endpoints
PAS will be used in the pharmacokinetic data analysis.
PK concentrations 
Descriptive statistics (n, m (number of non-zero concentrations), arithmetic mean, CV% mean, SD,
median, geometric mean, CV% geo-mean, minimum and maximum) for canakinumab concentration 
will be presented at each scheduled time point for the PAS.
Individual concentration-time profiles for canakinumab evaluable concentrations with median will be 
displayed graphically for PAS on the semi-log view. In addition, the mean (+/- SD) and geometric 
mean concentration-time profiles for canakinumab over time will be displayed graphically for PAS on 
the linear and semi-log view. Only time points with n ≥ 4 observations will be shown on the figure.
All individual plasma canakinumab concentration data will be listed by treatment for the FAS.
Handling of PK data below LLOQ or missing
All concentration values below the lower limit of quantitation (LLOQ) are set to zero by the Bioanalyst, 
and will be displayed in the listings as zero and flagged. LLOQ values will be treated as zero in any 
calculations of summary statistics, and treated as missing for the calculation of the geometric means 
and their CV%. The number of non-zero concentrations will also be reported in the summary statistics.


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Missing values for any PK data will not be imputed and will be treated as missing.
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 to characterize canakinumab exposure and to determine the 
effects of intrinsic (i.e. demographic factors) and extrinsic covariates (e.g. concomitant medications) 
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.
2.10
PD and PK/PD analyses
Analysis of relationship between canakinumab exposure and efficacy/safety
endpoints
2.10.1.1 Evaluable Ctrough concentration
For canakinumab, steady state pre-dose evaluable concentrations (as defined in PAS) collected before 
dose administration on and after Day 1 of Cycle 6 and beyond are steady state evaluable Ctrough. 
2.10.1.2 Average evaluable Ctrough concentration
Average steady state evaluable Ctrough concentration will be used in the exposure/response and 
exposure/safety analyses. Each subject may have one or more steady state evaluable Ctrough 
concentration values. The average steady state evaluable Ctrough is defined as:
Cmin_avg_ss = geometric mean of all steady state evaluable Ctrough for each subject, considering the 
distribution of PK concentration is generally lognormal
Quartile of average trough concentration is defined as:

<Q1: <25th percentile

Q1 to <Q2: ≥25th percentile and <50 percentile

Q2 to <Q3: ≥50th percentile and <75th percentile

≥Q3: ≥75th percentile
Subject demographic characteristics will be summarized for all subjects and by quartile of 
Cmin_avg_ss.
2.10.1.3 Correlations between PK exposure and efficacy measures
Correlations between efficacy endpoints and trough concentrations will be explored using the PAS. 
Analyses will be focused on the efficacy endpoints: DFS and OS. 
The relationship between DFS/OS and PK exposure will be analyzed using Kaplan-Meier 
methodology.  
Steady state evaluable Ctrough concentrations as defined in Section 2.10.1.2 will be included in 
calculating average steady state trough concentration with the following additional rules: 

for subjects who had a DFS event, only steady state trough concentrations observed on or 
before the date of DFS event will be included;




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to define clinically relevant changes in this population (lung cancer, adjuvant setting) a 10 point 
deterioration will be assumed to be clinically meaningful for the QLQ-LC13 and QLQ-C30 (Osoba 
1998).
The primary PRO variables of interest are: time to definitive 10 point deterioration symptom scores 
for each of chest pain, cough and dyspnea per QLQ-LC13 questionnaire
The secondary PRO variables of interest are:

Utilities derived from the EQ-5D-5L

Time to first 10 point deterioration symptom scores of pain, cough and dyspnea per QLQ-
LC13 questionnaire

Time to first 10 point deterioration of global health status/QoL, shortness of breath, pain, 
role functioning, physical functioning and fatigue per QLQ-C30 questionnaire

Time to 10 point definitive deterioration in global health status/QoL, shortness of breath,
pain, role functioning, physical functioning and fatigue per QLQ-C30
The time to 10 point definitive 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 worsening from baseline of the 
corresponding scale score, with no later change below this threshold, i.e. <10 points was observed or 
if this worsening was observed at the last assessment for the subject, or death due to any cause
(whichever occurs earlier). 
The time to first 10 point deterioration is defined as the time from the date of randomization to the first 
onset of at least 10 points absolute increase from baseline (worsening) in symptoms scores or at least 
10 points absolute decrease from baseline (worsening) in global health status/QoL and functioning 
scales (role functioning, physical functioning), or death due to any cause, whichever occurs earlier.
If a subject has not had an event, time to definitive deterioration or first deterioration will be censored 
at the date of the last adequate assessment. If deterioration occurs at the last adequate assessment, this 
will also be considered definitive. Subjects receiving any further anti-neoplastic therapy related to 
NSCLC before definitive worsening will be censored at the date of their last assessment before starting 
this therapy. If a definitive deterioration is observed after two or more missing assessments, subject is 
censored at the date of their last available questionnaire prior to the deterioration. Subjects with no 
baseline data will be censored at day 1. 
Death is considered as a definitive deterioration event when it occurs within a period of time defined 
by 2 times the period between two assessments as planned in the study protocol. This avoids 
overestimating the time to definitive worsening in subjects dying after an irregular assessment scheme. 
Subjects who die after more than twice the planned period between two assessments since the last 
assessment are censored at the date of their last available questionnaire.
Censoring reasons for time to definitive deterioration or first deterioration event will be summarized.
All assessments will be included in the time to definitive deterioration or first deterioration analysis. 
The distribution will be presented descriptively 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. Log-rank test stratified by randomization 
stratification factors will be performed. A Cox regression stratified by randomization stratification 
factors from IRT will be used to estimate the hazard ratio (HR), along with two-sided 95% confidence 
interval.


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Sensitivity analysis of time to definitive and first deterioration with 5 points will also be performed 
using the same methodology.
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 time point for each 
treatment arm using time windows as described in Table 2.1. Changes from the baseline by treatment 
arm at each visit will be ploted for all scales of QLQ-LC13, QLQ-C30 and EQ-5D-5L. 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. Tables of 
compliance and completion rates over time for QLQ-LC13, QLQ-C30 and EQ-5D-5L by treatment 
arm will be generated. 
In addition, a repeated measures 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 models will be first based on all assessments. In additional, the models 
will be repeated to include only assessments collected within 130 days of last study treatment. Any 
assessments collected after the start of further anti-tumor therapy will not be included in the models. 
The modeling will mainly be done on the actual score. Note that the modeling of the change in score 
or the actual score is equivalent since adjustment for baseline score is considered.  This repeated 
measures model will include terms for treatment, the stratification factors, time, and baseline value as 
main effects, and an interaction term for treatment by time. This analysis will be restricted to subjects 
with an evaluable baseline score and at least one evaluable post-baseline score. The differences in 
least square means between the treatment arms and corresponding 95% confidence interval at selected 
time points will be presented. 
Time will be considered as a continuous variable expressed in weeks, i.e. considering that PRO follow 
a linear trend. As a first approach, an unstructured correlation matrix will be used to model the 
correlation within subjects. Other structures of the correlation matrix, including AR (1), will be 
investigated and simplified using likelihood ratio tested if appropriate.
If PRO is found not to follow a linear trend, the time variable might be considered as a categorical 
variable instead of continuous in the model. 


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2.13
Interim analysis
Disease free survival (DFS)
One interim analysis is planned after approximately 196 of the approximately 392 targeted DFS events, 
i.e., at approximately 50% information fraction, respectively, has been documented. The primary intent 
of the interim analysis is to stop early for lack of efficacy (futility). There is no intent to carry out an 
analysis to declare superior efficacy at the time of the first interim analysis. 
An α-spending function according to a 2-look Lan-DeMets group sequential design with O’Brien-
Fleming type stopping boundary will be used to construct the efficacy stopping boundaries (Lan and 
DeMets 1983). A user-defined gamma function with γ = -3 stopping boundary will be used as a β-
spending function to determine the non-binding futility boundary. The choice of non-binding nature 
of the futility stopping boundary ensures that the efficacy stopping boundaries are not affected. Based 
on the choice of α-spending and β-spending function described above and if the interim analysis is 
performed exactly at 196 DFS events, the futility boundary expressed on p-value (or  Z-statistic) at the 
first interim is calculated as 0.411 (or 0.226), i.e., the observed p-value has to be greater than 0.411  
(or calculated Z-statistic is < 0.226) to conclude futility. 
Since the observed number of events at the interim analysis may not be exactly equal to the planned 
196 DFS events, the futility boundaries will need to be recalculated based on the exact information 
fraction. The observed p-value (or Z-test statistic) at the interim analyses will then be compared against 
the re-calculated futility boundary.


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If the study continues to the final DFS analysis, the final DFS analysis will be performed when 
approximately 392 DFS events have been documented. If exactly 196 events are observed at the 
interim analysis, exactly 392 events are obtained at the final analysis, the observed p-value will have 
to be less than 0.024 (or the observed Z statistics has to be > 1.969) to declare statistical significance. 
With consideration of the p-value has been spent at interim analyses, in practice, 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 0.025.
Since the planned efficacy interim analysis was not performed, the efficacy boundary and observed p-
value at the final DFS analysis will take into account only the interim analysis actually performed (i.e. 
futility analysis). The statistical properties of the group sequential design are summarized for DFS in 
Table 2-9 below.
Table 2-9 Simulated probabilities to stop for futility or efficacy at the interim or final DFS 
analysis
Scenario
Look
# DFS 
events
Simulated cumulative 
probabilities (%)
Simulated incremental 
probabilities (%)
Stop for 
efficacy
Stop for 
futility
Stop for 
efficacy
Stop for 
futility
Under H01 (HR=1)
1st IA (futility)
196
-
59.34
-
59.34
Final
392
2.36
-
2.18
-
Under Ha1
(HR=0.716)
1st IA (futility)
196
-
1.83
-
1.83
Final
392
89.56
-
63.7
-
Under HR=0.8
1st IA (futility)
196
-
9.28
-
9.28
Final
392
58.65
-
50.49
-
Note: Simulation is performed in East 6.4 with number of simulations = 10,000 and randomization 
seed = 1234
The interim analysis will be performed by an independent statistician (not involved with the conduct 
of the study). Further details are described in the DMC charter. The results of the interim analyses will 
be provided to the DMC by the independent statistician.
Key secondary endpoint: Overall survival (OS)
A hierarchical testing procedure will be adopted and the statistical tests for OS will be performed only 
if the primary efficacy endpoint DFS is statistically significant. 
A maximum of three analyses is planned for OS; at the time of final analysis for DFS provided DFS 
is significant, at which point a total of approximately 318 (63%) deaths are expected, an additional IA 
for OS when a total of approximately 418 (83%) deaths are expected, and a final analysis for OS when 
approximately 504 deaths are expected. 
A α-spending function according to Lan-DeMets (Lan and DeMets 1983) (O’Brien-Fleming) α-
spending function along with the testing strategy outlined below will be used to maintain the overall 
type I error probability. This guarantees the protection of the 2.5% overall level of significance across 
the two hypotheses and the repeated testing of the OS hypotheses in the interims and the final analysis 
(Glimm 2010). 
The trial allows for the stopping of the study for a superior OS result, provided the primary endpoint 
DFS has already been shown to be statistically significant favoring the test treatment arm. Further, the 


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exact nominal p-values that will need to be observed to declare statistical significance at the time of 
these analyses for OS will depend on the number of OS events that have been observed at the time of 
these analyses and the α for OS already spent at the time of earlier analyses.
Unblinded results from the interim analysis for DFS will not be communicated to the Sponsor's 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) DFS analysis has crossed the pre-specified 
boundary for efficacy, or ii) DMC determines if the study needs to be terminated due to any cause 
including futility or safety reasons. Further details will be described in the DMC Charter. At the time 
of final DFS analysis, both DFS and interim OS analysis will be performed by the Sponsor's clinical 
team. Investigators and subjects will remain blinded to study treatment and all subjects will continue 
to be followed for OS until the final OS analysis (or earlier if OS reaches statistical significance at any 
of the interim analyses).
The statistical properties of the group sequential design are summarized for OS in Table 10-2 below.
Table 2-3
Simulated cumulative power to stop for efficacy on overall survival at final 
DFS analysis or final OS analysis
Look
Months after 
randomization of 
the first subject 
(approximation)
# DFS Events
Cumulative 
power against 
a hazard ratio 
of  0.716
# OS
Events
Cumulative 
powerb
against a 
hazard ratio of 
0.776
1st DFS IA 
(futility)
27
196 (50.0%)
-
-
-
Final DFS
42
392 (100%)
89.56%
318 (63.1%)a
36.26%
OS IA
52
-
-
418 (82.9%)a
64.09%
Final OS
63
-
-
504 (100%)a
79.25%
a: To be performed only if the final DFS analysis is significant
b: Power conditional on DFS being significant
Simulations performed in East 6.4 with number of simulations = 10,000 and randomization seed =1234.
Confidentiality of interim results 
At the time of the interim analysis for DFS, interim analysis will be performed by an independent
statistician. Analysis results from the interim analysis for DFS will not be communicated to the
sponsor’s clinical team or to any party involved in the study conduct until the DMC has determined 
that the study needs to be terminated due to any cause including futility or safety reasons. Further
details will be described in the DMC Charter.
At the time of final DFS analysis, both DFS and interim OS analysis will be performed by the 
sponsor's clinical team. All subjects will continue to be followed for OS until the final OS analysis or 
earlier if OS reaches statistical significance at any of the interim analyses. Any subsequent OS interim 
analysis and final OS analysis will also be performed by the Sponsor’s clinical team.


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3
Sample size calculation
3.1
Primary analysis
The sample size calculation is based on the primary variable DFS. The hypotheses to be tested and 
details of the testing strategy are described in Sections 2.5.2.
Based on available data, the median DFS in the placebo arm is around 48 months (Kelly 2015). It is 
expected that treatment with canakinumab will result in a 28.4% reduction in the hazard rate for DFS 
(corresponding to an increase in median DFS from 48 months to 67 months under the exponential 
model assumption). 
Then, in order to ensure 90% power to test the null hypothesis: DFS hazard ratio = 1, versus the specific 
alternative hypothesis: DFS hazard ratio = 0.716, it is calculated that a total of 392 DFS events need
to be observed. This calculation assumes analysis by a one-sided log-rank test at the overall 2.5% level 
of significance, subjects randomized to the two treatment arms in a 1:1 ratio, and a 2-look group 
sequential design with a Lan-DeMets (O’Brien-Fleming) α-spending function and a user-defined 
gamma function with γ = -3 to define a non-binding futility rule at the interim analysis, using an 
information fraction of 50% for the interim analysis (futility only). Assuming that enrolment will 
continue for approximately 30 months at a rate of 50 subjects per month and a 5% annual dropout rate 
by the time of the final DFS analysis, a total of approximate 1500 subjects will need to be randomized 
to observe the targeted 392 DFS events at about 12 months after the randomization date of the last 
subject, i.e., 42 months after the randomization date of the first subject. These calculations were made 
using the software package East 6.4.
The final DFS analysis is planned to be performed when approximately 392 DFS events are 
documented to ensure the trial is not over-powered. At the time of the data cut-off for final DFS 
analysis, all subjects randomized prior to the data cut-off date for final DFS analysis who have had at 
least one post baseline recurrence assessment (i.e. all subjects have a minimal follow-up of 3 months) 
or discontinued study earlier will be included.
3.2
Power for analysis of key secondary variables
OS, as the key secondary variable, will be formally statistically tested, provided that the primary 
variable DFS is statistically significant. The hypotheses to be tested and details of the testing strategy 
are provided in Section 2.6.2. Based on available data, the median OS in the placebo arm is expected 
to be approximately 5 years (Pignon 2008). In addition, the OS result presented in (Kelly 2015) was 
not mature as the median was not reached at 5 years, but the overall trend indicates a median OS greater 
than 5 years. After taking these into consideration, the median OS for the placebo arm is assumed to 
be approximately 66 months. It is hypothesized that treatment with canakinumab will result in a 22.4% 
reduction in the hazard rate for OS, i.e., an expected hazard ratio of 0.776. It corresponds to an increase 
in median 66 to 85 months under the exponential model assumption. Then, in order to ensure 80% 
power to test the null hypothesis: OS hazard ratio = 1, versus the specific alternative hypothesis: OS 
hazard ratio = 0.776, it is calculated that a total of 504 deaths need to be observed. This calculation 
assumes analysis by a one-sided log-rank test at the overall 2.5% level of significance, subjects 
randomized to the two treatment arms in a 1:1 ratio, and a group sequential design with a Lan-DeMets 
α-spending function using information fractions according to actual events observed at performed 
analysis time points. All the efficacy boundaries will be calculated based on actual events and the 
number of interim analyses.


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4
Change to protocol specified analyses
Not applicable
5
Appendix
This will be used later for drafting CSR Appendix 16.1.9.
5.1
Imputation rules
Study treatment
No imputation of the start date of infusion or end date for infusion will be applied. Complete dates are 
required as per eCRF.
AE, ConMeds and safety assessment date imputation
Table 5-1   Imputation of start dates (AE, CM) and assessments (LB, EG, VS)
Missing 
Element
Rule
day, month, and 
year

No imputation will be done for completely missing dates
day, month

If available year = year of study treatment start date then 

If stop date contains a full date and stop date is earlier than study treatment start date then 
set start date = 01JanYYYY 

Else set start date = study treatment start date. 

If available year > year of study treatment start date then 01JanYYYY

If available year < year of study treatment start date then 01JulYYYY
day

If available month and year = month and year of study treatment start date then 
o
If stop date contains a full date and stop date is earlier than study treatment 
start date then set start date= 01MONYYYY. 
o
Else set start date = study treatment start date.

If available month and year > month and year of study treatment start date then 
01MONYYYY  

If available month and year < month year of study treatment start date then 
15MONYYYY  
Table 5-2   Imputation of end dates (AE, CM) 
Missing 
Element
Rule 
(*=last treatment date plus 130 days not > (death date, cut-off date, withdrawal of consent date))
day, month, and 
year

Completely missing end dates (incl. ongoing events) will be imputed by the end date of the 
on-treatment period* 
day, month

If partial end date contains year only, set end date = earliest of 31DecYYYY or end date of 
the on-treatment period * 
day

If partial end date contains month and year, set end date = earliest of last day of the month 
or end date of the on-treatment period*
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data listings.


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Any AEs and ConMeds which are continuing as per data cut-off will be shown as ‘ongoing’ rather 
than the end date provided. 
5.1.2.1
Other imputations
Not applicable
5.2
AEs coding/grading
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology.
AEs will be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0. 
The CTCAE represents a comprehensive grading system for reporting the acute and late effects of 
cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding to mild, 
moderate, severe, life threatening, and death. This grading system inherently places a value on the 
importance of an event, although there is not necessarily proportionality among grades (a grade 2 is 
not necessarily twice as bad as a grade 1). 
5.3
Laboratory parameters derivations
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. The calculation of CTCAE grades 
will be based on the observed laboratory values only, clinical assessments will not be taken into 
account. The criteria to assign CTCAE grades are given in Novartis internal criteria for CTCAE 
grading of laboratory parameters. The latest available version of the document based on the underlying 
CTCAE version 5.0 at the time of analysis will be used. For laboratory tests where grades are not 
defined by CTCAE version 5.0, results will be graded by the low/normal/high (or other project-specific 
ranges, if more suitable) classifications based on laboratory normal ranges.
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. Grade 
5 will not be used. For laboratory tests that are graded for both low and high values, summaries will 
be done separately and labelled by direction, e.g., sodium will be summarized as hyponatremia and 
hypernatremia.
Imputation Rules  
CTC grading for blood differentials is based on absolute values. However, this data may not be 
reported as absolute counts but rather as percentage of WBC. 
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to conversion of 
laboratory values to SI unit, these numeric values are set to X. 
The following rules will be applied to derive the WBC differential counts when only percentages are 
available for an xxx differential
xxx count = (WBC count) * (xxx %value / 100)
Further derivation of laboratory parameters might be required for CTCAE grading. For instance, 
corrected calcium can be derived using the reported total calcium value and albumin at the same 
assessment using the following formula:
         Corrected Calcium (mmol/L) = Calcium (mmol/L) + 0.020 [40 - albumin (g/L)]]


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In order to apply the above formula, albumin values in g/L will be converted to g/dL by multiplying
by 0.1), calcium values in mmol/L will be converted to mg/dL by dividing by 0.2495. For calculation 
of laboratory CTC grades 0 and 1, the normal range for derived corrected calcium is set to the same 
limits (in mg/dL) as for calcium.
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and corrected 
calcium will be assigned as described above for grading
5.4
Statistical models
Primary analysis
The LIFETEST procedure in SAS with the TIME statement including a variable with survival times 
and a (right) censoring variable, and with STRATA statement including variables of stratification 
factors and with GROUP option under STRATA statement. As an output of the procedure, the rank 
statistic S and variance var (S) will be obtained. Under the null hypothesis, the test statistic Z=S/√
[var (S)] is approximately normally distributed. The one-sided p-value will be obtained from normally 
distributed Z statistic.
This Section gives additional details regarding the analyses described in Section 2.5.2.
Kaplan-Meier estimates
An estimate of the survival function in each treatment arm will be constructed using Kaplan-Meier
(product-limit) method as implemented in PROC LIFETEST with METHOD=KM option. The PROC
LIFETEST statement will use the option CONFTYPE=LOGLOG.
Median survival for each treatment arm will be obtained along with 95% confidence intervals
calculated from PROC LIFETEST output using the method of (Brookmeyer and Crowley 1982). 
Kaplan-Meier estimates of the survival function with 95% confidence intervals at specific time
points will be summarized. The standard error of the Kaplan-Meier estimate will be calculated
using Greenwood’s formula (Collett 1994).
Hazard ratio
Hazard ratio will be estimated by fitting the Cox proportional hazards model using SAS procedure 
PHREG (with TIES=EXACT option in the MODEL statement). 
A stratified unadjusted Cox model will be, i.e. the MODEL statement will include the treatment arm
variable as the only covariate and the STRATA statement will include stratification variable(s).
Hazard ratio with two-sided 95% confidence interval will be based on Wald test.
Treatment of ties
The STRATA statement in LIFETEST procedure will be used to analyze time to event data with ties. 
The PHREG procedure in SAS with option TIES=EXACT will be used to fit the Cox proportional 
hazards model.
Checking proportionality of hazard assumption
Plots (SURVIVAL LOGSURV LOGLOGS) generated by LIFETEST procedure in SAS will be used 
to provide visual checks of the proportional hazard assumption. 

LOGLOGS plots log (cumulative hazard). The LOGLOG plot will show parallel curves if hazards 


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are proportional. 
Key secondary analysis
Same statistical methodologies will be used as in the primary efficacy analysis
5.5
Patient reported outcomes: EORTC QLQ-C30/LC13 and
EQ-5D-5L/VAS 
The text below gives more detailed instructions and rules needed for programming of the analyses 
described in Section 2.11.
EORTC QLQ-C30 scale scores will be generated by first obtaining the raw scores adding up the item 
responses on the questions which make up each domain and then applying the linear transformation to 
the raw scores in accordance with the respective scoring manual provided by the developers. Scores 
in each scale will be generated if at least half of the items comprising the scale have been answered. 
For single item scales with missing responses and scales where less than half of the items have not 
been answered, scale scores will be set to missing.
The scoring approach for the QLQ-LC13 is identical in principle to that for the symptom scales/single 
items of the QLQ-C30. The dyspnea scale of the QLQ-LC13 is the only multi item scale (all others are 
single item scales) and should only be used if all items comprising the scale have been answered.
For the calculation of EQ-5D-5L index value, the EQ-5D crosswalk value set for the UK using the 
time trade-off method will be used. If any one of the five dimensions of health state is missing, the 
index value will be set to missing.
A repeated measures model for longitudinal data will be used to compare the two treatment arms in 
terms of the domain scores over time. This longitudinal model will include terms for treatment, the 
randomization stratification factors, time of visit (duration in days from the time of baseline 
measurement to the time of a particular post baseline measurement), baseline value as fixed effects, 
and an interaction term for treatment by time. This analysis will be restricted to subjects with an 
evaluable baseline score and at least one evaluable post-baseline score. Time will be considered as a 
continuous variable in this analysis. As a first approach, an unstructured correlation matrix will be 
used to model the correlation within subjects. Other structures of the correlation matrix, including AR 
(1), will be investigated and simplified using likelihood ratio tested if appropriate. In particular 
situations, the non-convergence of the model may be caused by few subjects with assessments at later 
time points. The possibility of removing few assessments later than a certain time point will be 
investigated if appropriate.
5.6
Missing tumor assessments
The term ‘missing adequate tumor assessment’ is defined as a tumor assessment not done. For the sake 
of simplicity, a ‘tumor assessment’ will be referred to as an ‘assessment’ and a ‘missing adequate 
tumor assessment’ will be referred to as a ‘missing assessment’. 
The presence and the number of missing assessments affects DFS censoring and event date. 
An exact rule to determine whether there is no, one or two missing assessments is therefore needed. 
This rule is based:

on the duration between LATA date and the event date

on the duration between LATA date and the cut-off date


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In this study, the protocol defined schedule of assessments is

every 12 weeks during the first year (i.e. at weeks 12, 24, 36 and 48),

every 26 weeks through year 2 and year 3 (i.e. at weeks 74, 100,126 and 152),

every 52 weeks through year 4 and year 5 (i.e. at weeks 204 and 256).
The scheduled date of assessments (in weeks from randomization), protocol specified windows for 
assessment, and the thresholds for LARA to belong to a visit can be found in Table 5-3.
Table 5-3 Schedule for assessments, time windows and D1/D2 (weeks)
assessment 
schedule
Scheduled 
date – one 
week*
Schedule date
(weeks 
from 
randomization)
Scheduled 
date + one 
week*
Threshold 
(weeks)**
Boundary 
of 
assessment***
(start, end]
D1/D2****
Every 
12 
weeks 
for 
the 
first year
1st (C5D1)
11
12
13
18
(0,18]
14/26
2nd (C9D1)
23
24
25
30
(18,30]
14/26
3rd (C13D1)
35
36
37
42
(30,42]
14/40
4th (C17D1)
47
48
49
61
(42,61]
28/54
Every 
26 
weeks 
for 
the 
second 
and third 
year
5th
73
74
75
87
(61,87]
28/54
6th
99
100
101
113
(87,113]
28/54
7th
125
126
127
139
(113,139]
28/80
8th
151
152
153
178
(139,178]
54/106
Every 
52 
weeks 
for 
the 
four and 
fifth year
9th
203
204
205
230
(178,230]
54/106
10th
255
256
257
282
(230, 282]
54/106
* These start and end study weeks are used to determine if a visit is on schedule. For example, a visit between study week 
23 and study week 25 is considered the 2nd ‘on schedule’ assessment.
** The threshold correspond to the mid-point between current and next visit and to the upper limit for LARA to be matched 
to a certain scheduled assessment e.g. if LARA is at week 45, this is after the threshold for 3rd recurrence assessment 
(C13D1) and before that for the 4th recurrence assessment, so the matching schedule assessment is the 4th recurrence
assessment (C17D1).
*** These boundaries are defined according to assessment thresholds to calculate D1 and D2. For example: (30, 42] means 
any assessment falls into this time interval will be considered as the 3rd assessment visit. 
**** D1 and D2 are defined per the protocol-specified recurrence assessment schedule 

The threshold D1 is defined as the protocol-specified time interval between the assessments plus 2x the protocol-
allowed time window around the assessments (i.e. = 2*1 week=2 weeks).

The threshold D2 is defined as twice the protocol-specified time interval between the assessments plus 2x the 
protocol-allowed time window around the assessments 
Since there are changes in schedule for assessments during the 5 year tumor assessment period, D1 
and D2 are defined differently depending on when LATA occurs. Here are the rules based on when 
LATA occurs:


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
Rule 1: if LATA happens within 30 weeks after randomization (≤ study day 210 day), the
applicable scheduled tumor assessments are the 1st and 2nd assessment (on C5D1 and C9D1), 
D1= 12 + 2 = 14 weeks and D2=12*2 + 2 = 26 weeks.

Rule 2: if LATA happens after 30 weeks but within 42 weeks, the matched scheduled tumor
assessment is 3rd assessment (on C13D1), the study period: ≥ study day 211 and ≤ study day 
294, D1= 12 + 2 = 14 weeks and D2=12 + 26 + 2 = 40 weeks.

Rule 3: if LATA happens after 42 weeks but within 113 weeks, the applicable scheduled 
tumor assessments are  4th, 5th and 6th assessments, the study period: ≥ study day 295 and ≤ 
study day 791, D1= 26 + 2 = 28 weeks and D2=26*2 + 2 = 54 weeks.

Rule 4: if LATA happens after 113 weeks but within 139 weeks, the matched scheduled 
tumor assessment is 7th assessment, the study period: ≥ 792 days and ≤ 973 days, D1= 26 + 2 
= 28 weeks and D2=26 + 52 + 2 = 80 weeks.

Rule 5: if LATA happens after 139 weeks, the applicable scheduled tumor assessments are  
8th, 9th and 10th assessments, the study period: ≥ 974 days, D1= 52 + 2 = 54 weeks and 
D2=52*2 + 2 = 106 weeks.
The number of missing events is defined as:

An event after LATA+D1 weeks will be considered as having ≥1 missing assessment

An event after LATA+D2 weeks will be considered as having ≥2 missing assessments


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Reference
1. Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival Time. 
Biometrics, 38, 29 - 41. 
2. Collet D (1994). Modelling survival data in medical research. London, Chapman & Hall.
3. Fayers P.M. et al. on behalf of the EORTC Quality of Life Group. The EORTC QLQ-C30 
Scoring Manual (3rd edition). Published by: European Organization for Research and Treatment 
of Cancer, Brussels 2001.
4. Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in 
health-related quality-of-life scores. Journal of clinical oncology. 1998;16(1):139-144.
5. Fleming TR, Harrington DP and O’Brien PC (1984). Designs for group sequential tests. 
Controlled Clinical Trials, 5, 348-361.
6. Kelly K et al. Adjuvant Erlotinib versus Placebo in Subjects with Stage IB-IIIA Non–Small-Cell 
Lung Cancer (RADIANT): A Randomized, Double-Blind, Phase III Trial, Journal of Clinical 
Oncology 2015; 33, no. 34 4007-4014.
7. Lan KKG, DeMets DL (1983). Discrete sequential boundaries for clinical trials. Biometrika, 70, 
649-53.
8. Pignon JP et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative 
Group. J Clin Oncol 2008; Jul 20; 26(21):3552-9.
9. Van Reenen M. et al. EQ-5D-5L User Guide – Basic information on how to use the EQ-5D-5L 
instrument. http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Folders_ 
Flyers/EQ-5D-5L_UserGuide_2015.pdf.  Accessed Oct 2017.
10. European Medicines Agency (2020). Guidance on the management of clinical trials during the 
COVID-19 (coronavirus) pandemic
11. Food and Drug Administration (2020). FDA Guidance on Conduct of Clinical Trials of Medical 
Products during COVID-19 Pandemic: Guidance for Industry, Investigators, and Institutional 
Review Boards (2020)