Conditions: First Line Non-Small Cell Lung Cancer
Keywords: Avelumab MSB0010718C Non-Small Cell Lung Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1214
Healthy volunteers: no

Brief summary:
The purpose of this study was to demonstrate superiority with regard to Overall Survival (OS) or Progression Free Survival (PFS) of avelumab versus platinum-based doublet, based on an Independent Review Committee assessment, in Non-small cell lung cancer (NSCLC) participants with Programmed death ligand 1+ (PD-L1+) tumors.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None

Interventions: intervention 1: Avelumab intervention 2: Pemetrexed intervention 3: Paclitaxel intervention 4: Gemcitabine intervention 5: Gemcitabine intervention 6: Carboplatin intervention 7: Cisplatin intervention 8: Carboplatin intervention 9: Avelumab Weekly
Intervention descriptions: intervention 1: Participants received Avelumab at a dose of 10 milligrams per kilogram (mg/kg) as a 1-hour (-10/+20 minutes) intravenous (IV) infusion once every 2 weeks until disease progression or unacceptable toxicities. intervention 2: Participants received Pemetrexed 500 milligrams per square meter (mg/m\^2) by IV infusion on Day 1 of 3-Week cycle up to a maximum of 6 cycles of IV injection until disease progression or unacceptable toxicities. intervention 3: Participants received Paclitaxel 200 mg/m\^2 by IV infusion on Day 1 of 3-Week cycle up to a maximum of 6 cycles of IV injection until disease progression or unacceptable toxicities. intervention 4: Participants received Gemcitabine 1250 mg/m\^2 on Day 1 and Day 8 by IV infusion in 3-Week cycle up to a maximum of 6 cycles when combined with cisplatin of IV injection until disease progression or unacceptable toxicities. intervention 5: Participants received Gemcitabine 1000 mg/m\^2 on Day 1 and Day 8 by IV infusion in 3-Week cycle up to a maximum of 6 cycles of IV injection when combined with carboplatin until disease progression or unacceptable toxicities. intervention 6: Participants received Carboplatin area under concentration curve (AUC) 5 mg/mL\*min in 3-Week cycle up to a maximum of 6 cycles of IV injection when combined with gemcitabine until disease progression or unacceptable toxicities. intervention 7: Participants received Cisplatin 75 mg/m\^2 by IV infusion in 3-Week cycle up to a maximum of 6 cycles of IV injection until disease progression or unacceptable toxicities. intervention 8: Carboplatin AUC 6 mg/mL\*min by IV infusion in 3-Week cycle up to a maximum of 6 cycles of IV injection when combined with pemetrexed, or paclitaxel until disease progression or unacceptable toxicities. intervention 9: Participants received Avelumab at a dose of 10 mg/kg as a 1-hour (-10/+20 minutes) IV infusion every week for 12 consecutive weeks.

Protocol document:
Prot_000.pdf: 
A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1/ 1 5 4
Cli nic al Tri al Pr ot oc ol
Cli nic al Tri al Pr ot oc ol N u m ber
E M R 1 0 0 0 7 0- 0 0 5
Title
A P hase III, o pe n -la bel, m ultice nter trial of a vel u ma b 
( M S B 0 0 1 0 7 1 8 C) vers us plati n u m -base d d o u blet as a 
first-li ne treat me nt of rec urre nt or Sta ge I V P D -L 1 + 
n o n – s mall-cell l u n g ca ncer
S h ort Tri al N a me
J A V E LI N L u n g 1 0 0
P h ase
III
I N D N u m ber
E u dr a C T N u m ber
2 0 1 5- 0 0 1 5 3 7- 2 4
C o or di n ati n g I n vesti g at or
 
Tel:  
S p o ns or
F or all c o u ntries e xce pt t he U S A:
Merc k K Ga A, Fra n kf urter Str. 2 5 0, 
6 4 2 9 3 Dar msta dt, Ger ma n y
F or sites i n t he U S A:
E M D Ser o n o Researc h & De vel o p me nt I nstit ute, I nc.
4 5 A Mi d dlese x T ur n pi ke, 
Billerica, M A 0 1 8 2 1, U S A
Me dical Res p o nsi ble:
4 5 A Mi d dlese x T ur n pi ke
Billerica, M A 0 1 8 2 1, U S A
Tel:  
Fa x: 
Cli nic al Tri al Pr ot oc ol Versi o n
Re pl aces Versi o n
0 3 Ja n uar y 2 0 1 9 / Versi o n 6. 0
2 1 Fe b r uar y 2 0 1 8 / Versi o n 5. 0
P P D
P P D
P P D
P P D
P P D
C CI


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
2/154
Protocol Amendment Summary of Changes
Protocol History
Version Number
Type
Version Date
1.0
Original Protocol
13-Jul-2015
2.0
Amendment 1.0
25-Aug-2015
3.0
Amendment 2.0
14-Oct-2015
4.0
Amendment 3.0
21-Nov-2016
5.0
Amendment 4.0
21-Feb-2018
6.0
Amendment 5.0
03-Jan-2019
Protocol Version [6.0] (03-January-2019)
This amendment is substantial based on the criteria in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment
The scheduling of the study interim and primary analyses for both endpoints (progression-free 
survival [PFS] and overall survival [OS]) have been reconfigured based on updated assessments 
of the expected PFS events drop-out rate. The adjustment of statistical assumptions has been 
prompted by standard monitoring of the number of PFS events performed in a blinded fashion by 
the Sponsor. 
Based on the above available information, the current estimate of PFS drop-out rate in 
Study EMR100070-005 is considerably higher than the original assumption of 15% which would 
lead to a much later anticipated timepoint to reach the number of 171 PFS events required for the 
primary analysis in subjects with high expression PD-L1 status in the modified Full Analysis Set. 
Based on the new assumption of PFS drop-out rate and blinded monitoring of PFS and OS events, 
it is expected the required number of events for the primary analysis of both endpoints will be 
reached at a similar time. Consequently, it is reasonable to decouple the OS interim analysis from 
the PFS final analysis, and to perform interim and primary analyses for both endpoints at the same 
time and therefore, the analyses have been reconfigured accordingly. While efficacy objectives of 
the study will not change, there will be a change in protocol-defined main analyses affecting the 
timing of the interim and final analyses as well as the information fraction triggering the analyses.


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
3/ 1 5 4
S e cti o n # a n d 
N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
S y n o p si s 
( St ati sti c al 
M et h o d s), 
S e cti o n 5. 1. 1 
O v er all d e si g n, 
S e cti o n 8. 1 
S a m pl e Si z e, 
S e cti o n 8. 5. 1 
G e n er al 
C o n si d er ati o n s, 
S e cti o n 8. 5. 2
A n al y si s of 
Pri m ar y 
E n d p oi nt s, 
S e cti o n 8. 6 
I nt eri m A n al y si s
A s s u m pti o n s o n P F S dr o p -o ut r at e h a v e 
b e e n r e vi s e d. T h e s c h e d uli n g of i nt eri m 
a n d pri m ar y a n al y si s of P F S a n d O S h a s 
b e e n c h a n g e d t o h a v e i nt eri m a n d 
pri m ar y a n al y si s of b ot h e n d p oi nt s at t h e 
s a m e ti m e d et er mi n e d b y t h e n u m b er of 
O S e v e nt s a n d mi ni m u m -f oll o w-u p ti m e
M o nit ori n g o f t h e n u m b er of P F S e v e nt s l e d t o a 
r e vi s e d a s s u m pti o n of t h e dr o p-o ut r at e a n d t o a 
r e vi s e d e sti m ati o n w h e n t h e r e q uir e d n u m b er f or 
t h e i nt eri m a n d pri m ar y a n al y si s of P F S will b e 
m et .
– C o nfi de ntial –
T his d oc u me nt is t he pr o pert y of Merc k K Ga A, Dar msta dt, Ger ma n y,  or o ne of its s u bsi diaries.  It 
is i nte n de d f or restricte d use o nl y  an d m a y  not – i n f ull or part – be passe d o n, re pr o d uce d, 
p u blis he d or use d wit h o ut e x press per missi o n of Me rc k K Ga A, Dar msta dt, Ger ma n y,  or its 
s u bsi diar y.  Co p y ri g ht © 2 0 1 8 b y  Merc k K Ga A, Dar msta dt, Ger ma n y, o r its s u bsi diar y.  All ri g hts 
reser ve d.
C CI


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
4/ 1 5 4
Pr ot oc ol T a ble of C o nte nts
Pr ot oc ol A me n d me nt S u m mar y  of C ha n ges........................................................................ 2
Pr ot oc ol Ta ble of C o nte nts .................................................................................................. 4
Ta ble of I n -Te xt Ta bles ....................................................................................................... 9
List of A b bre viati o ns ......................................................................................................... 1 0
1
S y n o psis ..............................................................................................1 5
2
S p o ns or, I n vesti gat ors a n d Trial A d mi nistrati ve Str uct ure ................ 4 6
2. 1
I n vesti gati o nal Sites............................................................................ 4 6
2. 2
Trial C o or di nati o n/ M o nit ori n g ........................................................... 4 6
2. 3
Re vie w C o m mittees ............................................................................ 4 7
2. 3. 1
I n de pe n de nt Data M o nit ori n g C o m mittee .......................................... 4 7
2. 3. 2
I n de pe n de nt Re vie w C o m mittee ......................................................... 4 7
3
Bac k gr o u n d I nf or mati o n ..................................................................... 4 7
3. 1
N o n -S mall Cell L u n g Ca ncer ............................................................. 4 7
3. 2
Pr o gra m me d Deat h Rece pt or a n d L i ga n ds......................................... 4 8
3. 3
A vel u ma b ............................................................................................ 4 9
3. 3. 2
P har mac o ki netics ................................................................................ 5 1
3. 3. 3
Cli nical P har mac o d y na m ics ...............................................................5 3
3. 4
Rati o nale f or t he C urre nt Cli nical Trial .............................................. 5 3
3. 5
S u m ma r y of t he O verall Be nefit a n d Ris k.......................................... 5 4
4
Trial O bjecti ves .................................................................................. 5 5
4. 1
Pri mar y  O bjecti ves ............................................................................. 5 5
4. 2
Sec o n dar y  O bjecti ves ......................................................................... 5 5
5
I n vesti gati o nal Pla n ............................................................................ 5 6
5. 1
O verall Trial Desi g n a n d Pla n ............................................................ 5 6
5. 1. 1
O verall Desi g n .................................................................................... 5 7
5. 1. 2
Trial Me dicati o n A d mi nistrati o n a n d Sc he d ule .................................. 6 0
5. 1. 3
D ose M o dificati o n a n d A d verse Dr u g Reacti o ns Re q uiri n g 
Treat me nt Disc o nti n uati o n ................................................................. 6 1
5. 2
Rati o nale f or Trial Desi g n ..................................................................6 3
C CI
C CI


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
5/154
5.2.1
Requirement of PD-L1+ Disease Status.............................................64
5.2.2
Chemotherapy Doublet Comparator...................................................64
5.2.3
Open-label Design ..............................................................................64
5.2.4
Stratification by Histology and PD-L1 Tumor Expression ................64
5.2.5
PFS and OS as the Primary Endpoints ...............................................65
5.2.6
Dose Selection ....................................................................................65
5.2.7
Exclusion of Subjects with EGFR Mutations and ALK 
Translocation ......................................................................................67
5.2.8
Exclusion of Bevacizumab as a Comparator Therapy........................67
5.2.9
Inclusion of Special Populations ........................................................68
5.3
Selection of Trial Population..............................................................68
5.3.1
Inclusion Criteria ................................................................................68
5.3.2
Exclusion Criteria...............................................................................69
5.4
Criteria for Initiation of Trial Treatment ............................................71
5.5
Criteria for Subject Withdrawal..........................................................71
5.5.1
Withdrawal from Trial Therapy..........................................................71
5.5.2
Withdrawal from the Trial..................................................................72
5.6
Premature Termination of the Trial ....................................................72
5.7
Definition of End of Trial...................................................................73
6
Investigational Medicinal Product and Other Drugs Used in the 
Trial.....................................................................................................73
6.1
Description of the Investigational Medicinal Product........................73
6.1.1
Avelumab............................................................................................73
6.1.2
Chemotherapy.....................................................................................73
6.2
Dosage and Administration ................................................................75
6.2.1
Avelumab Dosage and Administration...............................................75
6.2.2
Chemotherapy Dosage and Administration........................................77
6.3
Assignment to Treatment Groups.......................................................78
6.4
Noninvestigational Medicinal Products to be Used............................79
6.5
Concomitant Medications and Therapies ...........................................80
6.5.1
Permitted Medicines...........................................................................80
6.5.2
Prohibited Medicines..........................................................................80
6.5.3
Other Interventions.............................................................................81


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
6/154
6.5.4
Special Precautions.............................................................................82
6.5.5
Management of Specific Adverse Events or Adverse Drug 
Reactions.............................................................................................90
6.6
Packaging and Labeling of the Investigational Medicinal Product....91
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product...............................................................................91
6.8
Investigational Medicinal Product Accountability.............................92
6.9
Assessment of Investigational Medicinal Product Compliance .........93
6.10
Blinding ..............................................................................................93
6.11
Emergency Unblinding.......................................................................93
6.12
Treatment of Overdose .......................................................................94
6.13
Medical Care of Subjects after End of Trial.......................................94
7
Trial Procedures and Assessments......................................................94
7.1
Schedule of Assessments....................................................................94
7.1.1
Screening and Baseline Procedures and Assessments........................94
7.1.2
Treatment Period ................................................................................96
7.1.3
End of Treatment ................................................................................99
7.1.4
Safety Follow-up ..............................................................................100
7.1.5
Safety Follow-up Phone Call............................................................100
7.1.6
Long-term Follow-up........................................................................100
7.1.7
Blood Draws for Clinical Assessments ............................................101
7.2
Demographic and Other Baseline Characteristics ............................101
7.2.1
Demographic Data............................................................................101
7.2.2
Diagnosis of Non-Small Cell Lung Cancer......................................101
7.2.3
Medical History ................................................................................102
7.2.4
Vital Signs and Physical Examination..............................................102
7.2.5
CT or MRI Scans for Tumor Assessment at Baseline......................102
7.2.6
Cardiac Assessments ........................................................................103
7.2.7
Clinical Laboratory Tests .................................................................103
7.3
Efficacy Assessments .......................................................................103
7.4
Assessment of Safety........................................................................105
7.4.1
Adverse Events .................................................................................105
7.4.2
Pregnancy and In Utero Drug Exposure...........................................110


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
7/ 1 5 4
7. 4. 3
Cli nical L a b orat or y Assess me nts .....................................................1 1 0
7. 4. 4
Vital Si g ns, P h y sical E xa mi nati o n a n d Ot her Assess me nts ............. 1 1 2
7. 7
Ot her Assess me nts ............................................................................ 1 1 6
7. 7. 1
Patie nt -re p orte d O utc o mes/ Q ualit y of Life...................................... 1 1 6
8. 2
Ra n d o mizati o n .................................................................................. 1 1 8
8. 3
E n d p oi nts .......................................................................................... 1 1 9
8. 3. 1
Pri mar y  E n d p oi nts............................................................................ 1 1 9
8. 3. 2
Sec o n dar y  E n d p oi nts........................................................................ 1 2 0
8. 3. 3
Safet y  E n d p oi nts............................................................................... 1 2 0
8. 4
A nal y sis Sets..................................................................................... 1 2 1
8. 5
Descri pti o n of Statistical A nal ys es ................................................... 1 2 2
8. 5. 1
Ge neral C o nsi derati o ns ..................................................................... 1 2 2
8. 5. 2
A nal y sis of Pri mar y E n d p oi nts......................................................... 1 2 4
8. 5. 3
A nal y sis of Sec o n dar y E n d p oi nts..................................................... 1 2 8
8. 5. 5
A nal y sis of Safety E n d p oi nts ............................................................ 1 3 0
8. 5. 6
S u b gr o u p A nal y ses ........................................................................... 1 3 1
8. 6
I nteri m A nalys is................................................................................1 3 1
9
Et hical a n d Re g ulat or y  As pects........................................................ 1 3 2
9. 1
Res p o nsi bilities of t he I n vesti gat or ..................................................1 3 2
9. 2
S u bject I nf or mati o n a n d I nf or me d C o nse nt ................................ .....1 3 3
9. 3
S u bject I de ntificati o n a n d Pri vac y ....................................................1 3 3
9. 4
E mer ge nc y  Me dical S u p p ort a n d S u bject Car d................................1 3 4
9. 5
Cli nical Trial I ns ura nce a n d C o m pe nsati o n t o S u bjects ................... 1 3 4
C CI
C CI
C CI
C CI


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
8/154
9.6
Independent Ethics Committee or Institutional Review Board........134
9.7
Health Authorities.............................................................................135
10
Trial Management.............................................................................135
10.1
Case Report Form Handling.............................................................135
10.2
Source Data and Subject Files..........................................................135
10.3
Investigator Site File and Archiving.................................................136
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities ........................................................................................136
10.5
Changes to the Clinical Trial Protocol..............................................137
10.6
Clinical Trial Report and Publication Policy....................................137
10.6.1
Clinical Trial Report.........................................................................137
10.6.2
Publication........................................................................................137
11
References Cited in the Text.............................................................138
12
Appendices .......................................................................................141
Appendix I:
Signature Pages and Responsible Persons for the Trial....................142
Signature Page – Protocol Lead.......................................................................................143
Signature Page – Coordinating Investigator ....................................................................144
Signature Page – Principal Investigator...........................................................................145
Sponsor Responsible Persons not Named on the Cover Page .........................................146
Appendix II:
Eastern Cooperative Oncology Group Performance Status..............147
Appendix III:
Guidance on contraception ...............................................................148
Appendix IV: 
Protocol Amendments History .........................................................149


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
9/ 1 5 4
T a ble of I n-Te xt T a bles
Ta ble 1
Sc he d ule of Assess me nts - A vel u ma b D ose d O nce E ver y  2 Wee ks 
( Ar m A) ..............................................................................................2 3
Ta ble 2
Sc he d ule of Assess me nts: C he m ot hera p y  ( Ar m B) f or S u bjects 
Recei vi n g Pe metre xe d, Cis plati n, Car b o plati n, or Paclita xel............. 2 8
Ta ble 3
Sc he d ule of Assess me nts f or C he m ot hera p y ( Ar m B) f or S u bjects 
Recei vi n g Ge mcita bi ne ....................................................................... 3 3
Ta ble 4
Sc he d ule of Assess me nts - A vel u ma b D ose d O nce a Wee k 
( Ar m C) ...............................................................................................3 8
Ta ble 7
D ose M o dificati o n Sc he d ule f or C he m ot hera p y ................................ 6 3
Ta ble 8
All o we d C he m ot hera p y Re gi me ns ..................................................... 7 8
Ta ble 9
Treat me nt M o dificati o n f or S y m pt o ms of I nf usi o n -relate d 
Reacti o ns Ass ociate d Wit h A vel u ma b ............................................... 8 2
Ta ble 1 0
Ma na ge me nt of I mm u ne -relate d A d verse E ve nts .............................. 8 3
Ta ble 1 1
Re q uire d F ull La b orat or y Safet y  Tests............................................. 1 1 1
Ta ble 1 2
Sa m ple Size O ver vie w f or Hi g h E x pressi o n P D- L 1 + ...................... 1 1 7
Ta ble 1 3
L ocal P o wer C o nsi derati o ns at Pri mar y  A nalys is ............................ 1 1 8
Ta ble 1 4
Ce ns ori n g R ules f or D urati o n of Pr o gressi o n Free S ur vi val 
F oll o w -u p.......................................................................................... 1 2 8
Ta ble 1 5
S u bject C ha racterizati o n Base d o n A D A Res ults............................. 1 2 9
Ta ble 1 6
I nteri m A nalys es ............................................................................... 1 3 2
Ta ble of I n-Te xt Fi g ures
Fi g ure 1
Trial Desi g n ........................................................................................ 5 8
Fi g ure 2
Se q ue nce of A nal ys es .......................................................................1 2 3
Fi g ure 3
E xe m plar y  Infere ntial Testi n g Pr oce d ure ......................................... 1 2 5
C CI


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 / 1 5 4
List of A b bre vi ati o ns
A C T H  
A dre n oc ortic otr o pic h or m o ne
A D A
A nti- dr u g A nti b o d y
A D C C
A nti b o d y -de pe n de nt cell -me diate d c y t ot o xicit y
A D L
Acti vities of dail y  li vi n g
A D R
A d verse dr u g reacti o n
A E(s)
A d verse e ve nt(s)
A E SI
A d verse e ve nt of s pecial i nterest
AJ C C
A merica n J oi nt C o m mittee o n Ca ncer
A L K
A na plastic l y m p h o ma ki nase
A L T
Ala ni ne a mi n otra nsferase
A N C
A bs ol ute ne utr o p hil c o u nt
A N C A
A nti ne utr o p hil c y t o plas mic a nti b o d y
a P T T
Acti vate d partial t hr o m b o plasti n ti me
A S T
As partate a mi n otra nsferase
A U C ta u
Area u n der t he c o nce ntrati o n -ti me c ur ve 
β- h C G
β- h u ma n c h ori o nic g o na d otr o pi n
B O R
Best o verall res p o nse
B U N
Bl o o d urea nitr o ge n
CI
C o nfi de nce i nter val(s)
C B C
C o m plete bl o o d c o u nt
C ma x
Ma xi m u m plas ma c o nce ntrati o n o bser ve d p os t d ose
C mi n
Mi ni m u m p ost d ose (tr o u g h) c o nce ntrati o n
C R
C o m plete res p o nse
C R A
Cli nical Researc h Ass ociate
C CI


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
11/154
CRO
Contract Research Organization
CRP
C-reactive protein
CT 
Computed tomography 
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
Cytotoxic T-lymphocyte antigen-4
CYP3A4
Cytochrome P450 3A4
DLT
Dose-limiting toxicity
DOR
Duration of response
ECG
Electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status
eCRF
Electronic case report form
EGFR
Epidermal growth factor receptor
EORTC
European Organization for Research and Treatment of Cancer
EQ-5D-5L
European Quality Of Life 5-dimensions 5-level questionnaire 
FAS
Full analysis set
FDA
Food and Drug Administration
FFPE
Formalin-fixed, paraffin embedded
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
Gamma-glutamyltransferase
GMP
Good Manufacturing Practice
H1
Histamine H1 receptor
HAHA
Human antihuman antibody
HBV
Hepatitis B virus
HCV
Hepatitis C virus


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
12/154
HIV
Human immunodeficiency virus
HR
Hazard ratio
ICF
Informed Consent Form
ICH
International Council for Harmonisation
ICU
Intensive Care Unit
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IPMP
Integrated Project Management Plan
IRC
Independent Review Committee
Ig
Immunoglobulin
IHC
Immunohistochemistry
IMP
Investigational medicinal product
INR
International normalized ratio
irAE
Immune-related adverse event
IRB
Institutional Review Board
IV
Intravenous
IWRS
Interactive web response system
LDH
Lactate dehydrogenase
LFT
Liver function test
LLN
Lower limit of normal
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MedDRA
Medical Dictionary for Regulatory Activities
MOP
Manual of Operations
MRI
Magnetic resonance imaging


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 / 1 5 4
N CI
Nati o nal Ca ncer I nstit ute 
N S AI D
N o nster oi dal a nti -i nfla m mat or y dr u g
N S C L C
N o n -s mall cell l u n g ca ncer
O R R
O bjecti ve res p o nse rate
O S
O verall s ur vi val 
P D
Pr o gressi ve disease
P D - 1
Pr o gra m me d deat h 1
P D -L 1
Pr o gra m me d deat h -li ga n d 1
P D -L 1 +
P D -L 1  p ositi ve
P D -L 2
Pr o gra m me d deat h -li ga n d 2
P F S
Pr o gressi o n free s ur vi val
 
P P
Per- pr ot oc ol 
P R
Partial res p o nse
R B C
Re d bl o o d cell
R E CI S T 1. 1
Res p o nse E val uati o n Criteria i n S oli d T u m ors versi o n 1. 1
S A E(s)
Seri o us a d verse e ve nt(s)
S A P
Statistical A nal y sis Pla n
S D
Sta ble disease
S O C
Sta n dar d of care
S U S A R
S us pecte d u ne x pecte d seri o us a d verse reacti o n
t1/ 2
Half -life
T 4
Free t h y r o xi ne
T E A E
Treat me nt -e mer ge nt a d verse e ve nt
C CI
C C
I


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
14/154
TLS
Tumor lysis syndrome
tmax
Time to reach maximum concentration
TO
Target occupancy
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
USA
United States
WBC
White blood cell


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 / 1 5 4
1
S y n o psis
Cli nic al Tri al Pr ot oc ol N u m ber
E M R 1 0 0 0 7 0- 0 0 5
Title
A 
P hase III, o pe n -la bel, m ultice nter 
trial of 
a vel u ma b 
( M S B 0 0 1 0 7 1 8 C) 
vers us 
plati n u m -base d d o u blet as a first -li ne treat me nt of 
rec urre nt or Sta ge I V P D-L 1 + n o n -s mall cell l u n g 
ca ncer
Tri al P h ase
III
I N D N u m ber
F D A c o vere d tri al
Yes
E u dr a C T N u m ber
2 0 1 5- 0 0 1 5 3 7- 2 4 
C o or di n ati n g I n vesti g at or
S p o ns or
F or all c o u ntries e xce pt t he U S A:
Merc k K Ga A, Fra n kf urter Str. 2 5 0, 
6 4 2 9 3 Dar msta dt, Ger ma n y
F or sites i n t he U S A:
E M D Ser o n o Researc h & De vel o p me nt I nstit ute, 
I nc.
4 5 A Mi d dlese x T ur n pi ke, 
Billerica, M A 0 1 8 2 1, U S A
Tri al ce nters/c o u ntries
T he trial will be c o n d ucte d at u p t o 3 8 6 sites
gl o ball y i n N ort h A merica (a p pr o xi matel y 2 7 i n 
t he U S A) , S o ut h A merica, Asia, Africa, a n d 
E ur o pe.
Pl a n ne d tri al peri o d
(first s u bject i n-l ast s u bject o ut)
First s u bject i n: Q 3, 2 0 1 5
Last s u bject o ut: Q 2, 2 0 2 0
Tri al Re gistr y
Cli n Trials. g o v
O bjecti ves: 
Pri m ar y o bjecti ve
T he pri mar y  objecti ve is t o de m o nstrate s u peri orit y wit h re gar d t o o verall s ur vi val ( O S) or 
pr o gressi o n free s ur vi val ( P F S) of a vel u ma b vers us plati n u m -base d d o u blet, base d o n a n 
in de pe n de nt re vie w co m mittee assess me nt as per R E CI S T 1. 1, i n N S C L C s u bjects wit h hi g h
e x pressi o n P D -L 1 + t u m ors.
C CI
P P D


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 6 / 1 5 4
Sec o n d ar y o bjecti ves
Sec o n dar y  o bjecti ves are as f oll o ws:

T o de m o nstrate s u peri orit y wit h re gar d t o O S or P F S base d o n a n i n de pe n de nt re vie w 
c o m mittee assess me nt per R E CI S T 1. 1 i n N S C L C s u bjects wit h m o derate
a n d hi g h
e x pressi o n P D -L 1 + t u m ors

T o de m o nstrate s u peri orit y wit h re gar d t o O S i n N S C L C s u bjects wit h a n y e x pressi o n 
P D -L 1 + t u m ors

T o c o m parati vel y assess t he o bjecti ve res p o nse rate ( O R R) b y  RE CI S T 1. 1 of a vel u ma b 
vers us c he m ot hera p y i n hi g h, m o derate a n d hi g h, a n d a n y e x pressi o n P D -L 1 + t u m ors

T o deter mi ne d urati o n of res p o nse ( D O R) of a vel u ma b vers us c he m ot hera p y   

T o c o m pare t he patie nt -re p orte d o utc o mes / q ualit y  of life w he n treate d wit h a vel u ma b 
vers us c he m ot hera p y usi n g t he E ur o pea n Q uality of Life ( E ur o Q O L) 5- di me nsi o ns 5 -le vel
q uesti o n naire (E Q - 5 D-5 L ), a n d t he E ur o pea n Or ga nizati o n f or Researc h a n d Treat me nt of 
Ca ncer ( E O R T C) Q L Q -C 3 0 a n d m o d ule Q L Q -L C 1 3

T o deter mi ne t he safet y a n d t olera bilit y of a vel u ma b 
Met h o d ol o g y: T his is a m ultice nter, i nter nati o nal, ran d o mize d, o pe n -la bel, P hase III trial i n 
c he m ot hera p y- naï ve (first li ne) metastatic or rec urre nt ( Sta ge I V) N S C L C s u bjects c o m pari n g 
a vel u ma b t o first-li ne plati n u m -base d d o u blet c he m ot hera p y.  T he trial c o nsists of a 2 8- da y  
scree ni n g peri o d, f oll o we d b y t he treat me nt p hase (wit hi n 4 da y s after ra n d o mizati o n).  
C CI


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
17/154
To achieve the target enrollment of 484 subjects randomized with high expression PD-L1+ 
tumors, approximately 1131 eligible subjects will be randomized with any expression PD-L1+ 
tumors and approximately 3100 subjects will be screened for study participation.  
Subjects will be randomly allocated into the 3 study arms as follows: 
Arm A: Avelumab at a dose of 10 mg/kg as a 1-hour (-10/+20 minutes) intravenous (IV) 
infusion once every 2 weeks until disease progression or unacceptable toxicities, or
Arm B: Investigator’s choice platinum-containing chemotherapy regimen to be 
administered in 3-week cycles up to a maximum of 6 cycles of IV injection until disease 
progression or unacceptable toxicities consisting of one of the following:
o
for subjects whose tumor is of non-squamous histology:

pemetrexed (500 mg/m2) in combination with cisplatin (75 mg/m2
administered on Day 1 of each cycle), or pemetrexed (500 mg/m2) in 
combination with carboplatin (AUC 6 mg/mL × min administered on 
Day 1 of each cycle). 
o
for subjects whose tumor is of squamous histology:

paclitaxel (200 mg/m2) plus carboplatin (AUC 6 mg/mL × min
administered on Day 1 of each cycle); or

gemcitabine (1250 mg/m2 administered on Day 1 and Day 8 of each 
cycle) plus cisplatin (75 mg/m2); or

gemcitabine (1000 mg/m2 administered on Day 1 and Day 8 of each 
cycle) plus carboplatin (AUC 5 mg/mL × min)
Arm C: Avelumab at a dose of 10 mg/kg as a 1-hour (-10/+20 minutes) intravenous (IV) 
infusion every week for 12 consecutive weeks, followed by avelumab at a dose of 10 mg/kg 
once every 2 weeks until disease progression or unacceptable toxicities.
Subjects will be randomly allocated to one of the 3 treatment arms, initially into Arm A and 
Arm B in a 1:1 ratio.  The allocation ratio will change to 1:2:2 (Arm A: Arm B: Arm C) once 
the IDMC recommends the avelumab once a week dosing regimen may be included in the 
randomization scheme after the initial safety evaluation of avelumab 10 mg/kg every week in 
a cohort of 6 subjects. 
NSCLC histology (squamous versus non-squamous cell) will be used as stratification factors 
for randomization. The PD-L1 tumor expression level at Baseline (low expression versus 
moderate expression versus high expression) will be supplemented as randomization strata for 
the 1:2:2 randomization scheme.
Tumor measurements by computed tomography (CT) scan or magnetic resonance imaging 
(MRI) will be performed every 6 weeks for the first 12 months and every 12 weeks thereafter 
to determine response to treatment.  Response will be evaluated using the Response Evaluation 
Criteria in Solid Tumors version 1.1 (RECIST 1.1).
Treatment with avelumab will continue until disease progression or unacceptable toxicity.  
Subjects receiving avelumab who have experienced a complete response (CR) should be 
treated for a minimum of 12 months and/or until disease progression or unacceptable toxicity, 
after confirmation of response. In case a subject with a confirmed CR relapses after stopping 


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
18/154
treatment, one re-initiation of treatment is allowed at the discretion of the Investigator and 
agreement of the medical monitor.  
Treatment with chemotherapy will continue until disease progression, unacceptable toxicity,
or after the completion of up to 6 cycles of chemotherapy.  Subjects with non-squamous 
histology are authorized to continue to receive pemetrexed as a maintenance therapy after 
4 cycles of platinum-based chemotherapy if their disease has not progressed, or in accordance 
with the pemetrexed local label. No other maintenance therapy is permitted.
Decisions regarding medical management of subjects will be made by the Investigator; 
however, the primary and secondary endpoint determinations (response and progressive 
disease [PD]) will be according to the central imaging assessment and review by a blinded 
Independent Review Committee (IRC).
Adverse events (AEs) will be assessed throughout the trial and evaluated using the National 
Cancer Institute (NCI) Common Technology Criteria version for Adverse Events version 4.03 
(CTCAE v 4.03).  
Periodic evaluations of the trial data will be conducted by the IDMC to ensure subject safety, 
and the validity and scientific merit of the trial. 
End-of-Treatment visit:  within 7 days from the decision to discontinue, or before the start 
of any other antineoplastic therapy including a full safety evaluation for subjects that have 
discontinued treatment due to an AE, and
Follow-up phase: Safety Follow-up visit 30 days (± 5 days) after the last administration of 
trial treatment, followed by a 90-day telephone Safety Follow-up (± 1 week), and Long-term 
Follow-up every 12 weeks (± 1 week).
Planned number of subjects: Approximately 3100 subjects will be screened.  Accrual will 
proceed up to a target number of approximately 1131 subjects randomized with any expression 
PD-L1+ tumors in order to obtain at least 484 subjects randomized with high expression 
PD-L1+ tumors.  This is based on the estimation that among subjects with any expression 
PD-L1+ tumors, approximately 45% of them will have high expression PD-L1 tumors.
Primary endpoints: The primary endpoints for the trial are PFS and OS.  Progression free 
survival is defined as the time from date of randomization until date of the first documentation 
of PD as determined by the independent review committee (per RECIST 1.1) or death due to 
any cause in the absence of documented PD, whichever occurs first.  Overall survival is defined 
as the time from randomization to the date of death, regardless of the actual cause of the 
subject’s death.
Secondary endpoints
The secondary endpoints include: 

BOR according to RECIST 1.1 and as adjudicated by the IRC

Duration of response according to RECIST 1.1

Patient-reported outcomes/quality of life (assessed by the EQ-5D-5L, and the 
EORTC QLQ-C30, and module QLQ-LC13 questionnaires)

Safety endpoints (including AEs, clinical laboratory assessments, vital signs, 
physical examination, electrocardiogram [ECG] parameters, and ECOG PS).


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 9 / 1 5 4
Di a g n osis a n d ke y i ncl usi o n a n d e xcl usi o n criteri a: 
Ke y i ncl usi o n criteri a:
Male or fe male s u bjects ≥ 1 8 years, wit h a n E C O G P S of 0 t o 1 at trial e ntr y, wit h
t he 
a vaila bilit y of a f or mali n-fi xe d, paraffi n -e m be d de d bl oc k c o ntai ni n g t u m or tiss ue or 
1 0 ( prefera bly 2 5 ) u nstai ne d t u m or sli des wit h P D -L 1 +, at least 1 meas ura ble t u m or lesi o n, a n d 
wit h hist ol o gicall y c o nfir me d metastatic or rec urre nt ( Sta ge I V) N S C L C.   S u bjects m ust n ot 
ha ve recei ve d a n y treat me nt f or s yste mic l u n g ca ncer, a n d ha ve a n esti mate d life e x pecta nc y 
of m ore t ha n 1 2 wee ks.
Ke y e xcl usi o n criteri a :
S u bjects w h ose disease har b ors a n E G F R m utati o n or a n a na plastic l ym p h o ma ki nase ( A L K) 
rearra n ge me nt are n ot eli gi ble.  Ot her e xcl usi o n criteria i ncl u de pri or t hera p y wit h an y  anti b o d y 
or dr u g tar geti n g T -cell c ore g ulat or y pr otei ns, c o nc urre nt a ntica ncer treat me nt, or 
i m m u n os u p pressi ve a ge nts, k n o w n se vere h y perse nsiti vit y  reacti o ns t o m o n ocl o nal a nti b o dies 
( Gra de ≥ 3 N CI -C T C A E v 4. 0 3), hist or y  of ana p h y la xis, or u nc o ntr olle d ast h ma (t hat is, 3 or 
m ore feat ures of partiall y c o ntr olle d ast h ma), a n d persisti n g t o xicit y  relate d t o pri or t hera py of 
Gra de > 1 N CI - CT C A E v 4. 0 3.   S u bjects wit h brai n metastases are e xcl u de d, e xce pt t h ose 
meeti n g t he f oll o wi n g criteria: brai n metastases t hat ha ve bee n treate d l ocall y an d are cli nicall y 
sta ble f or at least 2 wee ks pri or t o ra n d o mizati o n, s u bjects m ust be eit her off ster oi ds or o n a 
sta ble or decreasi n g d ose of ≤ 1 0 m g dail y  pre d nis o ne ( or e q ui vale nt) , a n d d o n ot ha ve o n g oi n g 
ne ur ol o gical s y m pt o ms t hat are relate d t o t he brai n l ocalizati o n of t he disease.
I n vesti g ati o n al Me dici n al 
Pr o d uct: d ose/ m o de of a d mi nistr ati o n/ d osi n g sc he d ule: 
A vel u ma b will be a d mi nistere d as a 1- h o ur (-1 0/ + 2 0 mi n utes) I V i nf usi o n at 1 0 m g/ k g o nce 
e ver y 2 wee ks or o nce a wee k
f or 1 2 c o nsec uti ve wee ks f oll o we d b y  once e ver y 2 wee ks, 
de pe n di n g o n ra n d o mizati o n, u ntil pr o gressi ve disease or u nacce pta ble t o xicit y.  I n or der t o 
miti gate i nf usi o n-relate d reacti o ns, all s u bjects will recei ve pretreat me nt wit h hista mi ne H 1 
rece pt or ( H 1) bl oc kers a n d aceta mi n o p he n 3 0 t o 6 0 mi n utes pri or t o e ver y a vel u ma b i nf usi o n.  
C CI


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
20/154
Premedication with an antihistamine and with paracetamol (acetaminophen) (for example, 
25 to 50 mg diphenhydramine and 500 to 650 mg paracetamol [acetaminophen] IV or oral 
equivalent) approximately 30 to 60 minutes prior to the first 4 infusions of avelumab is 
mandatory.  Premedication should be administered for subsequent avelumab doses based upon 
clinical judgment and presence/severity of prior infusion reactions.  This regimen may be 
modified based on local treatment standards and guidelines as appropriate provided it does not 
include systemic corticosteroids.  
Reference therapy: dose/mode of administration/dosing schedule: Subjects randomized to 
chemotherapy will be administered the Investigator-chosen chemotherapy regimen according 
to the protocol in 3-week cycles up to a maximum of 6 cycles or until progressive disease or 
unacceptable toxicities.  Dose adjustments can be made according to label instructions and 
local institutional practices.
Planned trial and treatment duration per subject: In this trial, treatment with avelumab will 
continue until disease progression or unacceptable toxicity.  Additionally, subjects receiving 
avelumab who have experienced a CR should be treated for a minimum of 12 months and/or 
until disease progression or unacceptable toxicity,
after confirmation
of
response.  
Chemotherapy will be administered until disease progression or unacceptable toxicity or for a 
maximum of 6 cycles of chemotherapy.  
Statistical methods: The aim of the study is to demonstrate superiority of either avelumab
regimen versus standard of care (SOC) in terms of PFS or OS time.
The OS or PFS time will serve as primary endpoints to test the superiority of each 
investigational treatment arm (Arm A, Arm C) versus SOC (Arm B). 
Statistical testing will consider hierarchically ordered hypothesis with respect to tumor PD-L1 
expression status at Baseline, starting with high PD-L1 expression, followed by moderate and 
high PD-L1 expression for both endpoints of OS and PFS.  Any PD-L1 expression will be 
tested only for OS.
Multiplicity adjustments will follow closed testing procedures with weighted Bonferroni tests 
including allocation of local significance levels to the next step of hypothesis testing in case of 
statistically significant results. Overall significance level of 0.025 (one-sided) will be split to 
local significance levels due to primary PFS or OS endpoints and two treatment group 
comparisons against control arm.
The OS and PFS time will be analyzed based on as-randomized principle using a one-sided 
stratified log-rank test. An interim analysis is planned after recruitment has been completed
based on required events for the high expression PD-L1+ population.  The interim analysis for 
PFS and OS is scheduled after approximately 130 OS events for the Arm C versus B 
comparison have been reached representing a 75% information fraction.  Interim analyses for 
PFS 
and 
OS 
will 
be 
conducted, 
considering 
Lan-DeMets 
α-spending 
with 
O’Brien-Fleming-like boundaries given the local significance levels at the first hierarchy step. 
No futility analysis is planned.
The primary statistical comparisons of Arm A vs Arm B will include all subjects who were 
randomized to trial treatment. The primary statistical comparison of Arm C vs Arm B will 
consider all randomized subjects after the first subject is randomly assigned according to 


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
21/154
Amendment 3 (1:2:2 allocation ratio) to ensure a randomized comparison of treatment arms 
that is not impacted by the time of randomization.
The total sample size will depend on the target to randomize at least 484 subjects with high 
expression PD-L1+ tumors.  Assuming a prevalence ratio of approximately 7/3 (70% 
prevalence rate for any PD-L1+ and 30% with high expression PD-L1+) the randomized 
allocation to treatment groups will proceed up to a target number of approximately
1131 subjects with any expression PD-L1+ tumors.  Further assumptions are given below:
Similar efficacy boundaries for treatment group comparisons i.e. for each endpoint 
determination of superiority of avelumab vs control a similar treatment effect is considered 
for both avelumab regimens.
HR=0.6 for Arm A or C versus Arm B for high expression PD-L1 populations, eg, median 
PFS prolongation from 6 to 10 months and median OS prolongation from 12 to 20 months 
under an exponential model assumption.
Subjects will initially be randomized in a 1:1 (Arm A: Arm B) allocation ratio. After this 
amendment, subjects will be randomized in a 1:2:2 (Arm A: Arm B: Arm C) allocation ratio.
PFS drop-out rate of approximately 25% and OS drop-out rate of approximately 5%
Overall, accrual time up to 24 months and 70% prevalence of any PD-L1 expression (accrual 
time up to 14 months after Amendment 3)
Minimum follow-up time of 10 months for interim analysis after randomization of the last 
subject
Minimum follow-up time of 20 months for final analysis after randomization of the last 
subject
Overall significance level of 0.025 (one-sided) split to local significance levels due to 
primary PFS and OS endpoints (2:1 ratio) and 2 treatment group comparisons against control 
(3:1 ratio), ie, αPFS=0.0125 (=0.025 × 6/12) and αOS=0.00625 (=0.025 × 3/12) for Arm C 
versus Arm B local comparisons and αPFS=0.00417 (=0.025 × 2/12) and αOS=0.00208 (=0.025
× 1/12) for Arm A versus Arm B local comparisons for high and moderate expression PD-
L1+ subsets.
Actual significant levels might differ according to multiple testing procedures. 
Local power > 80%.
Randomization into the 3rd treatment arm (Arm C) will start after approximately 
154 subjects with high PD-L1+ expression have been randomized to Arm A and B initially 
under the 1:1 randomization schema.
The data cut-off for the primary PFS and OS analyses will occur after the target number of 
173 OS events for Arm C versus B comparison of the randomized subjects with high expression 
PD-L1+ tumors has been reached and at least 20 months follow-up after the randomization of 
the last subject in the study.  


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
22/154
The PD-L1 IHC assay and the scoring algorithm to determine low, moderate, and high PD-L1 
expression status will be defined prior to conducting any statistical analyses.  Details will be 
specified in laboratory manual and statistical analysis plan.
Study procedures will be established to maintain data integrity in this open-label trial and to 
limit biased assessment of endpoints, e.g. by establishing an independent and blinded review 
of tumor images; by ensuring adequate blindness of the PD-L1+ status through regulating the 
flow of PD-L1 expression data between the laboratory site; by IWRS vendor for the 
stratification; and by IDMC during study conduct.
Safety data will be summarized, and AEs will be summarized by incidence, severity, 
seriousness, and relationship to trial drug according to the as-treated principle.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
23/154
Table 1
Schedule of Assessments- Avelumab Dosed Once Every 2 Weeks (Arm A) 
Screening/
Baseline 
Treatment Phaseb
End of 
Treatment
Follow-upc
V1
V2
V3
V4
V5
V6
V7
End-of-
Treatment 
Visit
Safety Follow-up Visit
Survival 
Long-
term 
Follow-
up
Day -28 to 
Random-
izationa
W 1
Day 1
W 3
Day 
15
W 5
Day 
29
W 7
Day 
43
W 9
Day 
57
W
11
Day 
71
W
13
Day 
85
Until 
progression
t
Within 7 
Days of 
Decision to 
Discontinue 
Treatmentd,e
Visit
30 Days 
after Last 
Treatment 
(± 5 days)
Phone 
Call
90 Days 
after Last 
Treatment 
(± 1 week)
Every   
12
Weeks 
(± 1
week)
Study Procedures
Written informed 
consent
X
PD-L1 tumor 
expression/Tumor 
tissue f
X
Inclusion/exclusion 
criteria
X
Medical 
history/smoking 
historyg
X
Demographic data
X
HBV and HCV 
testing
X
Patient-reported 
outcomes/quality of 
life assessmentsh
Xh
X
X
6 weeks
X
X
Physical 
examinationi
X
X
X
X
X
X
X
X
6 weeks
X
X
Vital signs
X
X
X
X
X
X
X
X
2 weeks
X
X
Weight
X
X
X
X
X
X
X
X
2 weeks
X
X


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
24/154
Screening/
Baseline 
Treatment Phaseb
End of 
Treatment
Follow-upc
V1
V2
V3
V4
V5
V6
V7
End-of-
Treatment 
Visit
Safety Follow-up Visit
Survival 
Long-
term 
Follow-
up
Day -28 to 
Random-
izationa
W 1
Day 1
W 3
Day 
15
W 5
Day 
29
W 7
Day 
43
W 9
Day 
57
W
11
Day 
71
W
13
Day 
85
Until 
progression
t
Within 7 
Days of 
Decision to 
Discontinue 
Treatmentd,e
Visit
30 Days 
after Last 
Treatment 
(± 5 days)
Phone 
Call
90 Days 
after Last 
Treatment 
(± 1 week)
Every   
12
Weeks 
(± 1
week)
ECOG PS
Xj
X
X
X
X
X
X
X
2 weeks
X
X
12-lead ECGk
X
X
Concomitant 
medications and 
procedures
Collected through the 30-day Safety Follow-up Visit
Further antitumor 
therapy
X
X
X
AE collection
AEs are collected through the Safety Follow-up Visit
Treatment-related non-serious AEs are collected until the 90-day Safety Follow-up Phone Callc
X
SAE collection
All SAEs are documented until the 90-day Safety Follow-up Phone Call,
Ongoing SAEs at the 90-day Safety Follow-up Phone Call will be followed upc
X
Samples and Laboratory Assessments
Hematology and 
hemostaseology
X
X
X
X
X
X
X
X
2 weeks
X
X
Full serum 
chemistryl
X
X
X
X
6 weeks
X
Core serum 
chemistrym
Xm
X
X
X
2 weeks
X
Urinalysisn
X
X
X
6 weeks
X
X
β-HCG pregnancy 
testo
X
X
X
X
X
4 weeks
X
X


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
25/154
Screening/
Baseline 
Treatment Phaseb
End of 
Treatment
Follow-upc
V1
V2
V3
V4
V5
V6
V7
End-of-
Treatment 
Visit
Safety Follow-up Visit
Survival 
Long-
term 
Follow-
up
Day -28 to 
Random-
izationa
W 1
Day 1
W 3
Day 
15
W 5
Day 
29
W 7
Day 
43
W 9
Day 
57
W
11
Day 
71
W
13
Day 
85
Until 
progression
t
Within 7 
Days of 
Decision to 
Discontinue 
Treatmentd,e
Visit
30 Days 
after Last 
Treatment 
(± 5 days)
Phone 
Call
90 Days 
after Last 
Treatment 
(± 1 week)
Every   
12
Weeks 
(± 1
week)
ACTHp
X
T4 and TSHp
X
X
X
6 weeks
X
X
Response Assessments
Tumor 
evaluation/staging 
(CT scan/MRI/Other 
established 
methods)q,r
X
X
X
6 weeks for 
the
first 12 
months,
Every 12 
weeks
Thereafter
X
Dosing
Pretreatments
X
X
X
X
X
X
X
2 weeks
Avelumab
X
X
X
X
X
X
X
2 weeks
Optional Tumor 
Biopsy 
After  progression
ACTH: adrenocorticotropic hormone; AE: adverse events; β-HCG: β-human chorionic gonadotropin; CT: computed tomography; D: Day; ECG: electrocardiogram;
ECOG PS: Eastern Cooperative Oncology Group Performance Status; EQ-5D-5L: European Quality Of Life 5-dimensions 5-level questionnaire; HBV: hepatitis B virus;
HCV: hepatitis C virus; ICF: Informed Consent Form; IV: intravenous; MRI: magnetic resonance imaging; PD-L1: programmed death-ligand 1; PR: partial response;  
T4: free thyroxine; TSH: thyroid-stimulating hormone; V: visit; W: Week.
a Randomization will be done after the confirmation of fulfilling all screening inclusion criteria (Section 5.3.1) without matching any exclusion criterion 
(Section 5.3.2).
b A time window of up to 3 days before or 1 day after the scheduled visit day (-3/+1 days) will be permitted for all trial procedures; however the bi-weekly 14-day 
schedule for avelumab dosing should be strictly adhered to, returning to the target date even if the previous visit was off schedule.  The calculation of the dose of 
avelumab will be based on the weight of the subject determined within 72 hours prior to the day of drug administration (see Section 5.1.3.1).


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
26/154
c Subjects with an AE will be documented until the Safety Follow-up visit.  After this visit, all SAEs and all treatment-related non-serious AEs need to be 
documented until the 90-day Safety Follow-up phone call.  Subjects with an ongoing SAE at the 90-day Safety Follow-up Phone Call must be monitored and 
followed up by the Investigator until stabilization or until the outcome is known, unless the subject is documented as “lost to follow-up”.  Any SAE assessed as 
related to IMP must be reported whenever it occurs, irrespective of the time elapsed since the last administration of IMP (see Section 7.1.5 for details).  In addition, 
survival information (including assessment of any further anticancer therapy) will be collected every 12 weeks (± 1 week).  The survival follow-up will continue until 
5 years after the last subject receives the last dose of avelumab (see Section 7.1.6 for details).  Adverse events and concomitant medications will be documented 
at each trial visit.
d Tumor evaluation at the End-of-Treatment visit should only be performed if no disease progression has been documented previously.  The subject may stay on a 
6 week schedule if they continue tumor evaluations in the absence of progression and there is no start of further anticancer therapy.
e If another antineoplastic therapy is administered before the end of this 7 day period, the End-of-Treatment visit should be conducted, if possible, prior to the start 
of this new therapy.  The End-of-Treatment visit should occur within 7 days of the decision to discontinue.  
f Tumor tissue must be available within 10 calendar days after the subject has signed the ICF in order to establish the PD-L1 status of the tumor.  A biopsy should 
be collected unless tissue from an archival specimen is available (biopsies are only to be obtained from safely accessible tumor tissue/sites).  Preferably, archived
samples, if needed should be less than 6 months old.  Samples can be provided as block or slides (see Section 7.6 for details).  Randomization cannot occur until 
PD-L1 expression has been determined by a companion diagnostic test under development and performed centrally.
g Medical history should include history of NSCLC, previous and ongoing medications, smoking history, and baseline medical conditions.
h The patient-reported outcomes/quality of life assessments (EQ-5D-5L, EORTC QLQ-C30, and module QLQ-LC13) should be completed by all subjects prior to 
any of the other trial-related assessments being performed, that is, physical examinations, blood draws, trial treatment administration, etc.  The pretreatment 
assessment should be conducted at Screening; in the event that this doesn’t occur, it can be done at Visit 1 (Day 1) prior to treatment.
i If the Screening physical examination was performed within 3 days prior to Day 1, it does not have to be repeated at Visit 1.  A full physical examination should be 
performed at Screening and the EOT visit.  Physical examinations at all other visits should be directed towards signs and symptoms.
j If the Screening ECOG PS was performed within 3 days prior to Day 1, it does not have to be repeated at Visit 1.
k 12-lead ECG should be assessed during screening and at the End-of-Treatment visit.  ECGs are to be performed as clinically indicated in case of abnormalities 
such as increased heart rate above the subject’s baseline detected during the physical examination and/or vital signs measurements performed prior to avelumab 
treatment. The avelumab administration should not be withheld in the isolated situation of an increased heart rate, unless the overall evaluation, including the 
ECG, is suggestive of myocarditis, in which case the protocol guidelines (as outlined in Table 10) should be followed.
l Full chemistry panel, which includes core serum chemistry, and other laboratory studies are detailed in Table 11.  Follicle-stimulating hormone at Screening, if 
applicable (Section 7.1.1).
m Core serum chemistry includes liver function panel (alkaline phosphatase, ALT, AST, bilirubin), acute chemistry panel (sodium, potassium, chloride, BUN/total 
urea, creatinine, glucose), and mineral panel (magnesium, phosphorus, calcium).  If Screening full chemistry was performed within 3 days prior to Day 1, core 
serum chemistry does not have to be completed at Visit 1.
n Full urinalysis (dipstick and microscopic evaluation) at the Screening and End-of-Treatment visits and a basic urinalysis (dipstick only) at each visit indicated prior 
to administration of trial drug.  If the basic urinalysis is abnormal, then a full urinalysis should be performed.
o β-hCG should be determined from serum at Screening and from urine or serum thereafter.  Results of the pregnancy test should be available prior to dosing of 
trial drug.
p ACTH will be collected only at Baseline.  T4 and TSH will be collected at Screening/Baseline, and every 6 weeks during the treatment phase, at the 
End-of-Treatment visit and the 30-day Safety Follow-up visit.  


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
27/154
q On study imaging will be performed every 6 weeks (±1 week) calculated from the randomization date and as clinically indicated and submitted for central 
radiology review.  The timing for imaging studies should follow calendar days and should not be adjusted for delays in cycle starts.  Subjects without progressive 
disease at End-of-Treatment visit will be followed up for disease progression (CT / MRI scans every 6 weeks [± 1 week] and every 12 weeks after 12 months) until 
PD is assessed by the Investigators according to RECIST 1.1 or start of new cancer therapy.  In case a tumor response according to RECIST 1.1 is documented 
during the course of the trial, confirmation of the response should be performed according to RECIST 1.1, preferably at the regularly scheduled 6-week 
assessment interval, but no sooner than 4 weeks after the initial documentation of CR or PR. Confirmation of PR can be confirmed at an assessment later than the 
next scheduled assessment after the initial documentation of PR.  After progression of disease and if clinically feasible, a subsequent scan at least 4 weeks after 
initial assessment of progression should be collected to confirm progression. In case of avelumab treatment beyond progression, additional images should be 
collected in accordance with imaging schedule as long as the subject continues on avelumab therapy. A CT scan or MRI should always be used (if MRI is used, 
CT of chest is mandatory).  
r A brain CT/MRI scan is required at Screening if not performed within 6 weeks prior to randomization, and beyond as clinically indicated.  A bone scan should be 
done as clinically indicated at Screening and beyond.  Bone metastases detected at Screening need to be followed at the tumor evaluation visits.
s Subjects must receive pretreatment with H1 blockers and acetaminophen 30 to 60 minutes prior to infusion of avelumab (10 mg/kg IV over 1 hour
[-10/+20 minutes]).  Premedication with an antihistamine and with paracetamol (acetaminophen) (for example, 25 to 50 mg diphenhydramine and 500 to 650 mg 
paracetamol [acetaminophen] IV or oral equivalent) approximately 30 to 60 minutes prior to the first 4 infusions of avelumab is mandatory.  Premedication should 
be administered for subsequent avelumab doses based upon clinical judgment and presence/severity of prior infusion reactions.  This regimen may be modified 
based on local treatment standards and guidelines as appropriate.
t If avelumab treatment is terminated before disease progression and no new cancer treatments are initiated and the subject is stable, all assessments (including 
tumor imaging) will continue on a 6-week schedule until disease progression (except pretreatment and avelumab administration).


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
28/154
Table 2
Schedule of Assessments: Chemotherapy (Arm B) for Subjects Receiving Pemetrexed, Cisplatin, 
Carboplatin, or Paclitaxel
Screening/
Baseline 
Chemotherapy Treatment Phaseb
End of 
Treatment
Follow-upd
V1
V2
V3
V4
V5
V6
End-of-
Treatment 
Visit
Safety Follow-up Visit
Survival 
Long-term 
Follow-up
Day -28 to 
Randomizationa
W1
Day 
1
W4
Day 
22
W7
Day 
43
W10
Day 
64
W13
Day 
85
W16
Day 
106
Until 
progressionc
Within 7 
Days of 
Decision to 
Discontinue 
Treatmente, 
f
Visit
30 Days 
after Last 
Treatment 
(± 5 days)
Phone 
Call
90 Days 
after Last 
Treatment 
(± 1 week)
Every   
12 Weeks 
(± 1 week)
Study Procedures
Written informed 
consent
X
PD-L1 tumor 
expression/Tumor 
tissue g
X
Inclusion/exclusion 
criteria
X
Medical 
history/smoking 
historyh
X
Demographic data
X
HBV and HCV 
testing
X
Patient-reported 
outcomes/quality 
of life 
assessmentsi
Xi
X
X
6 weeks
X
X
Physical 
examinationj
X
Xj
X
X
X
X
6 weeks
X
X
Vital signs
X
X
X
X
X
X
X
3 weeks
X
X
Weight
X
X
X
X
X
X
X
3 weeks
X
X


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
29/154
Screening/
Baseline 
Chemotherapy Treatment Phaseb
End of 
Treatment
Follow-upd
V1
V2
V3
V4
V5
V6
End-of-
Treatment 
Visit
Safety Follow-up Visit
Survival 
Long-term 
Follow-up
Day -28 to 
Randomizationa
W1
Day 
1
W4
Day 
22
W7
Day 
43
W10
Day 
64
W13
Day 
85
W16
Day 
106
Until 
progressionc
Within 7 
Days of 
Decision to 
Discontinue 
Treatmente, 
f
Visit
30 Days 
after Last 
Treatment 
(± 5 days)
Phone 
Call
90 Days 
after Last 
Treatment 
(± 1 week)
Every   
12 Weeks 
(± 1 week)
ECOG PSk
X
X
X
X
X
X
X
3 weeks
X
X
12-lead ECGl
X
X
Concomitant 
medications and 
procedures
Collected through the 30-day Safety Follow-up Visit
Further antitumor 
therapy
X
X
X
AE collection
AEs are collected through the Safety Follow-up Visit
Treatment-related non-serious AEs are collected until the 90-day Safety Follow-up Phone Calld
X
SAE collection
All SAEs are documented until the 90-day Safety Follow-up Phone Call,
Ongoing SAEs at the 90-day Safety Follow-up Phone Call will be followed upd
X
Samples and Laboratory Assessments
Hematology and 
hemostaseology
X
X
X
X
X
X
X
3 weeks
X
X
Full serum 
chemistrym
X
X
X
X
6 weeks
X
Core serum 
chemistryn
Xn
X
X
3 weeks
X
Urinalysiso
X
X
X
6 weeks
X
X
β-HCG pregnancy 
testp
X
X
X
X
X
X
X
3 weeks
X
X
ACTHq
X
T4 and TSHq
X
X
X
6 weeks
X
X


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
3 0 / 1 5 4
S cr e e ni n g/
B a s eli n e 
C h e m ot h er a p y Tr e at m e nt P h a s e b
E n d of 
Tr e at m e nt
F oll o w -u p d
V 1 
V 2 
V 3 
V 4 
V 5 
V 6
E n d -of -
Tr e at m e nt 
Vi sit
S af et y  F oll o w-u p Vi sit
S ur vi v al 
L o n g -t er m 
F oll o w -u p
D a y -2 8 t o 
R a n d o mi z ati o n a
W 1
D a y 
1
W 4
D a y 
2 2
W 7
D a y 
4 3
W 1 0
D a y 
6 4
W 1 3
D a y 
8 5
W 1 6
D a y 
1 0 6
U ntil 
pr o gr e s si o n c
Wit hi n 7 
D a y s  of 
D e ci si o n t o 
Di s c o nti n u e 
Tr e at m e nt e , 
f
Vi sit
3 0 D a y s 
aft er L a st 
Tr e at m e nt 
( ± 5 d a y s)
P h o n e 
C all
9 0 D a y s 
aft er L a st 
Tr e at m e nt 
( ± 1 w e e k)
E v er y    
1 2 W e e k s 
( ± 1 w e e k)
R e s p o n s e A s s e s s m e nt s
T u m or 
e v al u ati o n/ st a gi n g 
( C T 
s c a n/ M RI/ Ot h er 
e st a bli s h e d 
m et h o d s)
s,t
X
X
X
6 w e e k s f or t h e
fir st 1 2 m o nt h s,
E v er y 1 2 w e e k s
T h er e aft er
X
D o si n g
Pr etr e at m e nt u
X 
X 
X 
X 
X 
X 
X
3 w e e k s
C h e m ot h er a p y 
X 
X 
X 
X 
X 
X 
X
3 w e e k s
A C T H : a dr e n o c orti c otr o pi c h or m o n e ; A E : a d v er s e e v e nt s ; β-H C G : β- h u m a n c h ori o ni c g o n a d otr o pi n ; C T : c o m p ut e d t o m o gr a p h y ; D: D a y ; E C G : 
el e ctr o c ar di o gr a m ; E C O G P S : E a st er n C o o p er ati v e O n c ol o g y Gr o u p P erf or m a n c e St at u s ; E Q -5 D -5 L: E ur o p e a n Q u alit y Of Lif e 5 -di m e n si o n s 5 -l e v el 
q u e sti o n n air e ; H B V : h e p atiti s B vir u s ; H C V : h e p atiti s C vir u s; I C F: I nf or m e d C o n s e nt F or m; I V: i ntr a v e n o u s; M RI : m a g n eti c r e s o n a n c e i m a gi n g; P D -L 1 : 
pr o gr a m m e d d e at h -li g a n d 1; P R : p arti al r e s p o n s e ; T 4 : fr e e t h yr o xi n e; T S H : t h yr oi d-sti m ul ati n g h or m o n e ; V: vi sit, W : W e e k.
a R a n d o mi z ati o n will b e d o n e aft er t h e c o nfir m ati o n of f ulfilli n g all s cr e e ni n g i n cl u si o n crit eri a ( S e cti o n  5. 3. 1 ) wit h o ut m at c hi n g a n y e x cl u si o n crit eri o n 
(S e cti o n 5. 3. 2 ).
b A ti m e wi n d o w of u p t o 3 d a y s b ef or e or 1 d a y aft er t h e s c h e d ul e d vi sit d a y ( -3/ + 1 d a y s) will b e p er mitt e d f or all tri al pr o c e d ur e s.  T h e tri -w e e kl y 2 1 - d a y s c h e d ul e 
s h o ul d b e stri ctl y a d h er e d t o, r et ur ni n g t o t h e t ar g et d at e e v e n if t h e pr e vi o u s vi sit w a s off s c h e d ul e. 
C CI


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
31/154
c Chemotherapy to be administered to a maximum of 6 cycles of IV injection until disease progression or unacceptable toxicities. Pemetrexed may be continued as 
maintenance therapy, after 4 cycles of platinum-based chemotherapy in the absence of disease progression, or in accordance with pemetrexed local label.  No 
other maintenance therapy is permitted.  If chemotherapy treatment is terminated before disease progression and no new cancer treatments are initiated and the 
subject is stable, all assessments (including tumor imaging) will continue on a 6-week schedule until disease progression.
d Subjects with an AE will be documented until the Safety Follow-up visit.  After this visit, all SAEs and all treatment-related non-serious AEs need to be 
documented until the 90-day Safety Follow-up phone call.  Subjects with an ongoing SAE at the 90-day Safety Follow-up Phone Call must be monitored and 
followed up by the Investigator until stabilization or until the outcome is known, unless the subject is documented as “lost to follow-up.”  Any SAE assessed as 
related to IMP must be reported whenever it occurs, irrespective of the time elapsed since the last administration of IMP.  In addition, survival information
(including assessment of any further anticancer therapy) will be collected every 12 weeks (± 1 week).  The survival follow-up will continue until 5 years after the 
last subject receives the last dose of avelumab (see Section 7.1.5 for details).  Adverse events and concomitant medications will be documented at each trial visit.
e Tumor evaluation at the End-of-Treatment visit should only be performed if no disease progression has been documented previously.  The subject may stay on a 
6 week schedule if they continue tumor evaluations in the absence of progression and there is no start of further anticancer therapy.
f If another antineoplastic therapy is administered before the end of this 7 day period, the End-of-Treatment visit should be conducted, if possible, prior to the start 
of this new therapy.  The End-of-Treatment visit should occur within 7 days of the decision to discontinue. 
g Tumor tissue must be available within 10 calendar days after the subject has signed the ICF in order to establish the PD-L1 status of the tumor.  A biopsy should 
be collected unless tissue from an archival specimen is available (biopsies are only to be obtained from safely accessible tumor tissue/sites).  Samples can be 
provided as block or slides (see Section 7.6 for details).  Randomization cannot occur until PD-L1 expression has been determined by a companion diagnostic test 
under development and performed centrally.
h Medical history should include history of NSCLC, previous medications, smoking history, and Baseline medical condition.
i The patient-reported outcomes/quality of life assessments (EQ-5D-5L, EORTC QLQ-C30, and module QLQ-LC13) should be completed by all subjects prior to 
any of the other trial-related assessments being performed, that is, physical examinations, blood draws, trial treatment administration, etc.  The pre-treatment 
assessment should be conducted at Screening; in the event that this doesn’t occur, it can be done at Visit 1 (Day 1) prior to treatment.
j If the Screening physical examination was performed within 3 days prior to Day 1, it does not have to repeated at Visit 1.  A full physical examination should be 
performed at Screening and the EoT visit. Physical examinations at all other visits should be directed towards signs and symptoms.
k If the Screening ECOG PS was performed within 3 days prior to Day 1, it does not have to be repeated at Visit 1.
l 12-lead ECG should be assessed during screening and at the End-of-Treatment visit.  ECGs are to be performed as clinically indicated in case of abnormalities 
such as increased heart rate above the subject’s baseline detected during the physical examination and/or vital signs measurements performed prior to study 
treatment. The treatment administration should not be withheld in the isolated situation of an increased heart rate, unless the overall evaluation, including the ECG, 
is suggestive of myocarditis, in which case the protocol guidelines (as outlined in Table 10) should be followed
m Full chemistry panel, which includes core serum chemistry, and other laboratory studies are detailed in Table 11.  Follicle-stimulating hormone at Screening, if 
applicable (Section 7.1.1).
n Core serum chemistry includes liver function panel (alkaline phosphatase, ALT, AST, bilirubin), acute chemistry panel (sodium, potassium, chloride, BUN/total 
urea, creatinine, glucose), and mineral panel (magnesium, phosphorus, calcium).  If Screening full chemistry was performed within 3 days prior to Day 1, core 
serum chemistry does not have to be completed at Visit 1.
o Full urinalysis (dipstick and microscopic evaluation) at the Screening and End-of-Treatment visits and a basic urinalysis (dipstick only) at each visit indicated prior 
to administration of trial drug.  If the basic urinalysis is abnormal, then a full urinalysis should be performed.
p β-hCG should be determined from serum at Screening and from urine or serum thereafter.  Results of the most recent pregnancy test should be available prior to 
next dosing of trial drug.
q ACTH will be collected only at Baseline.  T4 and TSH will be collected at Screening/Baseline and every 6 weeks during the treatment phase, and continue 
thereafter until progression if progression does not occur at treatment termination at the End-of-Treatment visit, and the 30-day Safety Follow-up visit.  


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
3 2 / 1 5 4
s O n st u d y i m a gi n g will b e p erf or m e d e v er y 6 w e e k s ( ± 1 w e e k) c al c ul at e d fr o m t h e r a n d o mi z ati o n d at e a n d a s cli ni c all y i n di c at e d a n d s u b mitt e d f or c e ntr al 
r a di ol o g y r e vi e w.  T h e ti mi n g f or i m a gi n g st u di e s s h o ul d f oll o w c al e n d ar d a y s a n d s h o ul d n ot b e a dj u st e d f or d el a y s i n c y cl e st art s .  S u bj e ct s wit h o ut pr o gr e s si v e 
di s e a s e at E n d -of - Tr e at m e nt vi sit will b e f oll o w e d u p f or di s e a s e pr o gr e s si o n ( C T / M RI s c a n s e v er y 6 w e e k s [ ± 1 w e e k ] a n d e v er y 1 2 w e e k s aft er 1 2 m o nt h s) u ntil 
P D i s a s s e s s e d b y t h e I n v e sti g at or s a c c or di n g t o R E CI S T 1. 1.  I n c a s e a t u m or r e s p o n s e a c c or di n g t o R E CI S T 1. 1 i s d o c u m e nt e d d uri n g t h e c o ur s e of t h e tri al, 
c o nfir m ati o n of t h e r e s p o n s e s h o ul d b e p erf or m e d a c c or di n g t o R E CI S T 1. 1, pr ef er a bl y at t h e r e g ul arl y s c h e d ul e d 6- w e e k a s s e s s m e n t i nt er v al, b ut n o s o o n er t h a n 
4 w e e k s aft er t h e i niti al d o c u m e nt ati o n of C R or P R . C o nfir m ati o n of P R c a n b e c o nfir m e d at a n a s s e s s m e nt l at er t h a n t h e n e xt a s s e s s m e nt aft er t h e i niti al 
d o c u m e nt ati o n of P R .  Aft er pr o gr e s si o n of di s e a s e a n d if cli ni c all y f e a si bl e, a s u b s e q u e nt s c a n at l e a st 4 w e e k s aft er i niti al a s s e s s m e nt of pr o gr e s si o n s h o ul d b e 
c oll e ct e d t o c o nfir m pr o gr e s si o n . A C T s c a n or M RI s h o ul d al w a y s b e u s e d (if M RI i s u s e d, C T of c h e st i s m a n d at or y) .  
t A br ai n C T/ M RI s c a n i s r e q uir e d at S cr e e ni n g if n ot p erf or m e d wit hi n 6 w e e k s pri or t o r a n d o mi z ati o n, a n d b e y o n d a s cli ni c all y i n di c at e d .  A b o n e s c a n s h o ul d b e 
d o n e a s cli ni c all y i n di c at e d at S cr e e ni n g a n d b e y o n d .  B o n e m et a st a s e s d et e ct e d at S cr e e ni n g n e e d t o b e f oll o w e d at t h e t u m or e v al u ati o n vi sit s.
u S u bj e ct s will b e a d mi ni st er e d pr e tr e at m e nt pri or t o e a c h c h e m ot h er a p y i nf u si o n p er c h e m ot h er a p y la b el i n str u cti o n s, or e q ui v al e nt p er l o c al i n stit uti o n al pr a cti c e .  
A s t h e pr e m e di c ati o n f or p e m etr e x e d ( or al f oli c a ci d, vit a mi n B 1 2 i ntr a m u s c ul ar i nj e cti o n) will n e e d t o b e d eli v er e d i n t h e w e e k b ef or e t h e fir st d o s e of 
c h e m ot h er a p y, t hi s pr e m e di c ati o n i s p er mitt e d t o b e i niti at e d i n all s u bj e ct s wit h n o n - s q u a m o u s hi st ol o g y aft er si g ni n g t h e i nf or m e d c o n s e nt a n d pri or t o
r a n d o mi z ati o n ( S e cti o n 5. 1. 2. 2 ). 
C CI


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
33/154
Table 3
Schedule of Assessments for Chemotherapy (Arm B) for Subjects Receiving Gemcitabine
Screening/
Baseline 
Assessments
Chemotherapy Treatment Phase (Gemcitabine only)b
End of 
Treatment
Follow-upc
V1
V2
V3
V4
V5
V6
End-of-
Treatment 
Visit
Safety Follow-up Visit
Survival 
Long-ter
m Follow-
up
Day -28 to 
Randomizationa
W1
W2
W4
W5
W7
W8
W
10
W
11
W
13
W
14
W 
16
W
17
Until 
progressiond
Within 7 
Days of 
Decision to 
Discontinue 
Treatmente, f
Visit
30 Days 
after Last 
Treatment 
(±5 days)
Phone Call
90 Days 
after Last 
Treatment 
(±1 week)
Every   
12 Weeks 
(±1 week)
Day
1
8
22
29
43
50
64
71
85
92
106
11
3
Study Procedures
Written informed 
consent
X
PD-L1 tumor 
expression/Tumor 
tissue g
X
Inclusion/exclusio
n criteria
X
Medical 
history/smoking 
historyh
X
Demographic 
data
X
HBV and HCV 
testing
X
Patient-reported 
outcomes/quality 
of life 
assessmentsi
X
X
X
6 weeks
X
X
Physical 
examinationj
X
X
X
X
X
X
X
X
X
X
X
X
X
6 weeks
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
3 weeks
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
3 weeks
X
X
ECOG PSk
X
X
X
X
X
X
X
X
X
X
X
X
X
3 weeks
X
X


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
3 4 / 1 5 4
S cr e e ni n g/
B a s eli n e 
A s s e s s m e nt s
C h e m ot h er a p y  Tr e at m e nt P h a s e ( G e m cit a bi n e o nl y )b
E n d of 
Tr e at m e nt
F oll o w -u p c
V 1 
V 2 
V 3 
V 4 
V 5 
V 6
E n d -of -
Tr e at m e nt 
Vi sit
S af et y  F oll o w-u p Vi sit
S ur vi v al 
L o n g -t er
m F oll o w -
u p
D a y  -2 8 t o 
R a n d o mi z ati o n a
W 1  
W 2  
W 4  
W 5  
W 7  
W 8
W
1 0
W
1 1
W
1 3
W
1 4
W 
1 6
W
1 7
U ntil 
pr o gr e s si o n d
Wit hi n 7 
D a y s of 
D e ci si o n t o 
Di s c o nti n u e 
Tr e at m e nt e , f
Vi sit
3 0 D a y s 
aft er L a st 
Tr e at m e nt 
( ±5 d a y s)
P h o n e C all
9 0 D a y s 
aft er L a st 
Tr e at m e nt 
( ± 1 w e e k)
E v er y    
1 2 W e e k s 
( ±1 w e e k)
D a y
1 
8
2 2 
2 9 
4 3 
5 0 
6 4 
7 1 
8 5 
9 2 
1 0 6
1 1
3
1 2 -l e a d E C Gl
X
X
C o n c o mit a nt 
m e di c ati o n s a n d 
pr o c e d ur e s
C oll e ct e d t hr o u g h t h e 3 0 -d a y S af et y F oll o w -u p Vi sit
F urt h er a ntit u m or 
t h er a p y
X
X
X
A E c oll e cti o n
A E s ar e c oll e ct e d t hr o u g h t h e S af et y F oll o w -u p Vi sit
Tr e at m e nt -r el at e d n o n- s eri o u s A E s ar e c oll e ct e d u ntil t h e 9 0-d a y S af et y F oll o w -u p P h o n e C all c
X
S A E c oll e cti o n
All S A E s ar e d o c u m e nt e d u ntil t h e 9 0 -d a y S af et y F oll o w -u p P h o n e C all,
O n g oi n g S A E s at t h e 9 0- d a y S af et y F oll o w -u p P h o n e C all will b e f oll o w e d u p c
X
S a m pl e s a n d L a b or at or y  As s e s s m e nt s
H e m at ol o g y m a n d 
h e m o st a s e ol o g y
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
3 w e e k s
X
X
F ull s er u m 
c h e mi str y n
X
X 
X
X
6 w e e k s
X
C or e s er u m 
c h e mi str y o
X 
X 
X 
X 
X 
X 
X 
X
3 w e e k s
X
Uri n al y si s p
X
X
X
6 w e e k s
X
X
β- H C G pr e g n a n c y 
t e stq
X
X 
X 
X 
X 
X 
X
3 w e e k s
X
X
A C T H r
X
T 4 a n d T S H r
X
X
X
6 w e e k s
X
X
C CI


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
3 5 / 1 5 4
S cr e e ni n g/
B a s eli n e 
A s s e s s m e nt s
C h e m ot h er a p y  Tr e at m e nt P h a s e ( G e m cit a bi n e o nl y )b
E n d of 
Tr e at m e nt
F oll o w -u p c
V 1 
V 2 
V 3 
V 4 
V 5 
V 6
E n d -of -
Tr e at m e nt 
Vi sit
S af et y  F oll o w-u p Vi sit
S ur vi v al 
L o n g -t er
m F oll o w -
u p
D a y  -2 8 t o 
R a n d o mi z ati o n a
W 1  
W 2  
W 4  
W 5  
W 7  
W 8
W
1 0
W
1 1
W
1 3
W
1 4
W 
1 6
W
1 7
U ntil 
pr o gr e s si o n d
Wit hi n 7 
D a y s of 
D e ci si o n t o 
Di s c o nti n u e 
Tr e at m e nt e , f
Vi sit
3 0 D a y s 
aft er L a st 
Tr e at m e nt 
( ±5 d a y s)
P h o n e C all
9 0 D a y s 
aft er L a st 
Tr e at m e nt 
( ± 1 w e e k)
E v er y    
1 2 W e e k s 
( ±1 w e e k)
D a y
1 
8
2 2 
2 9 
4 3 
5 0 
6 4 
7 1 
8 5 
9 2 
1 0 6
1 1
3
R e s p o n s e A s s e s s m e nt s
T u m or 
e v al u ati o n/ st a gi n g 
( C T 
s c a n/ M RI/ Ot h er 
e st a bli s h e d 
m e t h o d s)t, u
X
X
X
6 w e e k s f or 
t h e fir st 1 2 
m o nt h s, 
e v er y  1 2 
w e e k s 
t h er e aft er
X
D o si n g
Pr etr e at m e nt v
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
3 w e e k s
C h e m ot h er a p y 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
3 w e e k s
A C T H : a dr e n o c orti c otr o pi c h or m o n e ; A E : a d v er s e e v e nt s ; β-H C G : β- h u m a n c h ori o ni c g o n a d otr o pi n ; C T : c o m p ut e d t o m o gr a p h y ; D: D a y ; E C G : el e ctr o c ar di o gr a m ;
E C O G P S : E a st er n C o o p er ati v e O n c ol o g y Gr o u p P erf or m a n c e St at u s ; E Q -5 D -5 L: E ur o p e a n Q u alit y Of Lif e 5- di m e n si o n s 5 -l e v el q u e sti o n n air e; H B V : h e p atiti s B 
vir u s ; H C V : h e p atiti s C vir u s; I C F: I nf or m e d C o n s e nt F or m; I V: i ntr a v e n o u s; M RI : m a g n eti c r e s o n a n c e i m a gi n g; P D -L 1 : pr o gr a m m e d d e at h-li g a n d 1; P R : p arti al 
r e s p o n s e; T 4 : fr e e t h yr o xi n e; T S H : t h yr oi d-sti m ul ati n g h or m o n e ; V: vi sit, W : W e e k.
a R a n d o mi z ati o n will b e d o n e aft er t h e c o nfir m ati o n of f ulfilli n g all s cr e e ni n g i n cl u si o n crit eri a ( S e cti o n  5. 3. 1 ) wit h o ut m at c hi n g a n y e x cl u si o n crit eri o n 
( S e cti o n 5. 3. 2 ).
b A ti m e wi n d o w of u p t o 3 d a y s b ef or e or 1 d a y aft er t h e s c h e d ul e d vi sit d a y ( -3/ + 1 d a y s) will b e p er mitt e d f or all tri al pr o c e d ur e s.  T h e tri-w e e kl y 2 1 - d a y s c h e d ul e 
s h o ul d b e stri ctl y a d h er e d t o, r et ur ni n g t o t h e t ar g et d at e e v e n if t h e pr e vi o u s vi sit w a s off s c h e d ul e.   W h il e e a c h tr e at m e nt c y cl e i s p erf or m e d e v er y 2 1 d a y s, 
tr e at m e nt vi sit s at t h e sit e s h o ul d b e c o m pl et e d o n D a y 1 a n d D a y 8 i n a c c or d a n c e wit h t h e g e m cit a bi n e a d mi ni str ati o n l a b el. 
C CI


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
3 6/ 1 5 4
c S u bj e ct s wit h a n A E will b e d o c u m e nt e d u ntil t h e S af et y F oll o w -u p vi sit.  Aft er t hi s vi sit, all S A E s a n d all tr e at m e nt -r el at e d n o n-s eri o u s A E s n e e d t o b e 
d o c u m e nt e d u ntil t h e 9 0 -d a y S af et y F oll o w -u p p h o n e c all .  S u bj e ct s wit h a n o n g oi n g S A E at t h e 9 0- d a y S af et y F oll o w -u p P h o n e C all m u st b e m o nit or e d a n d 
f oll o w e d u p b y t h e I n v e sti g at or u ntil st a bili z ati o n or u ntil t h e o ut c o m e i s k n o w n, u nl e s s t h e s u bj e ct i s d o c u m e nt e d a s “l o st t o f oll o w-u p.  A n y S A E a s s e s s e d a s 
r el at e d t o I M P m u st b e r e p ort e d w h e n e v er it o c c ur s, irr e s p e cti v e of t h e ti m e el a p s e d si n c e t h e l a st a d mi ni str ati o n of I M P.  I n a d diti o n, s ur vi v al i nf or m ati o n
(i n cl u di n g a s s e s s m e nt of a n y f urt h er a nti c a n c er t h er a p y) will b e c oll e ct e d e v er y 1 2 w e e k s ( ± 1 w e e k) .  T h e s ur vi v al f oll o w -u p will c o nti n u e u ntil 5 y e ar s aft er t h e 
l a st s u bj e ct r e c ei v e s t h e l a st d o s e of a v el u m a b ( s e e S e cti o n 7. 1. 5 f or d et ail s).  A d v er s e e v e nt s a n d c o n c o mit a nt m e di c ati o n s will b e d o c u m e nt e d at e a c h tri al vi sit.
d If c h e m ot h er a p y tr e at m e nt i s t er mi n at e d b ef or e di s e a s e pr o gr e s si o n a n d n o n e w c a n c er tr e at m e nt s ar e i niti at e d a n d t h e s u bj e ct i s st a bl e, all a s s e s s m e nt s
(i n cl u di n g t u m or i m a gi n g) will c o nti n u e o n a 6 -w e e k s c h e d ul e u ntil di s e a s e pr o gr e s si o n.
e T u m or e v al u ati o n at t h e E n d -of -Tr e at m e nt vi sit s h o ul d o nl y b e p erf or m e d if n o di s e a s e pr o gr e s si o n h a s b e e n d o c u m e nt e d pr e vi o u sl y.   T h e s u bj e ct m a y st a y o n a 
6 w e e k s c h e d ul e if t h e y c o nti n u e t u m or e v al u ati o n s i n t h e a b s e n c e of pr o gr e s si o n a n d t h er e i s n o st art of f urt h er a nti c a n c er t h er a p y.
f If a n ot h er a nti n e o pl a sti c t h er a p y i s a d mi ni st er e d b ef or e t h e e n d of t hi s 7 d a y p eri o d, t h e E n d-of -Tr e at m e nt vi sit s h o ul d b e c o n d u ct e d, if p o s si bl e, pri or t o t h e st art 
of t hi s n e w t h er a p y.  T h e E n d -of -Tr e at m e nt vi sit s h o ul d o c c ur wit hi n 7 d a y s of t h e d e ci si o n t o di s c o nti n u e. 
g T u m or ti s s u e m u st b e a v ail a bl e wit hi n 1 0 c al e n d ar d a y s aft er t h e s u bj e ct h a s si g n e d t h e I C F i n or d er t o e st a bli s h t h e P D- L 1 st at u s of t h e t u m or .  A bi o p s y s h o ul d 
b e c oll e ct e d u nl e s s ti s s u e fr o m a n ar c hi v al s p e ci m e n i s a v ail a bl e ( bi o p si e s ar e o nl y t o b e o bt ai n e d fr o m s af el y a c c e s si bl e t u m or ti s s u e/ sit e s).  S a m pl e s c a n b e 
pr o vi d e d a s bl o c k or sli d e s ( s e e S e cti o n  7. 6 f or d et ail s).  R a n d o mi z ati o n c a n n ot o c c ur u ntil P D -L 1 e x pr e s si o n h a s b e e n d et er mi n e d b y a c o m p a ni o n di a g n o sti c t e st 
u n d er d e v el o p m e nt a n d p erf or m e d c e ntr all y. 
h M e di c al hi st or y s h o ul d i n cl u d e hi st or y of N S C L C, pr e vi o u s m e di c ati o n s, s m o ki n g hi st or y, a n d B a s eli n e m e di c al c o n diti o n.
i T h e p ati e nt -r e p ort e d o ut c o m e s/ q u alit y of lif e a s s e s s m e nt s (E Q -5 D -5 L , E O R T C Q L Q-C 3 0, a n d m o d ul e Q L Q -L C 1 3) s h o ul d b e c o m pl et e d b y all s u bj e ct s pri or t o 
a n y of t h e ot h er tri al -r el at e d a s s e s s m e nt s b ei n g p erf or m e d, t h at i s, p h y si c al e x a mi n ati o n s, bl o o d dr a w s, tri al tr e at m e nt a d mi ni str ati o n, et c.  T h e pr e -tr e at m e nt 
a s s e s s m e nt s h o ul d b e c o n d u ct e d at S cr e e ni n g; i n t h e e v e nt t h at t hi s d o e s n’t o c c ur, it c a n b e d o n e at Vi sit 1 ( D a y 1) pri or t o tr e at m e nt.
j If t h e S cr e e ni n g p h y si c al e x a mi n ati o n w a s p erf or m e d wit hi n 3 d a y s pri or t o D a y 1, it d o e s n ot h a v e t o b e r e p e at e d at Vi sit 1 .  A f ull p h y si c al e x a mi n ati o n s h o ul d b e 
p erf or m e d at S cr e e ni n g a n d t h e E o T vi sit. P h y si c al e x a mi n ati o n s at all ot h er vi sit s s h o ul d b e dir e ct e d t o w ar d s si g n s a n d s y m p t o m s.
k If t h e S cr e e ni n g E C O G P S w a s p erf or m e d wit hi n 3 d a y s pri or t o D a y 1, it d o es n ot h a v e t o b e r e p e at e d at Vi sit 1.
l1 2 -l e a d E C G s h o ul d b e a s s e s s e d d uri n g s cr e e ni n g a n d at t h e E n d-of -Tr e at m e nt vi sit.   E C G s ar e t o b e p erf or m e d a s cli ni c all y i n di c at e d i n c a s e of a b n or m aliti e s 
s u c h a s i n cr e a s e d h e art r at e a b o v e t h e s u bj e ct’ s b a s eli n e d et e ct e d d uri n g t h e p h y si c al e x a mi n ati o n a n d/ or vit al si g n s m e a s ur e m e nt s p erf or m e d pri or t o a v el u m a b 
tr e at m e nt.
m H e m a st e ol o g y i s N O T p erf or m e d at D a y 8 of e a c h c y cl e.
n F ull c h e mi str y p a n el, w hi c h i n cl u d e s c or e s er u m c h e mi str y, a n d ot h er l a b or at or y st u di e s ar e d et ail e d i n  T a bl e 1 1 .  F olli cl e -sti m ul ati n g h or m o n e at S cr e e ni n g, if 
a p pli c a bl e ( S e cti o n  7. 1. 1 ).
o C or e s er u m c h e mi str y i n cl u d e s li v er f u n cti o n p a n el ( al k ali n e p h o s p h at a s e, A L T, A S T, bilir u bi n), a c ut e c h e mi str y p a n el ( s o di u m, p ot a s si u m, c hl ori d e, B U N/t ot al 
ur e a, cr e ati ni n e, gl u c o s e), a n d mi n er al p a n el ( m a g n e si u m, p h o s p h or u s, c al ci u m).   If t h e S cr e e ni n g f ull c h e mi str y w a s p erf or m e d wit hi n 3 d a y s pri or t o D a y 1, c or e 
s er u m c h e mi str y d o e s n ot h a v e t o b e c o m pl et e d at Vi sit 1.
p F ull uri n al y si s ( di p sti c k a n d mi cr o s c o pi c e v al u ati o n) at t h e S cr e e ni n g a n d E n d -of -Tr e at m e nt vi sit s a n d a b a si c uri n al y si s ( di p sti c k o nl y) at e a c h vi sit i n di c at e d pri or 
t o a d mi ni str ati o n of tri al dr u g.  If t h e b a si c uri n al y si s i s a b n or m al, t h e n a f ull uri n al y si s s h o ul d b e p erf or m e d.
q β- h C G s h o ul d b e d et er mi n e d fr o m s er u m at S cr e e ni n g a n d fr o m uri n e or s er u m t h er e aft er .  R e s ult s of t h e m o st r e c e nt pr e g n a n c y t e st s h o ul d b e a v ail a bl e pri or t o 
n e xt d o si n g of tri al dr u g.
r A C T H will b e c oll e ct e d o nl y at B a s eli n e.  T 4 a n d T S H will b e c oll e ct e d at S cr e e ni n g/ B a s eli n e a n d e v er y 6 w e e k s d uri n g t h e tr e at m e nt p h a s e, a n d c o nti n u e 
t h er e aft er u ntil pr o gr e s si o n if pr o gr e s si o n d o e s n ot o c c ur at tr e at m e nt t er mi n ati o n at t h e E n d -of -Tr e at m e nt vi sit, a n d t h e 3 0 -d a y S af et y F oll o w -u p vi sit.   
C CI


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
37/154
t On study imaging will be performed every 6 weeks (±1 week) calculated from the randomization date and as clinically indicated and submitted for central 
radiology review.  The timing for imaging studies should follow calendar days and should not be adjusted for delays in cycle starts.  Subjects without progressive 
disease at End-of-Treatment visit will be followed up for disease progression (CT / MRI scans every 6 weeks [± 1 week and every 12 weeks after 12 months) until 
PD.  In case a tumor response according to RECIST 1.1 is documented during the course of the trial, confirmation of the response should be performed according 
to RECIST 1.1, preferably at the regularly scheduled 6-week assessment interval, but no sooner than 4 weeks after the initial documentation of CR or PR. 
Confirmation of PR can be confirmed at an assessment later than the next assessment after the initial documentation of PR.  After progression of disease and if 
clinically feasible, a subsequent scan at least 4 weeks after initial assessment of progression should be collected to confirm progression. A CT scan or MRI should 
always be used (if MRI is used, CT of chest is mandatory).  
u A brain CT/MRI scan is required at Screening if not performed within 6 weeks prior to randomization, and beyond as clinically indicated.  A bone scan should be 
done as clinically indicated at Screening and beyond.  Bone metastases detected at Screening need to be followed at the tumor evaluation visits.
v Subjects will be administered pretreatment prior to each chemotherapy infusion per chemotherapy label instructions, or equivalent per local institutional practice.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
38/154
Table 4
Schedule of Assessments - Avelumab Dosed Once a Week (Arm C)
Screening/
Baseline 
Assessments
Treatment Phaseb
V1
V2
V3
V4
V5
V6
V7
(Roll-over into 
Once-every-2 weeks
dosing)
Day -28 to 
Randomizatio
na
W1
Day 
1
W2
Day 8
W3
Day 
15
W4
Day 
22
W5
Day 
29
W6
Day 
36
W7 
Da
y 
43
W8 
Da
y 
50
W9 
Day 
57
W10 
Day 
64
W11 
Day 
71
W12 
Day 
78
W13 
Day 85 (Follow 
Table 1 after 
V7/W13)
Study Procedures
Written informed 
consent
X
PD-L1 tumor 
expression/Tumor 
tissue c
X
Inclusion/exclusion 
criteria
X
Medical 
history/smoking 
historyd
X
Demographic data
X
HBV and HCV 
testing
X
Patient-reported 
outcomes/quality of 
life assessmentse
Xe
X
X
Physical 
examinationf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
ECOG PS
Xg
X
X
X
X
X
X
X
12-lead ECGh
X


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
39/154
Screening/
Baseline 
Assessments
Treatment Phaseb
V1
V2
V3
V4
V5
V6
V7
(Roll-over into 
Once-every-2 weeks
dosing)
Day -28 to 
Randomizatio
na
W1
Day 
1
W2
Day 8
W3
Day 
15
W4
Day 
22
W5
Day 
29
W6
Day 
36
W7 
Da
y 
43
W8 
Da
y 
50
W9 
Day 
57
W10 
Day 
64
W11 
Day 
71
W12 
Day 
78
W13 
Day 85 (Follow 
Table 1 after 
V7/W13)
Concomitant 
medications and 
procedures
Collected through the 30-day Safety Follow-up Visit
Further antitumor 
therapy
Collected through the 30-day Safety Follow-up Visit
AE collection
AEs are collected through the Safety Follow-up Visit
Treatment-related non-serious AEs are collected until the 90-day Safety Follow-up Phone Call
SAE collection
All SAEs are documented until the 90-day Safety Follow-up Phone Call,
Ongoing SAEs at the 90-day Safety Follow-up Phone Call will be followed up
Samples and Laboratory Assessments
Hematology and 
hemostaseology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Full serum 
chemistryi
X
X
X
X
X
X
X
X
Core serum 
chemistryj
Xj
X
X
X
X
X
Urinalysisk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
β-HCG pregnancy 
testl
X
X
X
X
X
ACTHm
X
T4 and TSHn
X
X
X
Response Assessments
Tumor 
evaluation/staging 
(CT 
scan/MRI/Other 
X
X
X


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
40/154
Screening/
Baseline 
Assessments
Treatment Phaseb
V1
V2
V3
V4
V5
V6
V7
(Roll-over into 
Once-every-2 weeks
dosing)
Day -28 to 
Randomizatio
na
W1
Day 
1
W2
Day 8
W3
Day 
15
W4
Day 
22
W5
Day 
29
W6
Day 
36
W7 
Da
y 
43
W8 
Da
y 
50
W9 
Day 
57
W10 
Day 
64
W11 
Day 
71
W12 
Day 
78
W13 
Day 85 (Follow 
Table 1 after 
V7/W13)
established 
methods)o,p
Dosing
Pretreatmentq
X
X
X
X
X
X
X
X
X
X
X
X
X
Avelumab
X
X
X
X
X
X
X
X
X
X
X
X
X
ACTH: adrenocorticotropic hormone;  AE: adverse events; β-HCG: β-human chorionic gonadotropin; CT: computed tomography; D: Day; ECG: electrocardiogram;
ECOG PS: Eastern Cooperative Oncology Group Performance Status; EQ-5D-5L: European Quality Of Life 5-dimensions 5-level questionnaire; HBV: hepatitis B 
virus; HCV: hepatitis C virus; ICF: Informed Consent Form; IV: intravenous; MRI: magnetic resonance imaging; PD-L1: programmed death-ligand 1; PR: partial 
response; T4: free thyroxine; TSH: thyroid-stimulating hormone; V: visit; W: Week.
a Randomization will be done after the confirmation of fulfilling all screening inclusion criteria (Section 5.3.1) without matching any exclusion criterion 
(Section 5.3.2).
b A time window of 1 day before or 1 day after the scheduled visit day (-1/+1 days) will be permitted for all trial procedures while subjects receive avelumab once 
weekly. A time window up to 3 days before or 1 day after the scheduled visit day (-3/+1 days) will be permitted for all trial procedures while subjects receive 
avelumab once every two weeks; however the weekly 7-day schedule for avelumab dosing should be strictly adhered to, returning to the target date even if the 
previous visit was off schedule.  The calculation of the dose of avelumab will be based on the weight of the subject determined within 72 hours prior to the day of 
drug administration (see Section 5.1.3.1).
c Tumor tissue must be available within 10 calendar days after the subject has signed the ICF in order to establish the PD-L1 status of the tumor.  A biopsy should 
be collected unless tissue from an archival specimen is available (biopsies are only to be obtained from safely accessible tumor tissue/sites).  Samples can be 
provided as block or slides (see Section 7.6 for details).  Randomization cannot occur until PD-L1 expression has been determined by a companion diagnostic test 
under development and performed centrally.
d Medical history should include history of NSCLC, previous and ongoing medications, smoking history, and Baseline medical condition.
e The patient-reported outcomes/quality of life assessments (EQ-5D-5L, EORTC QLQ-C30, and module QLQ-LC13) should be completed by all subjects prior to 
any of the other trial-related assessments being performed, that is, physical examinations, blood draws, trial treatment administration, etc.  The pretreatment 
assessment should be conducted at Screening; in the event that this doesn’t occur, it can be done at Visit 1 (Day 1) prior to treatment.
f If the Screening physical examination was performed within 3 days prior to Day 1, it does not have to be repeated at Visit 1.  A full physical examination should 
be performed at Screening and the EOT visit.  Physical examinations at all other visits should be directed towards signs and symptoms.
g If the Screening ECOG PS was performed within 3 days prior to Day 1, it does not have to be repeated at Visit 1.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
41/154
Screening/
Baseline 
Assessments
Treatment Phaseb
V1
V2
V3
V4
V5
V6
V7
(Roll-over into 
Once-every-2 weeks
dosing)
Day -28 to 
Randomizatio
na
W1
Day 
1
W2
Day 8
W3
Day 
15
W4
Day 
22
W5
Day 
29
W6
Day 
36
W7 
Da
y 
43
W8 
Da
y 
50
W9 
Day 
57
W10 
Day 
64
W11 
Day 
71
W12 
Day 
78
W13 
Day 85 (Follow 
Table 1 after 
V7/W13)
h 12-lead ECG should be assessed during screening and at the End-of-Treatment visit.  ECGs are to be performed as clinically indicated in case of abnormalities 
such as increased heart rate above the subject’s baseline detected during the physical examination and/or vital signs measurements performed prior to avelumab 
treatment. The avelumab administration should not be withheld in the isolated situation of an increased heart rate, unless the overall evaluation, including the 
ECG, is suggestive of myocarditis, in which case the protocol guidelines (as outlined in Table 10) should be followed
i Full chemistry panel, which includes core serum chemistry, and other laboratory studies are detailed in Table 11.  Follicle-stimulating hormone at Screening, if 
applicable (Section 7.1.1).
j Core serum chemistry includes liver function panel (alkaline phosphatase, ALT, AST, bilirubin), acute chemistry panel (sodium, potassium, chloride, BUN/total 
urea, creatinine, glucose), and mineral panel (magnesium, phosphorus, calcium).  If Screening full chemistry was performed within 3 days prior to Day 1, core 
serum chemistry does not have to be completed at Visit 1.
k Full urinalysis (dipstick and microscopic evaluation) at the Screening and End-of-Treatment visits and a basic urinalysis (dipstick only) at each visit indicated prior 
to administration of trial drug.  If the basic urinalysis is abnormal, then a full urinalysis should be performed.
l β-hCG should be determined from serum at Screening and from urine or serum thereafter.  Results of the pregnancy test should be available prior to dosing of 
trial drug.
m ACTH will be collected only at Baseline.  
n T4 and TSH will be collected at Screening/Baseline, and every 6 weeks during the treatment phase, and continue thereafter until progression if progression does 
not occur at treatment termination at the End-of-Treatment visit and the 30-day Safety Follow-up visit.  
o On study imaging will be performed every 6 weeks (±1 week) calculated from the randomization date and as clinically indicated and submitted for central 
radiology review.  The timing for imaging studies should follow calendar days and should not be adjusted for delays in cycle starts.  In case a tumor response 
according to RECIST 1.1 is documented during the course of the trial, confirmation of the response should be performed according to RECIST 1.1, preferably at 
the regularly scheduled 6-week assessment interval, but no sooner than 4 weeks after the initial documentation of CR or PR. Confirmation of PR can be confirmed 
at an assessment later than the next scheduled assessment after the initial documentation of PR.  After progression of disease and if clinically feasible, a 
subsequent scan at least 4 weeks after initial assessment of progression should be collected to confirm progression. In case of avelumab treatment beyond 
progression, additional images should be collected in accordance with imaging schedule as long as the subject continues on avelumab therapy. A CT scan or MRI 
should always be used (if MRI is used, CT of chest is mandatory).
p A brain CT/MRI scan is required at Screening if not performed within 6 weeks prior to randomization, and beyond as clinically indicated.  A bone scan should be 
done as clinically indicated at Screening and beyond.  Bone metastases detected at Screening need to be followed at the tumor evaluation visits.
q Subjects must receive pretreatment with H1 blockers and acetaminophen 30 to 60 minutes prior to infusion of avelumab (10 mg/kg IV over 1 hour [-10/+20 
minutes]).  Premedication with an antihistamine and with paracetamol (acetaminophen) (for example, 25 to 50 mg diphenhydramine and 500 to 650 mg 
paracetamol [acetaminophen] IV or oral equivalent) approximately 30 to 60 minutes prior to the first 4 infusions of avelumab is mandatory.  Premedication should 
be administered for subsequent avelumab doses based upon clinical judgment and presence/severity of prior infusion reactions.  This regimen may be modified 
based on local treatment standards and guidelines as appropriate.


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
4 2 / 1 5 4
C CI


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
4 3 / 1 5 4
C CI


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
4 4 / 1 5 4
C CI


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
4 5 / 1 5 4
C CI


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
4 6 / 1 5 4
2
S p o ns or, I n vesti g at ors a n d Tri al A d mi nistr ati ve Str uct ure
T he S p o ns or of t his cli nical trial wit h a vel u ma b is E M D Ser o n o Researc h & De vel o p me nt 
I nstit ute, I nc. ( E M D Ser o n o R & D), Billerica, M A, i n t he U nite d States ( U S A) , a n d Merc k K Ga A, 
D ar msta dt, Ger ma n y, i n rest of w orl d.
A c o ntract researc h or ga nizati o n ( C R O), 
, will u n derta ke 
t he o perati o nal as pects of t his trial.  Details of s uc h str uct ures a n d ass ociate d pr oce d ures will be 
defi ne d i n a se parate I nte grate d Pr oject Ma na ge me nt Pla n (IP M P) mai ntai ne d b y   
. T he 
I P M P will be pre pare d b y  the 
Cli nical Pr oject Ma na ger i n c o o perati o n wit h ot her 
O perati o nal Tea m Lea ds .
2. 1
I n vesti g ati o n al Sites
T he trial will be c o n d ucte d at u p t o 3 8 6 sites gl o ball y i n N ort h A merica (a p pr o xi matel y 2 7 i n t he 
U S A) , S o ut h A merica, Asia, Africa, a n d E ur o pe.
2. 2
Tri al C o or di n ati o n/ M o nit ori n g
T he S p o ns or will c o or di nate t he trial a n d will use t he s u p p ort of C R Os f or s o me acti vities of t he 
trial.  S p o ns or will perf or m o versi g ht of t he acti vities perf or me d b y  t he C R Os.
T he Cli nical Trial S u p plies de part me nt of t he S p o ns or will s u p pl y the trial me dicati o n of 
a vel u ma b.  Pac ka gi n g a n d distri b uti o n of cli nical s u p plies will be perf or me d b y  t he Cli nical Trial 
S u p plies de part me nt of t h e S p o ns or.  First -li ne c he m ot hera py will be s u p plie d b y  t he st u d y ce nter 
or b y  t he S p o ns or, acc or di n g t o l ocal la ws a n d re g ulati o ns.
S u bject ra n d o mizati o n will be ma na ge d b y a n i nteracti ve we b res p o nse s ys te m (IW R S).
Pr ot oc ol re q uire d safet y la b orat or y assess me nts will be perf or me d ce ntrall y.  Local la b orat ories 
ma y  be use d at t he discreti o n of t he I nvesti gat or as cli nicall y nee de d f or s afet y m a n a ge me nt of 
t he s u bject, a n d res ults fr o m t he l ocal la b orat ories will be e ntere d i n t he electr o nic case re p ort 
f orms (e C R Fs) per t he e C R F C o m pleti o n G ui deli nes.  Uri nal ysis a n d uri ne pre g na nc y testi n g will 
be perf or me d l ocall y.
T he Gl o bal Dr u g Safet y De part me nt, Merc k K Ga A, Dar msta dt, Ger ma n y, or t heir desi g nate d 
re prese ntati ves will s u per vise dr u g safety a n d t he ti mel y re p orti n g of a d verse e ve nts ( A Es) a n d 
seri o us a d verse e ve nts ( S A Es).
Q ualit y  ass ura nce of trial c o n d uct will be perf or me d b y  the De vel o p me nt Q ualit y  Ass ura nce 
De part me nt, Merc k K Ga A, Dar msta dt, Ger ma n y.
T he de part me nt of Gl o bal Bi ostatistics will s u per vise t he statistical a nal yses ( wit h t he e xce pti o n 
of t he P K data a nal y ses), w hic h will be o uts o urce d t o a C R O.
P P D
P P D
P P D
P P D


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
47/154
2.3
Review Committees
2.3.1
Independent Data Monitoring Committee
An Independent Data Monitoring Committee (IDMC) will be composed of a minimum of 
3 members who do not have any conflict of interests with the trial Sponsor, including 2 clinicians 
and a biostatistician.  The IDMC will periodically review safety data and conduct efficacy interim 
analyses.  The full membership, mandate, and processes of the IDMC will be detailed in the IDMC 
charter.
2.3.2
Independent Review Committee
A central facility will read and interpret all radiographic scans for this trial.  The data for all images 
will be transferred from each trial site to the central reading center for evaluation.  All scans will 
be evaluated at the central facility in accordance with Response Evaluation Criteria in Solid 
Tumors version 1.1 (RECIST 1.1, [1]).  The imaging data will be transferred to the Sponsor or 
designee at regular intervals throughout the trial.  A manual from the vendor will be provided to 
each trial site. 
The Independent Review Committee (IRC) will perform a blinded determination as to whether the 
criteria for tumor response or progression according to RECIST 1.1 have been met. The role of 
the IRC will be to review radiographic image findings for the determination of the time point 
overall response according to RECIST 1.1 for each subject. The IRC membership, assessment 
criteria details, mandate, and processes of the IRC are provided in the IRC charter.
3
Background Information
3.1
Non-Small Cell Lung Cancer
Non-small cell lung cancer is the leading cause of cancer-related death in men and women in the 
USA and in the EU, resulting in more cancer related deaths than breast cancer, prostate cancer, 
and colorectal cancer combined.  Worldwide, an estimated 1.8 million new cases of lung cancer 
were diagnosed in 2012, approximately 13% of the total of all new cancers diagnosed (2).  In 2014, 
an estimated 224,210 new cases (116,000 in men and 108, 210 in women) of lung and bronchial 
cancer will be diagnosed, and 149, 260 deaths (86, 930 in men and 72, 330 in women) are estimated 
to occur because of the disease.  Only 16.6% of all lung cancer patients are alive 5 or more years 
after diagnosis (3). 
In patients with NSCLC, outcomes from standard therapy are poor except for the most localized 
cancers where surgery and / or combined modality therapy can provide a cure in a small percentage 
of patients.  In patients with advanced or metastatic NSCLC, chemotherapy offers modest benefit, 
though overall survival (OS) remains poor (4, 5).  Despite treatment with platinum-based regimens 
with third generational agents, patients with metastatic NSCLC have a median survival of 
approximately 10 to 12 months, and a 5-year survival rate of approximately 15% (6).


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
48/154
Recently, personalized therapy for patients with tumors with specific genetic alternations, such as 
tyrosine kinase inhibitors for tumors with activating EGFR mutations, has resulted in better OS 
outcomes in these biologically selected subgroups.  However, these patients represent only 10-15% 
of patients and new treatment options are still needed to improve the prognosis for patients with 
lung cancer.  Novel agents that harness the immune system, such as vaccines and antibodies that 
modulate T-cell activity, offers an alternative treatment approach that could help improve 
outcomes.  Improvements in OS in randomized Phase III clinical trials have led to the approval of 
ipilimumab (anti-CTLA4) for melanoma, and sipuleucel-T for prostate cancer, and generated a 
renewed interest in immunotherapy for solid tumors.  In fact, while immunotherapy for lung cancer 
has not been successful in the past, nivolumab (anti-PD1) was recently approved by the FDA for 
the treatment of patients with metastatic squamous cell NSCLC based on a statistically significant 
improvement in OS in a randomized Phase III clinical trial.  In light of these recent data validating 
the clinical importance of blocking the PD-1/PD-L1 pathway in metastatic NSCLC, avelumab, 
which is an anti-PD-L1 monoclonal antibody, is being investigated in late stage clinical trials in 
patients with various advanced solid tumors, including NSCLC.
Refer to the Investigator’s Brochure (IB) for further information about the nonclinical and clinical 
programs and Guidance for the Investigator.
3.2
Programmed Death Receptor and Ligands
The programmed death 1 (PD-1) receptor and PD-1 ligands 1 and 2 (PD-L1, PD-L2) play integral 
roles in immune regulation.  Expressed on activated T-cells, PD-1 is activated by PD-L1 and 
PD-L2 expressed by stromal cells, tumor cells, or both, initiating T-cell death and localized 
immune suppression (7-10), potentially providing an immune-tolerant environment for tumor 
development and growth.  Conversely, inhibition of this interaction can enhance local T-cell 
responses and mediate antitumor activity in nonclinical animal models (8,11).
In the clinical setting, treatment with antibodies that block the PD-1 – anti-PD-L1 interaction have 
been reported to produce objective response rates of 7% to 38% in patients with advanced or 
metastatic solid tumors, with tolerable safety profiles (8,10,11).  Notably, responses appeared 
prolonged, with durations of 1 year or more for the majority of patients.
In 2015, pembrolizumab and nivolumab (anti-PD-1 antibodies) were approved by the US FDA for
the treatment of patients with NSCLC who had progressed following platinum-based therapy.  
While nivolumab was approved for patients with NSCLC regardless of PD-L1 expression, 
approval of pembrolizumab was restricted to patients whose tumors expressed PD-L1. 
In first line treatment setting of NSCLC, extensive studies are ongoing to evaluate anti-PD1/PD-L1 
agents based on various PD-L1 expression cutoffs.  Preliminary and emerging clinical data suggest 
that PD-1/PD-L1inhibitors are active in patients whose tumors exhibit tumor cell PD-L1 
expression.  While better clinical outcome in terms of ORR, PFS and OS has recently been reported 
in patients with increased levels of PD-L1 expression, its role in patients whose tumors express 
lower levels of PD-1 expression needs to be further characterized.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
49/154
In light of these recent data demonstrating the clinical efficacy of an anti-PD1 antibody in 
metastatic NSCLC and considering the clinical importance of PD-L1 expression by NSCLC tumor 
cells, avelumab (an anti-PD-L1 monoclonal antibody) is being developed in advanced NSCLC.
3.3
Avelumab
The investigational medicinal product (IMP) for the present trial is avelumab (formerly designated 
MSB0010718C), a fully human monoclonal antibody of the immunoglobulin (Ig) G1 isotype.  This 
anti-PD-L1 therapeutic antibody concept is being developed in oncological settings by Merck 
KGaA, Darmstadt, Germany, and by its subsidiary, EMD Serono R&D, Billerica, MA, USA.
Avelumab selectively binds to PD-L1 and competitively blocks its interaction with PD-1.  
Compared with anti-PD-1 antibodies that target T-cells, avelumab targets tumor cells, and 
therefore, is expected to have fewer side effects, including a lower risk of autoimmune-related 
safety issues, as blockade of PD-L1 leaves the PD-L2 – PD-1 pathway intact to promote peripheral 
self-tolerance (15).  For complete details of the in vitro and nonclinical studies, please refer to the 
IB.
Avelumab is currently being investigated in the following ongoing clinical studies:
Trial EMR100070-001 is a “Phase I, open-label, multiple-ascending dose trial to investigate the 
safety, tolerability, pharmacokinetics, biological, and clinical activity of avelumab in subjects 
with metastatic or locally advanced solid tumors.”
Trial EMR100070-002 is a “Phase I trial to investigate the tolerability, safety, pharmacokinetics, 
biological, and clinical activity of avelumab in Japanese subjects with metastatic or locally 
advanced solid tumors, with expansion part in Asian subjects with gastric cancer.”
Trial EMR100070-003 is a “Phase II, open-label, multicenter trial to investigate the clinical 
activity and safety of avelumab in subjects with Merkel cell carcinoma.”  This trial is ongoing 
and no data are available.
Trial EMR100070-004 is a “Phase III open-label, multicenter trial of avelumab 
(MSB0010718C) versus docetaxel in subjects with non-small cell lung cancer that has 
progressed after a platinum-containing doublet.”  This trial is ongoing and no data are available.
Trial EMR100070-007 is a “Phase III open-label, multicenter trial of maintenance therapy with 
avelumab (MSB0010718C) versus continuation of first-line chemotherapy in subjects with 
unresectable, locally advanced or metastatic, adenocarcinoma of the stomach, or of the 
gastro-esophageal junction”.  This trial is ongoing and no data are available.
Trial EMR100070-008 is
a
“Phase III open-label, multicenter trial of avelumab 
(MSB0010718C) as a third-line treatment of unresectable, recurrent, or metastatic gastric or 
gastroesophageal junction adenocarcinoma”.  This trial is ongoing and no data are available.
Trial B9991002 is a “Phase Ib open-label, dose-finding study to evaluate safety, PK and PD of 
avelumab (MSB0010718C) in combination with Axitinib (AG-013736) in patients with 
previously untreated advanced renal cell cancer.”  This trial is ongoing and no data are available.


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
5 0 / 1 5 4

Trial B 9 9 9 1 0 0 5 is a “ P hase I b a n d P hase II o pe n -la bel d ose -fi n di n g st u d y to e val uate safety a n d 
efficac y, P K a n d P D of a vel u ma b i n N S C L C i n c o m bi nati o n wit h criz oti ni b i n A L K ne gati ve 
disease or P F -0 6 4 6 3 9 2 2 i n A L K -p ositi ve disease .  O bjecti ve f or P hase I b: t o deter mi ne t he 
M T D a n d R P 2 D.”  T his trial is o n g oi n g a n d n o data are a vaila ble.

Trial B 9 9 9 1 0 0 7 is a “ P hase I, o pe n -la bel st ud y  to e val uate t he P K a n d P D of a vel u ma b i n 
s u bjects wit h pre vi o usl y treate d a d va nce d sta ge classical H o d g ki ns L ym p h o ma t o c haracterize 
t he P K of differe nt d osi n g re gi me ns a n d its relati o n t o tar get occ u pa nc y  in peri p heral bl o o d. ”  
T his trial is o n g oi n g a n d n o data are a vaila ble.

Trial B 9 9 9 1 0 0 9 is a “ P hase III Ra n d o mize d, o pe n -la bel st u d y of a vel u ma b ( M S B 0 0 1 0 7 1 8 C) 
al o ne or i n c o m bi nati o n wit h pe g y late d li p os o mal d o x or u bici n vers us pe g y late d li p os o mal 
d o x or u bici n al o ne i n patie nts wit h plati n u m -resista nt/refract or y ovaria n ca ncer.”  T his trial is 
o n g oi n g a n d n o data are a vaila ble.

Trial B 9 9 9 1 0 0 1 is a “ P hase III m ultice nter, m ulti nati o nal, o pe n-la bel ra n d o mize d parallel-ar m 
st u d y of a vel u ma b pl us B S C vs B S C al o ne as mai nte na nce treat me nt i n s u bjects wit h l ocall y 
a d va nce d or metastatic ur ot helial ca ncer w h ose disease di d n ot pr o gress after c o m pleti o n of 1 L 
plati n u m -c o ntai ni n g c he m ot hera p y to de m o nstrate be nefit i n o verall s ur vi val i n P D -L 1  positi ve 
s u bjects.”  T his trial is o n g oi n g a n d n o data are a vaila ble.

Tri al B 9 9 9 1 0 1 0 is a “ Ra n d o mize d, o pe n -la bel, m ultice nter, P hase 3 st u d y to e val uate t he 
efficac y an d safet y of a vel u ma b ( M S B 0 0 1 0 7 1 8 C) i n c o m bi nati o n wit h a n d/ or f oll o wi n g 
c he m ot hera p y i n patie nts wit h pre vi o usl y u ntreate d e pit helial o varia n ca ncer.”  T his trial is 
o n g oi n g a n d n o data are a vaila ble.
3. 3. 1
P h ase I D at a fr o m Tri al E M R 1 0 0 0 7 0 -0 0 1
A vaila ble safet y a n d efficac y data f or t he a vel u ma b pr o gra m are disc usse d i n t he I B a n d esta blis h 
a p ositi ve be nefit -ris k pr ofile f or c o n d ucti n g P hase III st u dies wit h 1 0 m g/ k g (t he d ose use d i n t his 
trial).  Hi g hli g hts rele va nt t o de vel o pi n g t his pr ot oc ol are pr o vi de d bel o w.   As of t he safet y c ut off 
C CI


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
51/154
date of 05 November 2015, 1353 subjects had received at least 1 dose of avelumab at doses ranging 
from 1.0 to 20 mg/kg administered once every 2 weeks (IB). In the dose escalation portion of the 
Phase I study a total of 53 subjects were treated, including 21 subjects who received 20 mg/kg, 
and there was no evidence of differences in the safety profile across all administered dose levels.
The MTD was not reached. Subsequently, 1300 subjects received 10 mg/kg administered once 
every 2 weeks in the pooled expansion cohort).
The safety data from subjects with different tumor types treated with avelumab suggests an 
acceptable safety profile of the compound. Most of the observed events were either in line with 
those expected in subjects with advanced solid tumors or with similar class effects of MoAB 
blocking the PD-1/PD-L1 axis. 
Infusion-related reactions, including hypersensitivity reactions and immune-mediated adverse 
reactions (eg, hypothyroidism, pneumonitis, hyperthyroidism, adrenal insufficiency, autoimmune 
hepatitis, colitis, thyroiditis, or myositis) have been identified as important risks for avelumab (see 
IB for details). 
Respective risk mitigation measures have been implemented in all ongoing clinical studies with 
avelumab, including this one (please see Sections 3.5, 5.1.2.1, 6.2.1, and 6.5.4).
3.3.2
Pharmacokinetics
Pharmacokinetic assessments have been performed in ongoing studies EMR100070-001 and 
EMR100070-002.  The PK results based on the data available as of 20 November 2015 are 
presented under the individual trial headings.
3.3.2.1
Trial EMR100070-001
The pharmacokinetics of avelumab has been examined at 1, 3, 10, and 20 mg/kg doses during the 
dose escalation phase and at 10 mg/kg dose during an expansion phase for selected indications, 
following iv infusion once every 2 weeks. As of the data cutoff date of 20 November 2015, a total 
of 53 subjects were enrolled and received at least 1 dose of study drug in the dose-escalation phase 
of the study and 1436 subjects across 16 expansion cohorts were enrolled and received at least 
1 dose of study drug in the expansion phase of the study (NDA 2.7.2). Frequent blood samples 
for the analysis of serum concentrations of avelumab were drawn from subjects in the dose 
escalation phase and 2 expansion cohorts. Sparse PK samples were collected and analyzed from 
all subjects.
Pharmacokinetics following the first 1-hour infusion and dose proportionality of avelumab have 
been characterized by standard non-compartmental analysis (NCA) based on the rich serum 
concentration-time data using recorded times obtained over a complete 2-week dosing interval.  
The dose-normalized exposure parameters, maximum concentration (Cmax) and area under the 
concentration-time curve (AUC0-336hr) after first dose appeared flat across 3 to 20 mg/kg, 
suggesting 
the 
exposure 
increased 
in 
an 
approximately 
dose-proportional 
manner 
between 3 to 20 mg/kg.  The concentration at the end of dose interval, Ctrough, increased 
proportionally with doses between 10 to 20 mg/kg, but more than proportionally for doses between 
1 to 10 mg/kg, likely due to the presence of target mediated drug disposition (TMDD) at these 


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
52/154
lower dose levels.  The t1/2 after the first dose increased with the dose for the 1 and 3 mg/kg dose 
groups.  However, the geometric mean values for t1/2 were similar for 10 mg/kg and 20 mg/kg dose 
levels, 94.6 hours (3.9 days) and 99.1 hours (4.1 days), respectively. 
The geometric mean 
clearance was estimated to be 0.362 mL/hr/kg (0.0264 L/hr for a subject who weighs 73 kg) for 
the 10 mg/kg dose. 
Following repeated 10 mg/kg once every 2 weeks dosing, the concentrations at the end of infusion 
(CEOI) reached the steady state approximately between the second and the third dosing with a 
minimal accumulation.  The Ctrough values were similar across subjects with different tumor types 
indicating that there is no meaningful difference in avelumab PK in subjects with different solid 
tumor types.
3.3.2.2
Trial EMR100070-002
Study EMR100070-002 is an ongoing Phase I dose escalation study with consecutive expansion 
to investigate the tolerability, safety, pharmacokinetics, biological and clinical activity of 
avelumab in Japanese subjects with metastatic or locally advanced solid tumors.  In the dose 
escalation part subjects received 3, 10, and 20 mg/kg of avelumab given as a 1-hour infusion.  The 
expansion part is being performed in Asian subjects with gastric cancer and who receive the 
10 mg/kg of avelumab once every 2 weeks until confirmed progression, unacceptable toxicity, or 
withdrawal from the study or study drug occurred.  As of the data cut-off date of 
20 November 2015, a total of 17 subjects had been enrolled in the dose-escalation part of the study 
and 34 subjects had been enrolled in the expansion part of the study.
Pharmacokinetic data were obtained from 5 Japanese subjects treated with 3 mg/kg, 6 Japanese 
subjects treated with 10 mg/kg and 6 Japanese subjects treated with 20 mg/kg of avelumab as a 
1-hour IV infusion once every 2 weeks in the dose escalation part of the study. 
After the first dose, the exposure parameters Cmax and AUC0-336hr after appeared to increase 
dose-proportionally between 3 to 20 mg/kg dose levels.  Ctrough increased proportionally with dose 
between 10 to 20 mg/kg, but more than proportionally for between dose levels 3 to 10 mg/kg, 
likely due to the presence of TMDD at these lower dose levels.  The geometric mean clearance 
was calculated to be 0.471 mL/hr/kg (0.0344 L/hr for a subject who weighs 73 kg) at the 10 mg/kg 
dose.  The t1/2 increased with the dose.  However, the geometric mean values were 122 hours 
(5.1 days) and 112 hours (4.7 days) for 10 and 20 mg/kg doses, respectively, similar between the
2 dose cohorts.
Following repeated 10 mg/kg once every 2 weeks dosing, CEOI values appeared stable over the 
treatment period at the 10 mg/kg dose level and moderate variability was observed, probably due 
to small sample size.  The mean CEOI at 10 mg/kg on Day 15 and Day 1 was 207 μg/mL and 
174 μg/mL, respectively, and the ratio between them was 1.19.  The extent of accumulation of 
serum concentration during the treatment period was mild, which is in line with the estimated t1/2
from the first administration and once every 2 weeks dosing frequency.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
53/154
3.3.3
Clinical Pharmacodynamics
Receptor occupancy was measured in vitro by flow cytometry on peripheral blood CD3+ T-cells 
after spiking of human whole blood samples from 8 healthy volunteers with avelumab over a 
concentration range of 0.003 to 10 μg/mL.  In this assay, free receptors were measured in samples 
spiked over this range and compared with the amount of free receptors in the unspiked sample.  A 
50% receptor occupancy was observed at a drug concentration of 0.122 μg/mL ± 0.042 μg/mL 
(standard deviation) and a plateau indicating at least 95% receptor occupancy was reached in all 
donor blood samples at 1 μg/mL.
These in vitro data combined with PK data were confirmed in ex vivo samples taken at Cmin after 
the first dose (Day 15) in a small number of subjects during the initial dose-escalation part of the 
Phase Ib Trial EMR100070-001 (n=9).  For doses of 10 mg/kg, target occupancy (TO) was greater 
than 90% for these 4 subjects, at trough serum levels ranging between 12.69 to 26.87 μg/mL.  Also, 
for doses of 3 mg/kg, available TO data for 2 subjects with trough levels ranging from 4.56 to 
6.99 μg/mL, showed greater than 90% TO at trough exposure levels.  At dose level 1 mg/kg, 2 out 
of 3 subjects displayed less than 90% TO at trough serum concentrations.  Avelumab serum 
concentrations were below the quantification limit of 0.2 μg/mL in these 2 subjects.
Based on the observed avelumab serum concentrations in the EMR100070-001 Phase I clinical 
trial and the in vitro receptor occupancy data, trough concentrations were sufficient to achieve full 
target occupancy throughout the entire dosing interval in all of the subjects receiving the 10 mg/kg 
dose, while after the 3 mg/kg dose, Ctrough values were insufficient in 3 of the 13 subjects to assure 
full target occupancy.
3.4
Rationale for the Current Clinical Trial
The rationale to include NSCLC subjects who have not received a systemic treatment for their 
metastatic disease and to administer avelumab is supported by the following:
The expression of PD-L1 by NSCLC tumor cells and by adjacent immune infiltrates 
The results from studies that used an anti-PD-1 antibody to block the interaction between PD-L1 
and PD-1
The interim data of the first 184 subjects with NSCLC (post platinum doublet) treated with 
avelumab, who were enrolled in the current EMR100070-001 Phase I study and were followed 
up for at least 13 weeks.
The interim data of the 156 subjects with NSCLC without prior systemic chemotherapy 
treatment for locally advanced or metastatic disease were treated with avelumab in the current 
EMR100070-001 Phase I study.  Of these subjects, 75 subjects were followed for at least 
13 weeks at the time of interim analysis (17).  Key results are described below.
The data from other Phase 1 checkpoint inhibitor studies that exhibit clinical activity (ORR, OS, 
PFS) in an advanced metastatic NSCLC, first line setting (16,18,19).  


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
54/154
These data suggest that the blockade of the PD-1/PD-L1 axis results in response rates that 
compares favorably against the existing standard of care, ie, platinum-based doublets
chemotherapy.
Avelumab is a fully human monoclonal antibody of the immunoglobulin (Ig) G1 isotype. This 
anti-PD-L1 therapeutic antibody concept is intended to be developed in oncological settings by 
Merck KGaA, Darmstadt, Germany, and by its subsidiary, EMD Serono R&D, Billerica, MA.  
In the avelumab Phase 1 Study EMR100070-001, 156 patients with advanced NSCLC have been
treated with avelumab 10 mg/kg intravenous (IV) once every 2 weeks until progression, 
unacceptable toxicity, or withdrawal. These patients had not been treated previously with 
systematic chemotherapy for metastatic or recurrent (Stage IV) disease and had not been selected 
for PD-L1 expression.  An interim analysis for 75 patients with ≥ 3 months follow-up was 
conducted in October 2015 (ASCO 2016; abstract 9036).  Objective response rate (ORR; 
unconfirmed) was 18.7% (95% CI: 10.6, 29.3) regardless of PD-L1 expression.
Of the 
14 - responses, 12 were still ongoing at the time of the interim analysis. PD-L1 expression was 
evaluable in 45 of 75 patients. Based on a ≥ 1% cutoff for tumor cell staining, 35 of 45 patients 
(77.8%) were PD-L1+ and the ORR in this subgroup was 20.0% (7 of 35 patients; CI: 8.4, 36.9) 
vs 0 of 10 patients (CI: 0.0, 30.8) in patients with PD-L1– tumors. Median PFS was 11.6 weeks 
(95% CI: 6.7, 17.9) for all patients. Subsequent follow-up of this cohort continues to demonstrate 
similar response rates and PFS.  The majority of responses occurred within the first 12 weeks of 
treatment, appear durable, and the rates increased with higher expression PD-L1 (Section 5.2.6).
Similarly, PFS also appeared to improve in patients with higher levels of PD-L1 expression. 
3.5
Summary of the Overall Benefit and Risk
Based on the nonclinical and Phase I data available to date, the dose and dose regimen of avelumab 
as specified in this clinical trial protocol are justified.  An IDMC (see Section 2.3.1) will assess
patient safety on an ongoing basis.  The trial will be discontinued in the event of any new findings 
that indicate a relevant deterioration of the risk-benefit relationship that would render continuation 
of the trial unjustifiable.
The primary known identified risks of exposure to avelumab include: 
Infusion-related reactions 
Immune-related adverse event (irAEs)
As of 05 November 2014, two Grade 4 infusion reactions have been reported in 480 subjects 
(0.4%) treated with avelumab (see IB); therefore, already implemented risk mitigation measures 
for infusion-related reactions / hypersensitivity have been extended by a mandatory premedication 
with H1 receptor blockers and acetaminophen for all subjects prior to any infusion.  Premedication 
with an antihistamine and with paracetamol (acetaminophen) (for example, 25 to 50 mg 
diphenhydramine and 500-650 mg paracetamol [acetaminophen] IV or oral equivalent) 
approximately 30 to 60 minutes prior to the first 4 infusions of avelumab is mandatory.  
Premedication should be administered for subsequent avelumab doses based upon clinical 


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
55/154
judgment and presence/severity of prior infusion reactions.  This regimen may be modified based 
on local treatment standards and guidelines as appropriate.  
As noted in Section 3.2, trials with antibodies that block the PD-1 – PD-L1 interaction have been 
reported to produce objective response rates of 7% to 38% in patients with advanced or metastatic 
solid tumors (16-21), with response durations of 1 year or more for the majority of patients.
Furthermore, a recent snapshot in Trial EMR100070-001 of subjects with NSCLC who had 
progressed after platinum-containing therapy (n=184 treated subjects with a minimum follow-up 
time of at least 6 months by the cut-off date of 15 January 2015) demonstrated an objective 
response rate (ORR) of 14.1% (26 of 184 subjects 95% CI: 9.4, 20.5%), including 1 subject with 
CR.  There were also 66 subjects with SD, 69 subjects with PD, and 23 subjects who were not 
evaluable.  Twenty (76.9%) out of the 26 responses were still ongoing at the cut-off date for this 
analysis (duration of response: range, 1 to 54.1 weeks; median not reached) including 3 subjects 
who continue to respond off-treatment.  The onset of response was rapid, with 11 of 22 (50.0%) 
subjects having their first documented response by Week 7. 
Close safety monitoring will be performed throughout the study by the IDMC (details in 
Section 5.1.1).  
Given the suboptimal treatment options for patients with recurrent or metastatic NSCLC and the 
safety profile of avelumab as currently demonstrated by ongoing Phase I trials, the risk-benefit 
ratio of treatment with avelumab in the targeted trial population is considered positive.  Overall, 
these data support the development of avelumab in subjects with metastatic or recurrent (Stage IV)
NSCLC who have not yet received systemic treatment for their metastatic disease.  This clinical 
trial will be conducted in compliance with the clinical trial protocol, ICH GCP, and the applicable 
national regulatory requirements.
4
Trial Objectives
4.1
Primary Objectives
The primary objective is to demonstrate superiority with regard to overall survival (OS) or 
progression free survival (PFS) of avelumab versus platinum-based doublet, based on an 
independent review committee assessment as per RECIST 1.1, in NSCLC subjects with 
high expression PD-L1+ tumors.
4.2
Secondary Objectives
Secondary objectives are as follows:

To demonstrate superiority with regard to OS or PFS based on an independent review 
committee assessment per RECIST 1.1 in NSCLC subjects with moderate and high 
expression PD-L1+ tumors

To demonstrate superiority with regard to OS in NSCLC subjects with any expression 
PD-L1+ tumors


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
5 6 / 1 5 4

T o c o m parati vel y assess t he o bjecti ve res p o nse rate ( O R R) b y  RE CI S T 1. 1 of a vel u ma b 
vers us c he m ot hera p y i n hi g h, m o derate a n d hi g h, a n d a n y  e x pressi o n P D -L 1 + t u m ors

T o deter mi ne d urati o n of res p o nse of a vel u ma b vers us c he m ot hera p y

T o c o m pare t he patie nt -re p orte d o utc o mes / q ualit y  of life w he n treate d wit h a vel u ma b 
vers us c he m ot hera p y usi n g t he E ur o pea n Q ualit y of Life (E ur o Q O L) 5- di me nsi o ns 5 -le vel 
q uesti o n naire ( E Q - 5 D-5 L ), a n d t he E ur o pea n Or ga nizati o n f or Researc h a n d Treat me nt of 
Ca ncer ( E O R T C) Q L Q -C 3 0 a n d m o d ule Q L Q -L C 1 3

T o deter mi ne t he safet y a n d t olera bilit y of a vel u ma b.
5
I n vesti g ati o n al Pl a n
5. 1
O ver all Tri al Desi g n a n d Pl a n
T his is a m ultice nter, i nter nati o nal, ra n d o mize d, o pe n -la bel, P hase III trial i n c he m ot hera p y- n aï ve 
(first li ne) metastatic or rec urre nt ( Sta ge I V) N S C L C s u bjects c o m pari n g a vel u ma b t o first-li ne 
plati n u m -base d d o u blet c he m ot hera p y.   
C CI


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
57/154
5.1.1
Overall Design
To achieve the target enrollment of 484 subjects randomized with high expression PD-L1+ tumors, 
approximately 1131 eligible subjects will be randomized with any expression PD-L1+ tumors and 
approximately 3100 subjects will be screened for study participation.
Subjects will be randomly allocated into the 3 study arms as follows:    
Arm A: Avelumab at a dose of 10 mg/kg as a 1-hour (-10/+20 minutes) intravenous (IV) 
infusion once every 2 weeks until disease progression or unacceptable toxicities, or
Arm B: Investigator’s choice platinum-containing chemotherapy regimen to be administered in 
3-week cycles up to a maximum of 6 cycles of IV injection until disease progression or 
unacceptable toxicities consisting of one of the following:
For subjects whose tumor is of non-squamous histology:
pemetrexed (500 mg/m2) in combination with cisplatin (75 mg/m2 administered on Day 
1 of each cycle), or pemetrexed (500 mg/m2) in combination with carboplatin (AUC 
6 mg/mL × min administered on Day 1 of each cycle). 
For subjects whose tumor is of squamous histology:
paclitaxel (200 mg/m2) plus carboplatin (AUC 6 mg/mL × min administered on Day 1 
of each cycle); or
gemcitabine (1250 mg/m2 administered on Day 1 and Day 8 of each cycle) plus 
cisplatin (75 mg/m2) or
gemcitabine (1000 mg/m2 administered on Day 1 and Day 8 of each cycle) plus 
carboplatin (AUC 5 mg/mL × min).
Arm C: Avelumab at a dose of 10 mg/kg as a 1-hour (-10/+20 minutes) intravenous (IV) infusion 
every week for 12 consecutive weeks, and then at Week 13, transition to avelumab at a dose of 
10 mg/kg once every 2 weeks until disease progression or unacceptable toxicities.
The NSCLC histology (squamous cell versus non-squamous cell) and PD-L1 tumor expression 
level at baseline (low versus moderate versus high) will be used as stratification factors for 
randomization (Figure 1). 
The trial will initially randomly allocate subjects into Arm A and Arm B in a 1:1 ratio.  A 
randomization ratio of 1:2:2 (Arm A: Arm B: Arm C) will start after the initial safety evaluation 
of avelumab 10 mg/kg every week in a cohort of 6 subjects. The IDMC will evaluate the safety 
data from this cohort once all of these 6 subjects have completed a minimum observation period 
of 4 weeks. The subjects treated with avelumab 10 mg/kg every week will receive a maximum of 
12 doses and, at Week 13, will transition to receive avelumab 10 mg/kg every 2 weeks (see Section 
5.1.3 for dosing requirements).  
The trial design schematic is presented in Figure 1. 


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
58/154
Figure 1
Trial Design
ALK: anaplastic lymphoma kinase; ECOG PS: Eastern Cooperative Oncology Group Performance Status; EGFR: 
epidermal growth factor receptor; NSCLC: non-small cell lung cancer; PD: progressive disease; PD-L1+: programmed 
death-ligand 1 positive; SOC: standard of care.
Subjects will return to the clinic at regular intervals for assessments.  Tumor measurements by
computed tomography (CT) scan or magnetic resonance imaging (MRI) will be performed every 
6 weeks for the first 12 months and every 12 weeks thereafter to determine response to treatment
and/or assessment of disease progression.  The CT/MRI scans will be collected until disease 
progression is assessed by the Investigators according to RECIST 1.1. For all subjects and if 
clinically feasible, a subsequent scan at least 4 weeks after the initial assessment of progressive 
disease should be collected to confirm progression.
Assessments will be made by the Investigator for the purpose of subject management. The disease 
response endpoint determinations including PD assessments associated with the trial endpoints 
will be supported by tumor assessments performed by an IRC (see Section 7.3). The central 
imaging laboratory will read and interpret all CT / MRI data.  Response will be evaluated using 
the RECIST 1.1 and as adjudicated by the blinded IRC.  
The subject’s treatment will continue until: 
Disease progression (see Section 5.5.1), 
Significant clinical deterioration (clinical progression, see Section 5.5.1), 
Unacceptable toxicity, or
Target enrolment is:
~3100 subjects screened and
~1131 subjects with any PD-L1+ expression randomly assigned
to achieve 484 subjects with high expression PD-L1+ tumors 
randomized 
Screening
28 days
Treatment until PD confirmed, clinical deterioration or toxicity
R
Arm A: Avelumab 10 mg/kg IV every 2 weeks
Arm B: SOC chemotherapy IV every 3 wks x 6 cycles
Arm C: Avelumab 10 mg/kg IV once a week for 12 weeks
At Week 13, followed by Avelumab 10 mg/kg IV every 2 weeks
Key inclusion criteria:
Stage IV NSCLC
First-line treatment 
setting
ECOG PS 0-1
PD-L1+ Tumors
EGFRwt/ALK-
Initial Randomization: 
Arm A: Arm B (1:1) 
Stratification by histology
Subsequent Randomization: 
Arm A: Arm B: Arm C (1:2:2)
Stratification by histology and PD-L1+ expression


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
59/154
Any criterion for withdrawal from the trial or trial drug is fulfilled (see Section 5.5).
For subjects receiving avelumab, treatment may continue past the initial determination of disease 
progression according to RECIST 1.1 if the subject’s performance status has remained stable, and 
if in the opinion of the Investigator, the subject will benefit from continued treatment and if other 
criteria are fulfilled as outlined in the protocol, that is, no new symptoms or worsening of existing 
symptoms and no decrease in performance score (see Section 6.2.1).
These subjects will be evaluated for further tumor response as per the protocol schedule.  For these 
subjects, further progression is defined as an additional increase in tumor burden of 20% and 
≥5 mm absolute increase from time of initial PD.  This includes an increase in the sum of all target 
lesions and/or the development of new measurable lesions.  Treatment should be discontinued 
permanently upon documentation of further disease progression.
New lesions are considered measureable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes, which must have a short axis of at least 
15 mm). Any new lesion considered nonmeasureable at the time of initial progression may become 
measureable and therefore included in the tumor burden if the longest diameter increases to at least 
10 mm (except for pathological lymph nodes, which must have a short axis of at least 15 mm).  
Subjects receiving avelumab who have experienced a CR should be treated for a minimum of 
12 months and/or disease progression or unacceptable toxicity, after confirmation of response.  In 
case a subject with a confirmed CR relapses after stopping treatment, during long term follow-up, 
one re-initiation of treatment is allowed at the discretion of the Investigator and agreement of the 
Medical Monitor. In order to be eligible for re-treatment, the subject must not have experienced 
any toxicity that led to treatment discontinuation of the initial avelumab therapy.  Subjects who 
re-initiate treatment will stay on trial and will be treated and monitored according to the protocol 
from Visit 1 and the “until progression” schedule in the Schedule of Assessments (see Table 1 for 
bi-weekly schedule or Table 4 for weekly schedule).
Subjects assigned to chemotherapy will be treated until disease progression, unacceptable toxicity, 
or after the completion of up to 6 cycles of chemotherapy.  Subjects with non-squamous histology 
will be authorized to continue to receive pemetrexed as a maintenance therapy after 4 cycles of 
platinum-based chemotherapy if their disease has not progressed, or in accordance with 
pemetrexed local label.  No other maintenance therapy is allowed.  
Subject management will be based on clinical assessments made by the Investigators.
Subjects will attend clinic visits at regular intervals to receive trial treatment and for efficacy and 
safety assessments (see Section 7.1.2).
Safety endpoints include AEs, assessed throughout the trial and evaluated using the NCI-CTCAE v
4.03 (CTCAE v 4.03), clinical laboratory assessments, vital signs, and electrocardiogram (ECG) 
parameters.
The initial safety evaluation of Arm C, avelumab 10 mg/kg every week for 12 consecutive weeks, 
followed by avelumab at a dose of 10 mg/kg once every 2 weeks will be performed during the 
study as follows: prior to randomization into the 3 arms of the study, 6 subjects will be enrolled at 


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
60/154
selected sites to receive avelumab 10 mg/kg every week for 12 weeks followed by avelumab 
10 mg/kg every 2 weeks.  After all of these 6 subjects have completed a minimum safety 
observation period of 4 weeks, the IDMC will evaluate all available safety data. 
If there are no safety concerns precluding inclusion of the Arm C dose schedule, the enrollment 
and the 1:2:2 randomization in the 3 study arms will proceed (Arm A: Arm B: Arm C).  Other 
options may be recommended by the IDMC, such as termination of this regimen or enrollment of 
6 additional subjects on this dose regimen prior to allowing randomization into Arm C including 
an additional IDMC safety evaluation after all of these 6 subjects have completed a minimum 
safety observation period of 4 weeks.  Once randomization to Arm C is initiated, a second safety 
evaluation will be performed by the IDMC when an additional 20 subjects in Arm C have been
followed for at least 4 weeks, without a subject enrollment hold in any arm.  The frequency of 
subsequent IDMC meetings for the entire study will be determined by the IDMC at the time of this 
second safety evaluation, which includes the additional 20 subjects’ safety information from 
Arm C. 
If safety data for 6 evaluable subjects treated with avelumab at 10 mg/kg once a week is available 
from the EMR100070-001 study, the IDMC may review the safety data after all of these 6 subjects 
have completed a minimum safety observation period of 4 weeks. The IDMC may determine the 
safety information as satisfactory and recommend that the initial safety evaluation of 6 subjects at 
10 mg/kg once a week in this study may not be performed. Alternatively, the IDMC may also 
recommend that the safety data from the safety evaluation periods from subjects in both 
Studies EMR100070-001 and EMR100070-005 may be combined, for up to 6-12 evaluable 
subjects, for further assessment by the IDMC.  
The safety evaluation period refers to the first 4 weeks of trial drug treatment for all subjects with 
data used by the IDMC to evaluate the safety.  The additional 20 subjects randomized in Arm C 
of study EMR100070-005 will have the secondary safety evaluation by IDMC which will be based 
on safety data collected for a minimum of 4 weeks for all subjects.
The data cut-off for the primary PFS and OS analyses will occur after the target number of 173 OS 
events for Arm C versus B comparison of the randomized subjects with high PD-L1 has been 
reached and at least 20 months follow-up after the randomization of the last subject in the study.  
5.1.2
Trial Medication Administration and Schedule
The trial Schedule of Assessments is presented in Table 1 to Table 4.
5.1.2.1
Avelumab
Subjects randomized to avelumab will receive IV infusion of avelumab (10 mg/kg over 1 hour
[-10/+20 minutes]) either once every 2 weeks (Arm A) for the full study, or once every week for 
12 consecutive weeks, followed by once every 2 weeks, starting Week 13  (Arm C).  Premedication 
with an antihistamine and with paracetamol (acetaminophen) (for example, 25 to 50 mg 
diphenhydramine and 500 to 650 mg paracetamol [acetaminophen] IV or oral equivalent) 
approximately 30 to 60 minutes prior to the first 4 infusions of avelumab is mandatory.  
Premedication should be administered for subsequent avelumab doses based upon clinical 


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
61/154
judgment and presence/severity of prior infusion reactions.  This regimen may be modified based 
on local treatment standards and guidelines as appropriate.
The formulation and packaging information of avelumab is provided in Sections 6.1.1 and 6.6, 
respectively.
5.1.2.2
Chemotherapy
Subjects randomized to the chemotherapy arm will receive IV infusion of chosen chemotherapy 
regimen according to the country-approved label and local institutional practice by IV infusion 
once every 3 weeks until disease progression, unacceptable toxicity, or any of the criteria for 
withdrawal from trial treatment is fulfilled (Section 5.5) or to a maximum of 6 cycles.  
Additionally, in order to reduce the incidence and severity of fluid retention as well as the severity 
of hypersensitivity reactions, subjects will be administered pre-treatment prior to each 
chemotherapy infusion per chemotherapy label instructions, or equivalent, per local institutional 
practice.  As the premedication for pemetrexed (oral folic acid, vitamin B12 intramuscular 
injection) will need to be delivered in the week before first dose of chemotherapy, this 
premedication is permitted to be initiated in all subjects with non-squamous histology after signing 
the informed consent and prior to randomization.  In the event that a subject is subsequently 
randomized to avelumab or is screen failed, vitamin B12 and the folic acid may be discontinued.
The formulation of the chemotherapy regimens is provided in Section 6.1.2.
5.1.3
Dose Modification and Adverse Drug Reactions Requiring 
Treatment Discontinuation
5.1.3.1
Dose Modification for Avelumab
The dose of avelumab will be calculated based on the weight of the subject determined within 
72 hours prior to the day of drug administration.  The dose of avelumab used for the previous 
administration can be repeated if the change in subject’s weight is 10% or less than the weight 
used for the last dose calculation. If the weight change is ≥ 10%, the intended dose should be 
recalculated. 
Each subject will stay on the avelumab assigned dose of 10 mg/kg unless treatment needs to be 
stopped.  Dosing modifications (changes in infusion rate) and dose delays due to adverse drug 
reactions (ADRs), infusion-related reactions and immune-related reactions are described in 
Sections 5.1.3.2, 6.5.4.1, and 6.5.4.2, respectively.  There will be no dose reductions.
Treatment with avelumab can be skipped for a delay of up to 4 weeks from the previous dose for 
any non-related AEs, laboratory abnormalities, or intercurrent illness, which in the judgment of 
the Investigator warrants delaying the dose of study medication.  If dosing is delayed more than 
4 weeks, treatment may be resumed only after consultation with the study Medical Monitor. Any 
delay in dosing in excess of 6 weeks is not permitted.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
62/154
5.1.3.2
Adverse 
Drug 
Reactions 
Requiring 
Avelumab
Discontinuation or Modifications
The following adverse drug reactions (ADRs, see Section 7.4.1.1) require permanent treatment 
discontinuation of avelumab:
Any Grade 4 ADRs: permanently discontinue avelumab except for laboratory values out of 
normal range that do not have any clinical correlate.
Any Grade 3 ADRs:
Withhold avelumab except for laboratory values out of normal range that do not have any 
clinical correlate.
Permanently discontinue avelumab if toxicity does not resolve to Grade ≤1 or baseline within 
12 weeks of last administration or if the same Grade 3 toxicity recurs (consider consult with the 
Medical Monitor before permanently discontinuing the treatment).
If dosing is delayed more than 4 weeks, treatment may be resumed after consultation with the 
study Medical Monitor.  Any delay in dosing in excess of 12 weeks is not permitted.
Infusion should not be given if ECOG PS is ≥ 3 on the day of trial treatment administration.  
Treatment should be discontinued if ECOG PS has not improved to ≤ 2 by the next scheduled 
treatment administration.
Dermatological irAEs Grade 3 and Grade 4 should be handled according to guidelines in Table 10.
Any Grade 2 ADR should be managed as follows:
If a Grade 2 ADR resolves to Grade ≤ 1 by the last day of the current cycle, treatment may 
continue.
If a Grade 2 ADR does not resolve to Grade ≤ 1 by the last day of the current cycle, infusions 
should not be given on the following cycle.  If at the end of the following cycle the event has 
not resolved to Grade 1, the subject should permanently discontinue treatment with a avelumab 
ADR (except for hormone insufficiencies, that can be managed by replacement therapy; for 
these hormone insufficiencies, up to 2 subsequent doses may be omitted).
If dosing is delayed more than 4 weeks, treatment may be resumed after consultation with the 
study Medical Monitor. Any delay in dosing in excess of 6 weeks is not permitted.
Upon the second occurrence of the same Grade 2 ADR (except for hormone insufficiencies that 
can be managed by replacement therapy) in the same subject, treatment with avelumab has to 
be permanently discontinued.
Infusion-related reactions, and irAEs should be handled according to guidelines in Sections 
6.5.4.1, and 6.5.4.2, respectively.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
63/154
5.1.3.3
Dose Modification for Chemotherapy
After the starting dose, dose modifications (dose delays and dose changes) for toxicity should be 
made in accordance with labeling instructions and local institutional guidelines.  Discontinuation 
of chemotherapy due to AEs should also be in accordance with the chemotherapy label and local 
institutional practice (see Table 7).
Table 7
Dose Modification Schedule for Chemotherapy
Dose Level
Gemcitabine
Pemetrexed
Cisplatin
Carboplatin
Paclitaxel
Starting dose
1250 mg/m2 
(with cisplatin) 
or 1000 mg/m2 
(with 
carboplatin)
500 mg/m2
75 mg/m2
AUC 
6 mg/mL × 
min (with 
pemetrexed 
or 
paclitaxel) 
or AUC 
5 mg/mL × 
min with 
gemcitabine
200 mg/m2
First dose 
reduction
950 mg/m2 (with 
cisplatin) or 
750 mg/m2 (with 
carboplatin)
375 mg/m2
56 mg/m2
AUC 
5 mg/mL × 
min (with 
pemetrexed 
or 
paclitaxel) 
or AUC 
4 mg/mL × 
min with 
gemcitabine
150 mg/m2
Second dose 
reduction
625 mg/m2 (with 
cisplatin) or 
500 mg/m2 (with 
carboplatin)
250 mg/m2
38 mg/m2
AUC 
4 mg/mL × 
min (with 
pemetrexed 
or 
paclitaxel) 
or AUC 
3 mg/mL × 
min with 
gemcitabine
100 mg/m2
Third dose 
reduction
Discontinue
Discontinue
Discontinue
Discontinue
Discontinue
AUC: area under the concentration-time curve.
5.2
Rationale for Trial Design
This is a Phase III, 3-arm, randomized, open-label trial to determine the efficacy and safety of 
avelumab compared with first-line platinum-containing chemotherapy in chemotherapy-naïve 
subjects with metastatic or recurrent (Stage IV) NSCLC.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
64/154
The following sections present the rationale for this trial design including the PD-L1 disease status, 
chemotherapy doublet comparator, open-label design, stratification by histology and PD-L1 tumor 
expression level at baseline (low versus moderate versus high), PFS and OS as primary endpoints, 
dose selection, and the exclusion/inclusion of special populations.  
5.2.1
Requirement of PD-L1+ Disease Status
All subjects randomized in the trial are expected to be PD-L1+ as determined by a companion 
diagnostic test under development.  The rationale to restrict subject eligibility to those with tumors 
that are PD-L1+ is based on the prevalence of PD-L1 positivity in the NSCLC cohort from 
EMR100070-001 and the decision to target subjects who may have a greater chance to respond to 
an anti-PD-L1 therapy while at the same time minimizing avelumab exposure and toxicity in 
subjects who may be less likely to benefit. 
5.2.2
Chemotherapy Doublet Comparator
Several platinum doublet chemotherapy regimens with similar efficacy are approved for first-line 
treatment of advanced NSCLC, although some agents have indications that are histology-specific.  
For example, pemetrexed is approved in first-line in combination with cisplatin for locally 
advanced or metastatic non-squamous NSCLC.  Pemetrexed has also been approved as 
continuation maintenance therapy in non-squamous subjects who have not progressed after four 
cycles of a first-line pemetrexed/platinum regimen.  In contrast, gemcitabine in combination with 
cisplatin has been demonstrated to yield improved overall survival compared to 
pemetrexed/cisplatin in subjects with squamous NSCLC.  Although some but not all meta-analyses 
and randomized studies have demonstrated that cisplatin-based regimens may produce improved 
survival compared to carboplatin-based regimens, many subjects are not ideal candidates for 
cisplatin due to its higher toxicity (29).
5.2.3
Open-label Design
This study will use an open-label design.  Due to the multiple options available for Investigator’s 
choice chemotherapy (described in Section 5.1.2.2), the different schedules and durations of 
therapy in the treatment arms, different dose modification rules for safety management, and 
different premedication requirements according to the Investigator’s choice chemotherapy, an 
open-label design is appropriate.  An open-label design will also help ensure that immune-related 
toxicities in subjects receiving avelumab are promptly identified and managed.  Because this study 
will be open label, a blinded IRC will be used to review tumor assessments in all randomized 
subjects to determine all response-related endpoints, including PFS.
5.2.4
Stratification by Histology and PD-L1 Tumor Expression
Among the different histologies of NSCLC, squamous histology typically represents 25% of all
lung cancer cases (25).  Most studies involving first-line and second-line therapy did not 
specifically separate subjects by histology, although this was recorded in all of the pivotal trials 
(26-29).  The first study that showed a difference in histology involved the comparison of 
gemcitabine and cisplatin to pemetrexed and cisplatin.  In this study, subjects with squamous cell 


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
65/154
NSCLC had a median survival time of 10.8 months with the gemcitabine combination while it was 
only 9.4 months with pemetrexed.  This is compared with the median survival time of 10.9 months 
with gemcitabine versus 12.6 months with pemetrexed in adenocarcinoma and 6.7 months with 
gemcitabine versus 10.4 months with pemetrexed in large cell lung cancer (26).  A subanalysis of 
the pemetrexed non-inferiority study in second-line therapy, showed a statistically significant 
improvement in the combined non-squamous histologies when compared with docetaxel 
(9.3 months vs. 8.0 months [HR 0.778]), but not in squamous (6.2 months vs. 7.4 months [HR 
1.563]) (30).  Additional data has shown that there is a poorer prognosis among subjects with 
squamous cell NSCLC due to comorbidities related to smoking history, larger tumors with 
lymphatic and vascular invasion, and the presence of more poorly differentiated tumors.  As a 
result of the potential differences in prognosis, outcome, and treatment for subjects with non-
squamous and squamous histology, although the risk of disease recurrence after initial treatment 
is the same between adenocarcinoma and squamous cell (31). 
Currently there are no data available to support potential differences in the prognosis of subjects 
in relation to the level of PD-L1 tumor expression.  However, PD-L1 expression level may be a 
predictive factor for the treatment outcome in first line monotherapy setting with checkpoint 
inhibitors as demonstrated by recent data from studies in subjects with advanced NSCLC.  Study 
KEYNOTE-024 evaluated pembrolizumab in subjects with advanced NSCLC, PD-L1 tumor 
proportion score (TPS) ≥50%.  Reported data have shown superior PFS and OS over platinum 
doublet chemotherapy in this patient population.  Study CheckMate 026 evaluated nivolumab in 
the same setting in subjects with PD-L1 tumor expression ≥1%.  Reported data have not 
demonstrated superior PFS over chemotherapy.
5.2.5
PFS and OS as the Primary Endpoints
FDA guidance for industry on clinical trial endpoints for NSCLC drugs recommends OS to be the 
standard clinical benefit endpoint.  However, the guidance also comments that other endpoints can 
be considered for regulatory decisions based on population and the risk benefit profile of the drug.  
Per the FDA guidance, PFS can be considered as a primary endpoint for demonstration of efficacy 
for drug approval based on magnitude of effect and risk benefit profile of the drug.
In this trial, efficacy of avelumab versus chemotherapy will be assessed based on various 
expression levels of PD-L1 and based on exposure to avelumab.  Based on data from the first-line 
NSCLC cohort of EMR100070-001, it is anticipated that both PFS and OS will be improved for 
subjects with high or moderate to high expression of PD-L1, and OS will be improved for subjects 
with any PD-L1 expression.  Since checkpoint inhibitors may already be available for subjects in 
the second line treatment setting, OS results may be confounded by such therapies. Thus, 
simultaneous assessment of PFS and OS will allow the analysis of treatment-effect in this 
population. 
5.2.6
Dose Selection
In this trial, avelumab will be evaluated in 2 dose regimens: 10 mg/kg once every 2 weeks (Arm A) 
and 10 mg/kg once a week for 12 weeks, followed by transition to once every 2 weeks at Week 13 


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
66/154
for the remainder of the study (Arm C) and compared to the platinum-containing chemotherapy 
regimen (Arm B).
In Arm A, the 10 mg/kg given by IV infusion once every 2 weeks dose is selected based on 
manageable safety profiles in Study EMR100070-001, EMR100070-002, and EMR100070-003 
and based on the preliminary efficacy data in 1L NSCLC cohort in Study EMR100070-001.
Avelumab has been studied in over 1600 subjects with advanced solid tumors, including 
27 subjects treated with 20 mg/kg once every 2 weeks and more than 1450 subjects treated with 
10 mg/kg 
once 
every 
2 
weeks 
(Studies 
EMR100070-001, 
EMR100070-002 
and 
EMR100070-003). This dose provides a high and sustained receptor occupancy in the blood 
throughout the dosing interval. The MTD was not reached in the dose escalation phase of Study 
EMR100070-001. For the safety profile, see the Investigator Brochure.
The preliminary efficacy analysis for 1L NSCLC cohort in Study EMR100070-001 (n=156) 
indicated clinical benefit to NSCLC subjects (Section 3.4).
Preliminary exposure-efficacy relationship in 1L NSCLC subjects suggests that an increase in 
exposure compared with the 10 mg/kg once every 2 weeks regimen may improve the efficacy with 
marginal if any impact on the safety profile, as demonstrated by the exposure safety evaluation.
An exposure-efficacy response relationship was observed in NSCLC subjects treated with 
10 mg/kg once every 2 weeks.  For 1L NSCLC cohort of Study EMR100070-001 (n=156), a 
relationship between predicted Ctrough,ss and BOR was observed and supported by logistic 
regression (univariate analysis): the response rate was higher in subjects with higher PK 
exposure (5%, 10%, 23%, and 36% objective response rate in 1st, 2nd, 3rd, and 4th exposure 
quartiles, respectively) regardless of PD-L1 expression.  Similarly for PFS and OS endpoints in 
NSCLC subjects, exposure-response relationship was suggested by COX models, though high 
uncertainty exists in these analyses. 
Population PK analysis and simulation showed that 10 mg/kg once every week regimen will 
increase the exposure, such that more than 90% of the subjects dosed with 10 mg/kg once every 
week will have a predicted Ctrough,ss higher than the lower bound of the 4th exposure quartile for 
the 10 mg/kg once every 2 weeks.  Specifically, the median (CI) Ctrough,ss is predicted to increase 
from 22.9 µg/mL (4.2-74.5 µg/mL) in the once-every-2-weeks regimen to 83.3 µg/mL
(28.6-204 µg/mL) in the once-a-week regimen (data on file), potentially enhancing efficacy as 
suggested by the exposure-efficacy analyses described above. 
For Arm C, the 12-week duration for avelumab once a week administration, followed by once 
every 2 weeks, was selected for this study based on preliminary observations from the 1L 
NSCLC cohort of EMR100070-001 dosed with 10 mg/kg avelumab once every 2 weeks, which 
showed that:
o Approximately 80% of responses occurred within 12 weeks of treatment initiation, and
o Majority of responses appeared to be durable.
It is not expected that the exposure at 10 mg/kg once every week would substantially impact the 
manageable safety profile currently observed with 10 mg/kg once every 2 weeks dosing:


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
6 7 / 1 5 4

T he e x p os ure -ir A E relati o ns hi p c ur ve a p peare d t o be flat or s hall ow f or s h orter treat me nt 
d urati o ns ( ≤1 8 wee ks) 
base d o n dataset t hat i ncl u de d > 1 4 5 0 s u bjects fr o m st u dies 
E M R 1 0 0 0 7 0 - 0 0 1, E M R 1 0 0 0 7 0 - 0 0 2, a n d E M R 1 0 0 0 7 0 - 0 0 3 (refer t o e x p os ure -safety re p ort). 
F or all ot her A Es a nal yz e d, A E i nci de nce a p peare d t o n ot i ncrease wit h i ncreasi n g e x p os ure. 

Base d o n p o p ulati o n P K m o deli n g, me dia n
e x p os ures are n ot e x pecte d t o e xcee d t h ose f or 
pre vi o usl y  ad mi nistere d re gi me ns:  Cma x,ss is si milar t o t hat f or 1 0 m g / k g o nce e ver y 2 wee ks 
re gi me n, w hile A U C ss is si milar t o t hat f or 2 0 m g/ k g o nce e ver y 2 wee ks re gi me n ( data o n file). 

A vel u ma b has s h o w n a de q uate safety pr ofile i n 2 7 s u bjects treate d wit h 2 0 m g/ k g o nce e ver y 
2 wee ks a n d m ore t ha n 1 4 5 0 s u bjects treate d wit h 1 0 m g/ k g o nce e ver y 2 wee ks.  T he M T D 
was n ot reac h e d i n t he d ose escalati o n p hase of St u d y  E M R 1 0 0 0 7 0 - 0 0 1.  
I n s u m mar y, t he d osi n g re gi me n of 1 0 m g / k g o nce a wee k f or 1 2 wee ks f oll o we d b y  10 m g / k g
o nce e ver y 2 w ee ks is s u p p orte d b y  t he e x p os ure -efficac y relati o ns hi p, 
, 
a n d a n acce pta ble be nefi t-ris k pr ofile, as descri be d a b o ve. T his re gi me n als o all o ws t he e val uati o n 
of cli nical o utc o mes i n s u bjects wit h hi g her e x pos ure a n d hi g h e x pressi o n of P D -L 1  (See 
Secti o n 3. 4 ).
5. 2. 7
E xcl usi o n 
of S u bjects wit h 
E G F R 
M ut ati o ns 
a n d A L K 
T r a nsl oc ati o n
F or s u bjects wit h E G F R m utati o ns a n d A L K tra nsl ocati o ns, t he c urre nt sta n dar d of care f or i nitial 
t hera py is tar gete d age nts rat her t ha n c he m ot hera p y. I n a d diti o n, s u bjects wit h E G F R m utati o ns 
ha ve a better pr o g n osis, e ve n i n t he a bse nce of E G F R i n hi bit or t hera p y (2 2 ) a n d m a y  ha ve a n 
i m pr o ve d resp o nse t o c he m ot hera p y co m pare d t o s u bjects wit h o ut E G F R m utati o ns (2 3 ). S u bject s 
wit h A L K tra nsl ocati o ns, w h o are treate d wit h c he m ot hera p y, a p pear t o ha ve si milar P F S 
c o m pare d t o s u bjects wit h o ut A L K tra nsl ocati o ns w h o are treate d wit h c he m ot hera p y  (2 4 ). As a 
res ult, s u bjects k n o w n t o ha ve t hese a b n or malities will be e xcl u de d fr o m t his st u d y. F urt her m ore, 
e xcl u di n g s u bjects wit h E G F R m utati o n a n d A L K tra nsl ocati o n will hel p t o re d uce t he p ote ntiall y 
c o nf o u n di n g effects of t hese a b n or malities o n t he st u d y  e n d p oi nts.
S u bjects wit h u n k n o w n A L K a n d E G F R stat us a n d t h ose wit h eit her n o n-s q ua m o us hist ol o g y or 
t h ose w h o are ne ver -s m o kers will re q uire testi n g (l ocal la b orat or y, or ce ntral la b orat or y if l ocal 
testi n g is n ot a vaila ble) a n d m ust be deter mi ne d t o be w il d t ype t o be eli gi ble f or t his trial. If a n 
In vesti gat or dee ms it i m p orta nt t o c o n d uct E G F R/ A L K tests i n s u bjects ot her t ha n t h ose wit h 
n o n- s q ua m o us hist ol o g y or ne ver -s m o kers, (e g, e x -s m o kers, t u m or wit h mi xe d hist ol o g y) i n or der 
t o offer E G F R/ A L K tar gete d t hera p y, s uc h testi n g ma y be c o n d ucte d.
5. 2. 8
E xcl usi o n of B e v aciz u m a b as a C o m p ar at or T her a p y
Be vaciz u ma b was a p pr o ve d i n 2 0 0 6 b y  the F D A f or s u bjects wit h u nresecta ble l ocall y a d va nce d 
rec urre nt or metastatic n o n-s q ua m o us N S C LC.
Be vaciz u ma b i n c o m bi nati o n wit h c he m ot hera p y 
is i n dicate d i n P S 0- 1 s u bjects wit h a d va nce d or rec urre nt n o n- s q ua m o us N S C LC.  H o we ver, o nly 
select N S C LC s u bjects m a y be a p pr o priate f or be vaciz u ma b t hera p y.  F or e xa m ple, s u bjects w h o 
ha ve acti ve car di o vasc ular disease or w h o ha ve a rece nt hist or y of he m o pt ysis s h o ul d n ot recei ve 
be vaciz u ma b gi ve n t he ass ociati o n bet wee n be vaciz u ma b a n d t hr o m b oc yt o pe nia a n d blee di n g 
C CI


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
68/154
events. Due to these restrictions, bevacizumab has not been widely adopted as standard of care 
therapy in clinical practice and therefore it is not included as one of the physician choice 
therapeutic options for this trial.
5.2.9
Inclusion of Special Populations
Not applicable.
5.3
Selection of Trial Population
Subject randomization will be managed by an IWRS (see Section 7.1.1).  Only persons meeting 
all inclusion criteria and no exclusion criteria may be randomized into the trial as subjects.  Prior 
to performing any trial assessments not part of the subject’s routine medical care, the Investigator 
will ensure that the subject or the subject’s legal representative has provided written informed 
consent following the procedure described in Section 9.2.  
5.3.1
Inclusion Criteria
For inclusion in the trial, all of the following inclusion criteria must be fulfilled:
1. Signed written informed consent before any trial-related procedure is undertaken that is not 
part of the standard subject management
2. Male or female subjects aged ≥ 18 years
3. Availability of a recently-obtained, formalin-fixed, paraffin-embedded (FFPE) tissue sample 
containing tumor (biopsy from a non-irradiated area preferably within 6 months) or a minimum 
number of 10 (preferably 25) unstained tumor slides cut within 1 week, and suitable for PD-L1 
expression assessment
4. Tumor determined to be positive for any PD-L1 expression per the evaluation of a central 
laboratory 
5. At least 1 measurable lesion per RECIST 1.1 criteria.  A lesion that has been irradiated can be 
used as a measurable lesion providing that disease has progressed at that site
6. Subjects with histologically-confirmed Stage IV metastatic or recurrent (Stage IV) NSCLC as 
per the 7th International Association for the Study of Lung Cancer and the American Joint 
Committee on Cancer classifications
7. Subjects must not have received any treatment for systemic lung cancer, including EGFR 
inhibitors or anaplastic lymphoma kinase (ALK) inhibitors
8. Subjects could have received neoadjuvant/adjuvant chemotherapy or loco-regional treatment 
that included chemotherapy for locally advanced disease, as long as disease recurrence 
occurred at least 6 months after the completion of the last administration of chemotherapy
treatment.  Subjects who received thoracic radiation therapy of >30 Gy within 2 months of the 
first dose of trial treatment are not eligible.
9. ECOG PS of 0 to 1 at trial entry
10. Estimated life expectancy of more than 12 weeks
11. Adequate hematological function defined by white blood cell (WBC) count ≥ 2.5 × 109/L with 
absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count ≥100 × 109/L, and hemoglobin 
≥9 g/dL (may have been transfused)


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
69/154
12. Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × the upper limit of normal 
(ULN) range and AST and alanine aminotransferase (ALT) levels ≤ 2.5 × ULN for all subjects, 
or for subjects with documented metastatic disease to the liver and AST and ALT levels 
≤5 x ULN. Subjects with documented Gilbert disease are allowed if total bilirubin is less than 
3 x ULN.
13. Adequate renal function defined by an estimated creatinine clearance ≥ 50 mL/min according 
to the Cockcroft-Gault formula (or local institutional standard method)
14. Negative blood pregnancy test at screening for women of childbearing potential.  For the 
purposes of this trial, women of childbearing potential are defined as: “All female subjects 
after puberty unless they are post-menopausal or not sexually active.”  Females are considered 
postmenopausal if they have age-related amenorrhea ≥ 12 consecutive months or if they have 
undergone hysterectomy or bilateral oophorectomy.  If necessary to confirm postmenopausal 
status, follicle-stimulating hormone (FSH) may be drawn at Screening with documented 
increased FSH > 40 mIU/mL.
15. Highly effective contraception (ie, methods with a failure rate of less than 1 % per year) for 
both male and female subjects if the risk of conception exists (Note: The effects of the trial 
treatment on the developing human fetus are unknown; thus, women of childbearing potential 
and men must agree to use highly effective contraception, defined in Appendix III or as 
stipulated in national or local guidelines. Highly effective contraception must be used for the 
duration of trial treatment, and at least for 60 days after stopping trial treatment.  Should a 
woman become pregnant or suspect she is pregnant while she or her partner is participating in 
this trial, the treating physician should be informed immediately).  For subjects randomized to 
the avelumab arm of the study, highly effective contraception is required at least 30 days prior 
and 60 days after avelumab treatment.  All female subjects of childbearing potential who are 
randomized to the chemotherapy arm are required to use highly effective contraception for up 
to 6 months after chemotherapy treatment, and male subjects will be advised not to father a 
child during the 6 months after treatment with chemotherapy.
5.3.2
Exclusion Criteria
Subjects are not eligible for this trial if they fulfill any of the following exclusion criteria:
1. Subjects whose disease harbors an EGFR mutation.  Subjects with non-squamous histology of 
unknown EGFR status will require testing for EGFR mutations (local laboratory, or central 
laboratory if local testing is not available) and must be determined to be EGFR wild-type to be 
eligible for this trial
2. Subjects with non-squamous cell NSCLC whose disease harbors an ALK rearrangement.  
Subjects with non-squamous histology of unknown ALK status will require testing for ALK 
rearrangement (local laboratory, or central laboratory if local testing is not available) and must 
be determined to be ALK wild-type to be eligible for this trial. Subjects with indeterminate 
ALK status may be enrolled, unless they are non-smokers and < 40 years old with tumors of 
adenocarcinoma histology.
3. Subjects with tumors known to harbor molecular alterations for which a targeted therapy is 
approved.
4. Prior therapy with any antibody or drug targeting T-cell coregulatory proteins, concurrent 
anticancer treatment, or immunosuppressive agents.  


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
70/154
5. Concurrent anticancer treatment (for example, cytoreductive therapy, radiotherapy [with the 
exception of palliative bone-directed radiotherapy], immune therapy, or cytokine therapy 
except for erythropoietin)
6. Major surgery for any reason, except diagnostic biopsy, within 4 weeks of randomization and 
/ or if the subject has not fully recovered from the surgery within 4 weeks of randomization
7. Subjects receiving immunosuppressive agents (such as steroids) for any reason should be 
tapered off these drugs before initiation of the trial treatment (with the exception of subjects 
with adrenal insufficiency, who may continue corticosteroids at physiologic replacement dose, 
equivalent to ≤10 mg prednisone daily).
Note:  Previous or ongoing administration of systemic steroids for the management of an acute 
allergic phenomenon is acceptable as long as it is anticipated that the administration of steroids 
will be completed in 14 days, or that the daily dose after 14 days will be ≤ 10 mg per day of 
equivalent prednisone
8. All subjects with brain metastases, except those meeting the following criteria:

Brain metastases that have been treated locally and are clinically stable for at least 
2 weeks prior to randomization

No ongoing neurological symptoms that are related to the brain localization of the disease 
(sequelae that are a consequence of the treatment of the brain metastases are acceptable)

Subjects must be either off steroids or on a stable or decreasing dose of ≤ 10 mg daily 
prednisone (or equivalent)
9. Previous malignant disease (other than NSCLC) with the exception of adequately treated basal 
or squamous cell carcinoma of the skin or carcinoma in situ (bladder, cervical, colorectal, 
breast or prostate) is an exclusion unless a complete remission without further recurrence was 
achieved at least 2 years prior to study entry, and the subject was deemed to have been cured 
with no additional therapy required or anticipated to be required.
10. Prior organ transplantation, including allogeneic stem-cell transplantation 
11. Significant acute or chronic infections including, among others:

Known history of testing positive test for human immunodeficiency virus (HIV) or 
known acquired immunodeficiency syndrome (AIDS)

Positive test for HBV surface antigen and / or confirmatory HCV RNA (if anti-HCV 
antibody tested positive)
12. Active autoimmune disease that might deteriorate when receiving an immunostimulatory 
agent:

Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not 
requiring immunosuppressive treatment are eligible

Subjects requiring hormone replacement with corticosteroids are eligible if the steroids 
are administered only for the purpose of hormonal replacement and at doses ≤ 10 mg or 
10 mg equivalent prednisone per day

Administration of steroids through a route known to result in a minimal systemic 
exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable
13. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI-CTCAE v 
4.03), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially 
controlled asthma)
14. Persisting toxicity related to prior therapy of Grade > 1 NCI-CTCAE v 4.03
15. Pregnancy or lactation


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
71/154
16. Known alcohol or drug abuse
17. The subject has uncontrolled intercurrent illness including not limited to:

Hypertension uncontrolled by standard therapies (not stabilized to 150/90 mm Hg or 
lower)

or, uncontrolled active infection, 

or, uncontrolled diabetes (eg, HgbA1c ≥ 8%) 
18. Clinically significant (that is, active) cardiovascular disease: cerebral vascular accident / stroke 
(< 6 months prior to randomization), myocardial infarction (< 6 months prior to 
randomization), unstable angina, congestive heart failure (New York Heart Association 
Classification Class ≥ II), or serious uncontrolled cardiac arrhythmia requiring medication 
19. All other significant diseases (for example, inflammatory bowel disease, uncontrolled asthma), 
which, in the opinion of the Investigator, might impair the subject’s tolerance of trial treatment.  
Cisplatin should not be employed in subjects with hearing impairment.
20. Any psychiatric condition that would prohibit the understanding or rendering of informed 
consent
21. Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except 
for administration of inactivated vaccines (for example, inactivated influenza vaccines)
22. Legal incapacity or limited legal capacity.
5.4
Criteria for Initiation of Trial Treatment
The inclusion and exclusion criteria will be checked at the Screening visit.  Eligible subjects will 
be randomized before treatment start after verification of fulfilling all inclusion criteria without 
matching any exclusion criteria.
5.5
Criteria for Subject Withdrawal
5.5.1
Withdrawal from Trial Therapy 
Subjects will be withdrawn from trial treatment for any of the following reasons:
PD per RECIST 1.1 (subjects receiving avelumab treatment may continue past the initial 
determination of disease progression if the subject’s ECOG PS has remained stable, and if in 
the opinion of the Investigator, the subject will benefit from continued treatment, see 
Section 6.2.1)
Significant clinical deterioration (clinical progression), defined as new symptoms that are 
deemed by the Investigator to be clinically significant or significant worsening of existing 
symptoms
Unacceptable toxicity 
Withdrawal of consent
Occurrence of an exclusion criterion, which is clinically relevant and affects the subject’s 
safety, if discontinuation is considered necessary by the Investigator and/or Sponsor
Therapeutic failure requiring urgent additional drug (if applicable)


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
72/154
Occurrence of any Grade ≥ 3 ADRs or repetitive Grade 2 ADRs as defined in Section 5.1.3.2
Occurrence of AEs resulting in the discontinuation of the trial drug being desired or considered 
necessary by the Investigator and/or the subject 
Occurrence of pregnancy 
Use of a nonpermitted concomitant drug, as defined in Section 6.5.2, where the predefined 
consequence is withdrawal from the trial drug
Noncompliance (see Section 6.9).
5.5.2
Withdrawal from the Trial
Subjects may withdraw from the trial at any time without giving a reason.  Withdrawal of consent 
will be considered withdrawal from the trial.
A subject must be withdrawn if any of the following occur during the trial:
Withdrawal of the subject’s consent
Participation in any other therapeutic trial during the treatment duration of this trial; however, 
subjects will continue to be followed for survival
If a subject fails to attend scheduled trial assessments, the Investigator must determine the reasons 
and the circumstances as completely and accurately as possible.
In case of withdrawal from the trial, the assessments scheduled for the last visit (End-of-Treatment 
visit) should be performed (see Section 7.1.3), if possible, with focus on the most relevant 
assessments.  In any case, the appropriate End-of-Treatment electronic case report form (eCRF) 
visit must be completed.  In case of withdrawal, subjects will be asked to continue safety and 
survival follow-up, which includes the collection of data on survival, patient-reported 
outcomes/quality of life questionnaires, and subsequent anticancer therapy. For subjects 
withdrawing from trial-related procedures, collection of survival data will be pursued as permitted 
by local regulations. This may include accessing public records such as survival registries, and 
obituaries.   
If a subject is withdrawn prior to progression for any reason, the subject will not be replaced.
5.6
Premature Termination of the Trial
The whole trial may be discontinued prematurely in the event of any of the following:
New information leading to unfavorable risk-benefit judgment of the trial drug, for example, 
due to: 
Evidence of inefficacy of the trial drug
Occurrence of significant previously unknown adverse reactions or unexpectedly high 
intensity or incidence of known adverse reactions
Other unfavorable safety findings.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
73/154
(Note: Evidence of inefficacy may arise from this trial or from other trials; unfavorable safety 
findings may arise from clinical or nonclinical examinations, for example, toxicology.)
Sponsor’s decision that continuation of the trial is unjustifiable for medical or ethical reasons
Poor enrollment of subjects making completion of the trial within an acceptable time frame 
unlikely
Discontinuation of development of the Sponsor’s trial drug.
Health Authorities and Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs)
will be informed about the discontinuation of the trial in accordance with applicable regulations.
The whole trial may be terminated or suspended upon request of Health Authorities.
5.7
Definition of End of Trial
If the trial is not terminated for a reason given in Section 5.6 or within this Section, the survival 
follow-up will continue until 5 years after the last subject receives the last dose of avelumab.  
Under some circumstances, the subject may not be followed for 5 years for survival in this study, 
for example, the subjects may be offered to enter into a roll-over study or the Sponsor may 
terminate the study early.
6
Investigational Medicinal Product and Other Drugs Used in 
the Trial
The term IMP refers to the investigational drug undergoing a clinical trial, as well as to any 
comparator drug or placebo (as applicable).  In this trial, the investigational drug is avelumab and 
the comparator is a first-line platinum-containing chemotherapy regimen (based on Investigator’s 
discretion).
6.1
Description of the Investigational Medicinal Product
6.1.1
Avelumab
Avelumab is a sterile, clear, and colorless solution intended for IV administration.  It is presented 
at a concentration of 20 mg/mL in single-use glass vials closed with a rubber stopper and sealed 
with an aluminum polypropylene flip-off seal.
6.1.2
Chemotherapy
Subjects will receive the physician’s choice of chemotherapy among the following treatments:
6.1.2.1
Carboplatin
Carboplatin is a platinum-based drug that is used in NSCLC.  Carboplatin is administered 
intravenously at a dose of AUC 6 mg/mL × min (per Calvert formula) over 15 to 30 minutes after 
the use of paclitaxel (33) or pemetrexed (34). Carboplatin may also be given at a dose of AUC 


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
74/154
5 mg/mL × min (per Calvert formula) with gemcitabine (35).  Subjects who are receiving 
carboplatin must be monitored for myelosuppression and anaphylaxis.  Dose modifications 
according to toxicities are noted in Section 5.1.3.3.  For preparation and storage, please consult the 
local prescribing information for carboplatin or the Summary of Product Characteristics (SMPC)
(36).
6.1.2.2
Cisplatin
Cisplatin is a platinum-based drug that is used in NSCLC.  Cisplatin is administered intravenously 
at a dose of 75 mg/m² over 30 minutes after gemcitabine or pemetrexed.  Subjects who are 
receiving cisplatin must be monitored for nephrotoxicity, ototoxicity, and neuropathy in addition 
to myelosuppression.  Cisplatin should not be employed in subjects with hearing impairment.  
Caution must be observed in the case of nausea, vomiting, and dehydration.  Dose modifications 
according to toxicities are noted in Section 5.1.3.3. For preparation and storage, please consult the
local prescribing information for cisplatin or the SMPC (37).
6.1.2.3
Gemcitabine
Gemcitabine is indicated in combination with cisplatin in first-line treatment of inoperable, locally 
advanced (Stages IIIA or IIIB) or metastatic (Stage IV) NSCLC.  Using the 3-week schedule, 
gemcitabine is administered intravenously at a dose of 1250 mg/m² over 30 minutes on Days 1 and 
8 of each 21-day cycle.  Cisplatin should be administered 30 minutes after gemcitabine on Day 1 
only at a dose of 75 mg/m².  Gemcitabine may also be given at a dose of 1000 mg/m² over 
30 minutes on Days 1 and 8 or each 21-day cycle, in combination with carboplatin at AUC 
5 mg/mL × min (per Calvert formula), as first-line treatment of advanced NSCLC.  Dose 
adjustments for hematology toxicity may be required for gemcitabine and cisplatin (individually).  
Gemcitabine dosage adjustment for hematologic toxicities based upon the granulocyte and platelet 
counts on the day of treatment.  Subjects receiving gemcitabine should be monitored prior to each 
dose using complete blood counts (CBC).  If marrow suppression is noted, dose modifications are 
noted in Section 5.1.3.3. For non-hematologic toxicities, other than alopecia and nausea, dose 
modifications should be considered for both gemcitabine and cisplatin.  For preparation and 
storage, please consult the local prescribing information for gemcitabine or the SMPC (38).
6.1.2.4
Pemetrexed
Pemetrexed is a folate analog metabolic inhibitor indicated as initial treatment for locally advanced 
or metastatic non-squamous NSCLC in combination with cisplatin.  Pemetrexed is also indicated 
as maintenance treatment for locally advanced or metastatic non-squamous NSCLC subjects 
whose disease has not progressed after platinum-based first-line chemotherapy.  Pemetrexed is 
administered intravenously at a dose of 500 mg/m² on Day 1 of each 21-day cycle.  Cisplatin 
should be administered 30 minutes after pemetrexed at a dose of 75 mg/m².  The premedication 
regimen for pemetrexed includes folic acid and vitamin B12 as well as dexamethasone or 
equivalent to reduce cutaneous reactions. Subjects receiving pemetrexed should be monitored 
prior to each dose using CBC and renal function tests. If marrow suppression is noted, dose 
modifications are noted in Section 5.1.3.3. For renal toxicity, pemetrexed should be held when 
the CrCl < 45 mL/minute. Caution should be used among subjects who are receiving non-steroidal 


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
75/154
anti- inflammatory drugs (NSAIDs) and who have mild to moderate renal insufficiency (CrCl 
between 45 and 79 mL/minute). Caution should also be used when nephrotoxic drugs are 
administered with pemetrexed. For preparation and storage, please consult the local prescribing 
information for pemetrexed or the SMPC (39).
6.1.2.5
Paclitaxel
Paclitaxel is a taxane that is indicated in combination with cisplatin in first-line treatment for 
inoperable, locally advanced (Stages IIIA and IIIB) or metastatic (Stage IV) NSCLC. Paclitaxel 
is administered intravenously at 200 mg/m2
over 3 hours, and premedication using 
diphenhydramine (or equivalent) and dexamethasone (or equivalent) is required. Subjects must 
be observed for hypersensitivity reactions, myelosuppression, and neuropathy. 
Dose 
modifications according to toxicities are noted in Section 5.1.3.3. For preparation and storage, 
please consult the local prescribing information for paclitaxel or the SMPC (40).
6.2
Dosage and Administration
6.2.1
Avelumab Dosage and Administration
Subjects will receive an IV infusion of avelumab at a dose of 10 mg/kg (over the duration of 1 hour
[-10/+20 minutes]) following pretreatment with histamine H1 blockers and acetaminophen 30 to 
60 minutes prior to each avelumab infusion, either once a week (for 12 weeks followed by once 
every 2 weeks, starting at Week 13 [see Table 4]) or every 2 weeks (see Table 1).  Premedication 
with an antihistamine and with paracetamol (acetaminophen) (for example, 25 to 50 mg 
diphenhydramine and 500 to 650 mg paracetamol [acetaminophen] IV or oral equivalent) 
approximately 30 to 60 minutes prior to the first 4 infusions of avelumab is mandatory.  
Premedication should be administered for subsequent avelumab doses based upon clinical 
judgment and presence/severity of prior infusion reactions.  This regimen may be modified based 
on local treatment standards and guidelines as appropriate.  Modifications of the infusion rate due 
to infusion-related reactions are described in Section 6.5.4.1.  The dose of avelumab will be 
calculated based on the weight of the subject determined within 72 hours prior to the day of drug 
administration.  The dose of avelumab used for the previous administration can be repeated if the 
change in the subject’s weight is 10% or less of weight used for the last dose calculation.    
Subjects will receive avelumab either once a week (for 12 weeks) or every 2 weeks until the criteria 
in Sections 5.5 through 5.7 are met.
For subjects receiving avelumab, treatment may continue past the initial determination of disease 
progression per RECIST 1.1 as long the following criteria are met:
Investigator-assessed clinical benefit, without any rapid disease progression
Tolerance of avelumab
Stable ECOG PS
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (for example, central nervous system metastases).


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
76/154
In addition, if disease progression is due to brain metastasis, subjects may continue avelumab 
treatment after the local treatment of the brain lesions provided that the above criteria are met in 
addition to the following:
Brain metastases have been treated locally and are clinically stable for at least 2 weeks prior to 
re-initiation of treatment with avelumab 
There are no ongoing neurological symptoms that are related to the brain localization of the 
disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable)
Subjects must be either off steroids or on a stable or decreasing dose of ≤ 10 mg daily 
prednisone (or equivalent)
In addition, if disease progression is mainly due to a metastatic lesion (nodal or visceral) which 
in the opinion of the investigator may be surgically removed or treated with palliative radiation 
therapy, subjects may continue avelumab treatment after the local treatment of such a lesion 
provided that:
•
It has been at least 2 weeks (post minor surgery) or 4 weeks (post major surgery) and the 
subject has fully recovered from the surgery.
•
It has been at least 2 weeks since the subject’s last dose of radiation therapy and any 
toxicity related to the radiation therapy is recovered to < Grade 2.  
The decision to continue treatment post disease progression should be discussed with the medical 
monitor and documented in the trial records.
Subjects in Arm C for whom there is a decision to continue treatment post disease progression and 
who are on every two week treatment administration may re-initiate treatment with weekly 
treatment administration for a duration of up to 12 weeks. This alternative should be considered 
by the treating physician taking into consideration the subject general status and the comparison 
of subject’s treatment toxicities reported during the prior weekly versus every two week treatment 
administration.
A radiographic assessment should be performed within 6 weeks of original PD to determine 
whether there has been a decrease in the tumor size, or continued PD.  The assessment of clinical 
benefit should be balanced by clinical judgment as to whether the subject is clinically deteriorating 
and unlikely to receive any benefit from continued treatment with avelumab.
If the Investigator feels that the subject continues to achieve clinical benefit by continuing 
treatment, the subject should remain on the trial and continue to receive monitoring according to 
the Schedule of Assessments (Table 1).
For subjects who continue avelumab trial therapy beyond progression, they will be evaluated for 
further tumor response as per the protocol schedule.  For these subjects, further progression is 
defined as an additional increase in tumor burden of 20% and ≥ 5 mm absolute increase from time 
of initial PD.  For subjects who underwent treatment for progression (brain metastasis or metastatic 
lesion [nodal or visceral]), the evaluation of further progression will be based on increase in tumor 
burden from the time of post treatment of progression.  This includes an increase in the sum of all 


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
77/154
target lesions and/or the development of new measurable lesions.  Treatment should be 
discontinued permanently upon documentation of further disease progression.
New lesions are considered measureable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes, which must have a short axis of at least 
15 mm).  Any new lesion considered nonmeasureable at the time of initial progression may become 
measureable and therefore included in the tumor burden if the longest diameter increases to at least 
10 mm (except for pathological lymph nodes, which must have a short axis of at least 15 mm).
Additionally, subjects receiving avelumab who have experienced a CR should be treated for a
minimum of 12 months and/or until disease progression or unacceptable toxicity, after 
confirmation of response at the discretion of the Investigator.  In case a subject with a confirmed 
CR relapses after stopping treatment, 1 re-initiation of treatment is allowed at the discretion of the 
Investigator and agreement of the medical monitor.  To be eligible for re-treatment, the subject 
must not have experienced any toxicity that led to treatment discontinuation of the initial avelumab 
therapy.  Subjects who re-initiate treatment will stay on trial and will be treated and monitored 
according to the protocol and the “until progression” schedule in the Schedule of Assessments (see 
Table 1 for bi-weekly schedule or Table 4 for weekly schedule).
6.2.2
Chemotherapy Dosage and Administration
The standard of care for chemotherapy-naïve (first line) patients with metastatic NSCLC is to 
receive a platinum-based chemotherapy regimen (see Table 2 and Table 3).  Chemotherapy should 
be administered at the clinic in accordance to the label instructions and per local administration 
guidelines for a maximum of 6 cycles.  The choice of the chemotherapy administered will depend 
on histology and clinical judgment of the Investigator.
In order to accommodate subjects with both squamous and non-squamous histology in this study, 
squamous subjects randomized to the comparator arm may receive the Investigator’s choice of any 
of the following platinum-based chemotherapy regimens:
Gemcitabine/cisplatin (up to 6 cycles)
Gemcitabine/carboplatin (up to 6 cycles)
Paclitaxel/carboplatin (up to 6 cycles)
Subjects with non-squamous histology who are randomized to the comparator arm (Arm B) may 
receive Investigator’s choice of any of the following pemetrexed/platinum regimens, including the 
option for continuation of pemetrexed as maintenance therapy:
Pemetrexed/cisplatin (up to 6 cycles)
Pemetrexed/carboplatin (up to 6 cycles)
Pemetrexed/cisplatin (up to 4 cycles), followed by pemetrexed maintenance (and/or, in 
accordance to the local label instructions)
Pemetrexed/carboplatin (up to 4 cycles), followed by pemetrexed maintenance (and/or, in 
accordance to the local label instructions)


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
78/154
Subjects with non-squamous histology who have been assigned to receive pemetrexed might, 
based on Investigator judgment, continue to receive pemetrexed as a maintenance therapy after 
4 cycles of platinum-based chemotherapy if their disease has not progressed, or in accordance with 
pemetrexed local label.  No other maintenance therapy is permitted.  In addition, if there is toxicity 
to a given platinum agent (cisplatin or carboplatin) for which its administration should be 
discontinued, the platinum agent may, at the Investigator’s discretion, be either discontinued or 
switched to another platinum agent (cisplatin or carboplatin) and treatment continued for up to 
6 cycles in total, provided that there was no disease progression.
Subjects will receive trial treatment until PD per RECIST 1.1, significant clinical deterioration 
(clinical progression), unacceptable toxicity, withdrawal of consent, or if any criterion for 
withdrawal from the trial or trial treatment is fulfilled, or for a maximum of 6 cycles.
Table 8
Allowed Chemotherapy Regimens
Product Description
Dosage Form
Potency
Dose
Dosing 
Frequency
Carboplatin
Solution for infusion
150 mg/vial 
(10 mg/mL)
AUC 5 with 
gemcitabine/AUC 
6 with 
paclitaxel/pemetrexed
Day 1 of each 
cycle
Cisplatin
Solution for infusion
50 mg/vial (1 
mg/mL)
75 mg/m2
Day 1 of each 
cycle
Gemcitabine
Solution for infusion 
1000 mg/vial
1250 mg/m2 with 
cisplatin/1000 mg/m2 
with carboplatin
Day 1 and Day 8 
of each cycle
Pemetrexed
Powder for infusion 
solution
500 mg/vial
500 mg/m2
Day 1 of each 
cycle
Paclitaxel
Solution for infusion
100 mg/vial 
(6 mg/mL)
200 mg/m2
Day 1 of each 
cycle
6.3
Assignment to Treatment Groups
Once the subject has provided a signed Informed Consent Form (ICF) and has been determined to 
meet inclusion and exclusion criteria, the Investigator or delegate will request the trial treatment 
assignment using the IWRS. The trial is fully controlled by the IWRS, which assigns treatment 
individual (unique) vial numbers for each subject.  The vial number is linked via the Good 
Manufacturing Practice (GMP) qualified system to the corresponding treatment as well as to the 
subject.
Qualified subjects will be randomized overall to receive avelumab once a week, avelumab once 
every 2 weeks, or chemotherapy using stratified permuted block randomization via the IWRS. 
Subjects will be randomly allocated to one of the 3 treatment arms, initially into Arm A and Arm 
B in a 1:1 ratio.  The allocation ratio will change to 1:2:2 (Arm A: Arm B: Arm C) once the IDMC 
recommends the avelumab once a week dosing regimen may be included in the randomization 
scheme after the initial safety evaluation of avelumab 10 mg/kg every week in a cohort of 
6 subjects.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
79/154
NSCLC histology (squamous versus non-squamous cell) will be used as stratification factors for 
randomization. The PD-L1 tumor expression level at baseline (low expression versus moderate 
expression versus high expression) will be supplemented as randomization strata for the 1:2:2 
randomization scheme. This stratified randomization will be centrally allocated across all trial 
sites via the IWRS.
Subject identifiers will comprise 17 digits, the first 10 digits representing the trial number, the 
following 3 digits representing the site number, and the last 4 digits representing the subject 
number, which is allocated sequentially starting with 0001. 
6.4
Noninvestigational Medicinal Products to be Used
Subjects randomized to receive avelumab will receive pretreatment with H1 blockers and 
acetaminophen 30 to 60 minutes prior to each avelumab infusion.  Premedication with an 
antihistamine and with paracetamol (acetaminophen) (for example, 25 to 50 mg diphenhydramine 
and 500 to 650 mg paracetamol [acetaminophen] IV or oral equivalent) approximately 30 to 
60 minutes prior to the first 4 infusions of avelumab is mandatory.  Premedication should be 
administered for subsequent avelumab doses based upon clinical judgment and presence/severity 
of prior infusion reactions.  This regimen may be modified based on local treatment standards and 
guidelines as appropriate.
Subjects randomized to receive chemotherapy will receive pretreatment prior to each 
chemotherapy infusion per chemotherapy label instructions, or equivalent, per local institutional 
practice.
Immediate access to an intensive care unit (ICU) or equivalent environment and appropriate 
medical therapy (including epinephrine, corticosteroids, IV antihistamines, bronchodilators, and 
oxygen) must be available for use in the treatment of infusion-related reactions.  Infusion of 
avelumab will be stopped in case of Grade ≥ 2 infusion-related, allergic, or anaphylactoid 
reactions.  Following avelumab infusions, subjects must be observed for 1 hour post infusion, for 
the first 4 infusions, for potential infusion-related reactions. 
As with all monoclonal antibody therapies, there is a risk of allergic reaction.  Avelumab 
should be administered in a setting that allows for immediate access and administration of 
therapy for severe allergic/hypersensitivity reactions, such as the ability to implement 
immediate resuscitation measures.  Steroids (dexamethasone 10 mg), epinephrine (1:1000 
dilution), allergy medications (antihistamines), or equivalents should be available for 
immediate access.
If hypersensitivity reaction occurs, the subject must be treated according to the best available 
medical practice.  Guidelines for management of infusion-related reactions according to the NCI 
is found in Section 6.5.4.1.  A complete guideline for the emergency treatment of anaphylactic 
reactions according to the Working Group of the Resuscitation Council (United Kingdom) can be 
found at https://www.resus.org.uk/anaphylaxis/emergency-treatment-of-anaphylactic-reactions/.  
Subjects should be instructed to report any delayed reactions to the Investigator immediately.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
80/154
6.5
Concomitant Medications and Therapies
6.5.1
Permitted Medicines
Any medications (other than those excluded by the clinical trial protocol) that are considered 
necessary to protect subject welfare and will not interfere with the trial medication may be given 
at the Investigator’s discretion.
The Investigator will record all concomitant medications taken by the subject during the trial, from 
the date of signature of informed consent, in the appropriate section of the eCRF.
Any additional concomitant therapy that becomes necessary during the trial and any change to 
concomitant drugs must be recorded in the corresponding section of the eCRF, noting the name, 
dose, duration, and indication of each drug.
Palliative bone-directed radiotherapy may be administered during the trial.  The assessment of PD 
will be made according to RECIST 1.1 (1) and not based on the necessity for palliative bone 
directed-radiotherapy.
Administration of steroids through a route known to result in a minimal systemic exposure (topical, 
intranasal, intro-ocular, inhalation, or local steroid injections [eg, intra-articular injections]) are 
acceptable.
Bisphosphonate or denosumab treatment is allowed during the study provided that they are 
administered as concomitant palliative and supportive care for disease related symptoms.  Disease 
progression should be completely ruled out and the exact reason for the use of these therapies must 
clearly be documented.
Rescue medications may be administered to address ineffective treatment, anticipated adverse 
reactions, or anticipated emergency situations.
6.5.2
Prohibited Medicines
Prohibited medicines are listed in the exclusion criteria (see Section 5.3.2).
The following treatments must not be administered during the trial:
cytoreductive therapy, 
radiotherapy (with the exception of palliative bone-directed radiotherapy, or radiotherapy 
administered on superficial lesions) as long as there is no identified soft tissue component which
has been selected as target lesion, 
cytokine therapy except for erythropoietin (only for subjects randomized to avelumab),
use of any investigational drug within 28 days before randomization.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
81/154
In addition, the following treatments must not be administered during the trial:
Immunotherapy, immunosuppressive drugs (that is, chemotherapy or systemic corticosteroids)
except:
o
When required for treatment of allergic reactions or for the treatment of irAEs or 
infusion related reactions/hypersensitivity
o
Systemic corticosteroids for management of patients with allergy to CT IV 
Radiographic Contrast Media.
o
Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or 
equivalent
Note: The use of systemic corticosteroids for subjects randomized to receive chemotherapy is per 
Investigator’s discretion and is to be based on local and institutional guidelines.
Growth factors for subjects randomized to receive avelumab (granulocyte colony stimulating 
factor or granulocyte macrophage colony stimulating factor).  Exception: Erythropoietin and 
darbepoietin alpha may be prescribed at the Investigator’s discretion
For subjects randomized to receive paclitaxel, use of concomitant strong cytochrome P450 3A4 
(CYP3A4) inhibitors should be avoided (for example, ketoconazole, itraconazole, 
clarithromycin, 
atazanavir, 
indinavir, 
nefazodone, 
nelfinavir, 
ritonavir, 
saquinavir, 
telithromycin, and voriconazole).  For more information on CYP3A4 substrates, Investigators 
are directed to the following URL: http://medicine.iupui.edu/clinpharm/ddis/.
If the administration of a nonpermitted concomitant drug becomes necessary during the trial, the 
subject will be withdrawn from trial treatment (the Sponsor may be contacted to discuss whether 
the trial treatment must be discontinued).  The subject should complete the End-of-Treatment visit 
(Section 7.1.3) and be followed for survival according to Section 7.1.6. 
Medications other than those specifically excluded in this trial (see above) may be administered 
for the management of symptoms associated with the administration of avelumab or chemotherapy 
as required.  These might include analgesics, antinausea medications, antihistamines, diuretics, 
anti-anxiety medications, and medication for pain management, including narcotic agents.
Any additional concomitant therapy that becomes necessary during the trial and any change to 
concomitant drugs must be recorded in the corresponding section of the eCRF, noting the name, 
dose, duration, and indication of each drug.
6.5.3
Other Interventions
The following nondrug therapies must not be administered during the trial (or within 28 days 
before randomization):
Surgery to any tumor lesion for symptom management or tumor control is not permitted during 
the study treatment. For any other surgical interventions planned during the study, study 
treatment should be delayed to allow subject’s recovery, for up to a maximum of 4 weeks.
Herbal remedies with immunostimulating properties (for example, mistletoe extract) or known 
to potentially interfere with major organ function (for example, hypericin)


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
82/154
Subjects should not abuse alcohol or other drugs during the trial.
6.5.4
Special Precautions
As a routine precaution, subjects randomized to the avelumab arm must be observed for 1 hour 
post infusion, for the first 4 infusions, in an area with resuscitation equipment and emergency 
agents.  At all times during avelumab or chemotherapy treatment, immediate emergency treatment 
of an infusion-related reaction or a severe hypersensitivity reaction according to institutional 
standards must be assured. In order to treat possible hypersensitivity reactions, for instance, 
dexamethasone 10 mg and epinephrine in a 1:1000 dilution or equivalents should always be 
available along with equipment for assisted ventilation. 
Infusion of avelumab will be stopped in case of Grade ≥ 2 hypersensitivity, inflammatory response, 
or infusion-related reaction.  The treatment recommendations for infusion-related reactions, 
according to the NCI are as outlined in Section 6.5.4.1.
Investigators should also monitor subjects closely for potential irAEs, which may first become 
manifest after weeks of treatment.  Such events may consist of persistent rash, diarrhea and colitis, 
autoimmune hepatitis, arthritis, glomerulonephritis, cardiomyopathy, or uveitis and other 
inflammatory eye conditions.  The spectrum of hypothetical irAEs also includes formation of 
auto-antibodies like antinuclear antibodies (ANAs) or antineutrophil cytoplasmic antibodies 
(ANCAs).  See Section 6.5.4.2 for details on the management of irAEs.
6.5.4.1
Infusion-related Reactions
Symptoms of infusion-related reactions are fever, chills, rigors, diaphoresis, and headache.  These 
symptoms can be managed according to Table 9.
Table 9
Treatment Modification for Symptoms of Infusion-related Reactions 
Associated With Avelumab
NCI-CTCAE Grade 
Treatment Modification for Avelumab
Grade 1 – mild

Mild transient reaction; infusion interruption not 
indicated; intervention not indicated.

Decrease the avelumab infusion rate by 50% and 
monitor closely for any worsening.
Grade 2 – moderate

Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (for 
example, antihistamines, NSAIDs, narcotics, IV 
fluids); prophylactic medications indicated for 24 
hours.

Temporarily discontinue avelumab infusion.

Resume infusion at 50% of previous rate once 
infusion-related reaction has resolved or decreased 
to at least Grade 1 in severity, and monitor closely 
for any worsening.
Grade 3 or Grade 4 – severe or life-threatening

Grade 3: Prolonged (for example, not rapidly 
responsive to symptomatic medication and / or 
brief interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical sequelae.

Stop the avelumab infusion immediately and 
disconnect infusion tubing from the subject.

Subjects have to be withdrawn immediately from 
avelumab treatment and must not receive any 
further avelumab treatment.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
83/154

Grade 4: Life-threatening consequences; urgent 
intervention indicated.
IV: intravenous; NCI-CTCAE: National Cancer Institute-Common Terminology Criteria for Adverse Event; NSAIDs: 
nonsteroidal anti-inflammatory drugs.
Once the avelumab infusion rate has been decreased by 50% or interrupted due to an infusion 
related reaction, it must remain decreased for all subsequent infusions.  If a subject experiences a 
Grade 3 or 4 infusion-related reaction at any time, the subject must discontinue avelumab. If an 
infusion reaction occurs, all details about drug preparation and infusion must be recorded.
6.5.4.2
Immune-related Adverse Events
Because inhibition of PD-L1 stimulates the immune system, irAEs may occur.  Treatment of irAEs 
is mainly dependent upon severity (NCI-CTCAE grade):
Grades 1 to 2: treat symptomatically or with moderate dose steroids, more frequent monitoring
Grades 1 to 2 (persistent): manage similar to high grade AE (Grades 3 to 4)
Grades 3 to 4: treat with high dose corticosteroids.
Treatment of irAEs should follow the guidelines in Table 10.
Table 10
Management of Immune-related Adverse Events
Gastrointestinal irAEs
Severity of Diarrhea/Colitis
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Diarrhea: < 4 stools/day over 
Baseline
Colitis: asymptomatic 
Continue avelumab therapy
Symptomatic treatment (eg, 
loperamide)
Close monitoring for worsening symptoms
Educate subject to report worsening 
immediately
If worsens:
Treat as Grade 2 or 3/4 
Grade 2
Diarrhea: 4 to 6 stools per day over 
Baseline; IV fluids indicated < 24 
hours; not interfering with ADL
Colitis: abdominal pain; blood in 
stool 
Withhold avelumab therapy
Symptomatic treatment
If improves to Grade ≤ 1: 
Resume avelumab therapy
If persists > 5-7 days or recurs:
Treat as Grade 3 or 4.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
84/154
Grade 3 to 4
Diarrhea (Grade 3): ≥ 7 stools per 
day over Baseline; incontinence; IV 
fluids ≥24 hrs; interfering with ADL
Colitis (Grade 3): severe abdominal 
pain, medical intervention indicated, 
peritoneal signs
Grade 4: life-threatening, perforation
Withhold avelumab for 
Grade 3.
Permanently discontinue 
avelumab for Grade 4 or 
recurrent Grade 31.0 to 2.0 
mg/kg/day prednisone IV or 
equivalent
Add prophylactic antibiotics for 
opportunistic infections 
Consider lower endoscopy 
If improves: 
Continue steroids until Grade ≤1, then taper 
over at least 1 month; resume avelumab 
therapy following steroids taper (for initial 
Grade 3)
If worsens, persists > 3 to 5 days, or recurs 
after improvement:
Add infliximab 5 mg/kg (if no 
contraindication), Note: Infliximab should not 
be used in cases of perforation or sepsis 
Dermatological irAEs
Grade of Rash
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grades 1 to 2 
Covering ≤ 30% body surface area 
Continue avelumab therapy
Symptomatic therapy (for 
example, antihistamines, 
topical steroids) 
If persists > 1 to 2 weeks or recurs: 
Withhold avelumab therapy
Consider skin biopsy 
Consider 0.5 to 1.0 mg/kg/day prednisolone 
or equivalent.  Once improving, taper 
steroids over at least 1 month, consider 
prophylactic antibiotics for opportunistic 
infections, and resume avelumab therapy
following steroids taper
If worsens: 
Treat as Grades 3 to 4 
Grades 3 to 4
Grade 3: Covering > 30% body 
surface area; 
Grade 4: life threatening 
consequences 
Withhold avelumab for 
Grade 3.
Permanently discontinue for 
Grade 4 or recurrent Grade 3. 
Consider skin biopsy 
Dermatology consult 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent
Add prophylactic antibiotics for 
opportunistic infections
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month; 
resume avelumab therapy following steroids 
taper (for initial Grade 3)
Pulmonary irAEs
Grade of Pneumonitis
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Radiographic changes only 
Consider withholding avelumab 
therapy 
Monitor for symptoms every 
2 to 3 days 
Consider Pulmonary and 
Infectious Disease consults 
Re-assess image at least every 3 weeks
If worsens: 
Treat as Grade 2 or Grade 3 to 4 


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
85/154
Grade 2
Mild to moderate new symptoms 
Withhold avelumab therapy
Pulmonary and Infectious 
Disease consults
Monitor symptoms daily, 
consider hospitalization 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent
Add prophylactic antibiotics for 
opportunistic infections 
Consider bronchoscopy, lung 
biopsy 
Re-assess image every 1 to 3 days 
If improves: 
When symptoms return to Grade ≤ 1, taper 
steroids over at least 1 month, and then 
resume avelumab therapy following steroids 
taper If not improving after 2 weeks or 
worsening: 
Treat as Grade 3 to 4 
Grades 3 to 4
Grade 3: Severe new symptoms; 
New / worsening hypoxia; 
Grade 4: life-threatening 
Permanently discontinue 
avelumab therapy
Hospitalize 
Pulmonary and Infectious 
Disease consults
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics for 
opportunistic infections 
Consider bronchoscopy, lung 
biopsy 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month 
If not improving after 48 hours or worsening: 
Add additional immunosuppression (for 
example, infliximab, cyclophosphamide, IV 
immunoglobulin, or mycophenolate mofetil).  
Hepatic irAEs
Grade of Liver Test Elevation
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Grade 1 AST or ALT > ULN to 3.0 x 
ULN and / or total bilirubin > ULN to 
1.5 x ULN 
Continue avelumab therapy
Continue liver function monitoring 
If worsens: 
Treat as Grades 2 or 3 to 4 
Grade 2
AST or ALT > 3.0 to ≤ 5 x ULN and / 
or total bilirubin > 1.5 to ≤ 3 x ULN 
Withhold avelumab therapy
Increase frequency of 
monitoring to every 3 days 
If returns to Grade ≤ 1:
Resume routine monitoring; resume 
avelumab therapy.
If elevation persists > 5 to 7 days or 
worsens: 
Treat as Grade 3 to 4
Grades 3 to 4
AST or ALT > 5 x ULN and / or total 
bilirubin > 3 x ULN 
Permanently discontinue 
avelumab therapy 
Increase frequency of 
monitoring to every 1 to 2 days 
1.0 to 2.0 mg/kg/day 
prednisolone or equivalent
Add prophylactic antibiotics for 
opportunistic infections 
Consult 
gastroenterologist/hepatologist
Consider obtaining MRI / CT 
scan of liver and liver biopsy if 
clinically warranted
If returns to Grade ≤1: 
Taper steroids over at least 1 month 
If does not improve in > 3 to 5 days, 
worsens or rebounds: 
Add mycophenolate mofetil 1 gram (g) twice 
daily 
If no response within an additional 3 to 5 
days, consider other immunosuppressants 
per local guidelines.  


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
86/154
Renal irAEs
Grade of Creatinine Increased 
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Creatinine increased > ULN to 1.5 
x ULN
Continue avelumab therapy
Continue renal function monitoring
If worsens:
Treat as Grade 2 to 3 or 4.
Grade 2 to 3
Creatinine increased > 1.5 and ≤ 6 x 
ULN
Withhold avelumab therapy
Increase frequency of 
monitoring to every 3 days
1.0 to 2.0 mg/kg/day prednisone 
or equivalent.
Add prophylactic antibiotics for 
opportunistic infections
Consider renal biopsy
If returns to Grade ≤1:
Taper steroids over at least 1 month, and 
resume avelumab therapy following steroids 
taper.
If worsens: 
Treat as Grade 4.
Grade 4
Creatinine increased > 6 x ULN
Permanently discontinue 
avelumab therapy
Monitor creatinine daily
1.0 to 2.0 mg/kg/day prednisone 
or equivalent.
Add prophylactic antibiotics for 
opportunistic infections
Consider renal biopsy
Nephrology consult
If returns to Grade ≤1:
Taper steroids over at least 1 month.
Cardiac irAEs
Myocarditis 
Initial Management
Follow-up Management


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
87/154
New onset of cardiac signs or 
symptoms and / or new laboratory 
cardiac biomarker elevations (e.g. 
troponin, CK-MB, BNP) or cardiac 
imaging abnormalities suggestive of 
myocarditis.
Withhold avelumab therapy
Hospitalize 
In the presence of life 
threatening cardiac 
decompensation, consider 
transfer to a facility 
experienced in advanced heart 
failure and arrhythmia 
management
Cardiology consult to establish 
etiology and ruleout immune-
mediated myocarditis.
Guideline based supportive 
treatment as per cardiology 
consult.*
Consider myocardial biopsy if 
recommended per cardiology 
consult.
If symptoms improve and immune-mediated 
etiology is ruled out, re-start avelumab 
therapy.
If symptoms do not improve/worsen, viral 
myocarditis is excluded, and immune
mediated etiology is suspected or confirmed 
following cardiology consult, manage as 
immune-mediated myocarditis.
Immune-mediated myocarditis
Permanently discontinue 
avelumab.
Guideline based supportive 
treatment as appropriate as per 
cardiology consult.*
1.0 to 2.0 mg/kg/day 
prednisone or equivalent
Add prophylactic antibiotics for 
opportunistic infections.
Once improving, taper steroids over at least 
1 month and add prophylactic antibiotics for 
opportunistic infections.
If no improvement or worsening, consider
additional immunosuppressants 
(e.g. azathioprine, cyclosporine A)
*Local guidelines, or eg. ESC or AHA guidelines
ESC guidelines website: https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines
AHA guidelines website:
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
88/154
Endocrine irAEs
Endocrine Disorder
Initial Management
Follow-up Management 
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, hyperthyroidism, 
adrenal insufficiency, type I 
diabetes mellitus)
Continue avelumab therapy
Endocrinology consult if 
needed
Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for 
hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for 
Type I diabetes mellitus) as 
appropriate.  
Rule-out secondary 
endocrinopathies (i.e. 
hypopituitarism / hypophysitis)
Continue hormone replacement/suppression 
and monitoring of endocrine function as 
appropriate.
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, hyperthyroidism, 
adrenal insufficiency, type I 
diabetes mellitus)
Withhold avelumab therapy
Consider hospitalization
Endocrinology consult
Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for 
hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for 
type I diabetes mellitus) as 
appropriate.  
Rule-out secondary 
endocrinopathies (i.e. 
hypopituitarism / hypophysitis)
Resume avelumab once symptoms and/or 
laboratory tests improve to Grade ≤ 1 (with 
or without hormone 
replacement/suppression).
Continue hormone replacement/suppression 
and monitoring of endocrine function as 
appropriate. 


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
89/154
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies)
If secondary thyroid and/or 
adrenal insufficiency is 
confirmed (i.e. subnormal 
serum FT4 with 
inappropriately low TSH 
and/or low serum cortisol with 
inappropriately low ACTH):

Refer to endocrinologist 
for dynamic testing as 
indicated and 
measurement of other 
hormones (FSH, LH,
GH/IGF-1, PRL, 
testosterone in men, 
estrogens in women) 

Hormone 
replacement/suppressive 
therapy as appropriate 

Perform pituitary MRI and 
visual field examination as 
indicated
If hypophysitis confirmed:

Continue avelumab if mild 
symptoms with normal 
MRI. Repeat the MRI in 1 
month

Withhold avelumab if 
moderate, severe or life-
threatening symptoms of 
hypophysitis and/or 
abnormal MRI. Consider 
hospitalization. Initiate 
corticosteroids (1 to 
2 mg/kg/day prednisone 
or equivalent) followed by 
corticosteroids taper 
during at least 1 month.
Add prophylactic antibiotics for 
opportunistic infections.
Resume avelumab once symptoms and 
hormone tests improve to Grade ≤ 1 (with or 
without hormone replacement).
In addition, for hypophysitis with abnormal 
MRI, resume avelumab only once shrinkage 
of the pituitary gland on MRI/CT scan is 
documented. 
Continue hormone replacement/suppression 
therapy as appropriate.
Other irAEs (not described above)
Grade of other irAEs
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 2 or Grade 3 clinical signs 
or symptoms suggestive of a 
potential irAE
Withhold avelumab therapy 
pending clinical investigation
If irAE is ruled out, manage as appropriate 
according to the diagnosis and consider 
re-starting avelumab therapy
If irAE is confirmed, treat as Grade 2 or 3 
irAE.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
90/154
Grade 2 irAE  or first occurrence 
of Grade 3 irAE
Withhold avelumab therapy
1.0 to 2.0 mg/kg/day 
prednisone or equivalent  
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult as 
appropriate
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month and 
resume avelumab therapy following steroids 
taper.
Recurrence of same Grade 3 irAEs
Permanently discontinue 
avelumab therapy
1.0 to 2.0 mg/kg/day
prednisone or equivalent
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult as 
appropriate
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month.
Grade 4 
Permanently discontinue 
avelumab therapy
1.0 to 2.0 mg/kg/day
prednisone or equivalent 
and/or other 
immunosuppressant as 
needed
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult.
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month
Requirement for 10 mg per day or 
greater prednisone or equivalent 
for more than 12 weeks for 
reasons other than hormonal 
replacement for adrenal 
insufficiency
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer
Permanently discontinue 
avelumab therapy
Specialty consult
ACTH=adrenocorticotropic hormone; ADL=activities of daily living; ALT=alanine aminotransferase; AST=aspartate 
aminotransferase; BNP=B-type natriuretic peptide; CK-MB=creatine kinase MB;  CT= computed tomography;
FSH=follicle-stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; irAE=immune-related 
adverse event; IV=intravenous; LH=luteinizing hormone; MRI=magnetic resonance imaging; NCI-CTCAE=National 
Cancer Institute-Common Terminology Criteria for Adverse Events; PRL=prolactin;; T4: free thyroxine;
TSH: thyroid-stimulating hormone; ULN: upper limit of normal.
6.5.5
Management of Specific Adverse Events or Adverse Drug 
Reactions
The management of irAEs is described in Section 6.5.4.2.


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
9 1 / 1 5 4
6. 6
P ac k a gi n g a n d L a beli n g
of t he I n vesti g ati o n al Me dici n al 
Pr o d uct
A vel u ma b is f or m ulate d as a 2 0. 0 m g/ m L sol uti o n a n d is s u p plie d b y  the S p o ns or i n si n gle use 
glass vials, 
 
All I MPs will be pac ka ge d a n d la bele d i n acc or da nce wit h all a p plica ble re g ulat or y  re q uire me nts 
a n d G M P G ui deli nes .  A vel u ma b will be pac ke d i n b o xes b y  usi n g a s uita ble pac ka gi n g desi g n .  
T he i nf or mati o n o n t he trial dr u g will be i n acc or da nce wit h a p pr o ve d s u b missi o n d oc u me nts. 
A vel u ma b will be s hi p pe d i n tra ns p ort 
 ( 
) t hat are m o nit ore d wit h 
te m perat ure c o ntr ol de vices.
Pe metre xe d, cis plati n, car b o plati n, pacl ita xel, a n d ge mcita bi ne will be s u p plie d b y  the st u d y ce nter 
or b y  t he Sp o ns or, acc or di n g t o l ocal la ws a n d re g ulati o ns.
6. 7
Pre p ar ati o n, H a n dli n g , a n d St or a ge of t he I n vesti g ati o n al 
Me dici n al Pr o d uct
T he c o nte nts of t he a vel u ma b vials are sterile a n d n o n p yr o g e nic, a n d d o n ot c o ntai n bacteri ostatic 
preser vati ves .  A n y s pills t hat occ ur s h o ul d be clea ne d u p usi n g t he facilit y’s sta n dar d clea n u p 
pr oce d ures f or bi ol o gic pr o d ucts.
A vel u ma b dr u g pr o d uct m ust be st ore d at  
 u ntil use, wit h a te m perat ure l o g mai ntai ne d 
dail y .  All me dicati o n b o xes s u p plie d t o eac h trial site m ust be st ore d caref ull y, safel y, a n d 
se paratel y fr o m ot her dr u gs.
A vel u ma b dr u g pr o d uct st ore d at r o o m te m perat ure (
 or at ele vate d te m perat ures 
(
) f or e xte n de d p eri o ds is s u bject t o de gra dati o n .  A vel u ma b m ust n ot be fr oze n.  
R o u g h s ha ki n g of a vel u ma b m ust be a v oi de d.
F or a p plicati o n i n t his trial, a vel u ma b dr u g pr o d uct m ust be dil ute d wit h 
 
  Alter nati vel y, a 
 ca n be use d if nee de d.  Detaile d 
i nf or mati o n o n i nf usi o n ba gs a n d me dical de vices t o be use d f or t he pre parati o n of t he dil uti o ns 
a n d s u bse q ue nt a d mi nistrati o n are o utli ne d i n t he M O P , a n d i ncl u de d i n t he p har mac y  ma n ual 
w hic h will be s hare d wit h sites .
A vel u ma b m ust n ot be use d f or a n y  p ur p ose ot her t ha n t he trial.  T he a d mi nistrati o n of a vel u ma b
t o s u bjects w h o ha ve n ot bee n ra n d o mize d i nt o t he trial is n ot c o vere d b y  t he trial i ns ura nce.
A n y  un use d p orti o n of t he s ol uti o n s h o ul d be discar de d i n bi o hazar d waste dis p osal wit h fi nal 
dis p osal b y  acce pte d l ocal a n d nati o nal sta n dar ds of i nci nerati o n.
St ora ge, ha n dli n g, pre parati o n, a n d dis p osal of c he m ot hera p y  s h o ul d be acc or di n g t o t he pac ka ge 
i nsert.
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
92/154
6.8
Investigational Medicinal Product Accountability
The Investigator is responsible for ensuring accountability for avelumab or chemotherapy, 
including reconciliation of drugs and maintenance of drug records.
Upon receipt of trial drug, the Investigator (or designee) will check for accurate delivery and 
acknowledge receipt by signing (or initialing) and dating the documentation provided by the 
Sponsor and returning it to the Sponsor.  A copy will be retained for the Investigator File.
The dispensing of the trial drug will be carefully recorded in the IWRS system. The IWRS 
system will also be used to document drug accountability and an accurate accounting will be 
available for verification by the clinical research associate (CRA) at each monitoring visit.
Trial drug accountability records will include:
1. Confirmation of trial drug delivery to the trial site
2. The inventory at the site of trial drug provided by the Sponsor and prepared at the 
site
3. The use of each dose by each subject
4. The return to the Sponsor or alternative disposition of unused trial drug
5. Dates, quantities, batch numbers, expiry dates and (for trial drug prepared at the site) 
formulation, as well as the subjects’ trial numbers.
The Investigator should maintain records that adequately document
1. That the subjects were provided the doses specified by the clinical trial 
protocol/amendment(s)
2. That all trial drug provided by the Sponsor was fully reconciled.
Unused trial drug must not be discarded or used for any purpose other than the present trial.  Any 
trial drug that has been dispensed to a subject must not be redispensed to a different subject.
The CRA will periodically collect the trial drug accountability forms (both unused and used 
containers) before authorizing their destruction by the trial site.
At the conclusion or termination of this trial, trial site personnel and the CRA will conduct a final 
product supply inventory on the investigational drug accountability forms and all unused 
containers will be destroyed.  Instructions for destruction of product will be provided to the site.  
The clinical trial monitor will be supplied with a copy for filing of the investigational drug 
accountability forms.  This documentation must contain a record of clinical supplies used, unused, 
and destroyed and shall include information on:
All administered units
All unused units
All destroyed units (during the trial)
All destroyed units at the End of Trial


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
93/154
Date of destruction(s)
Name and signature of the Investigator/pharmacist.
It must be ensured at each trial site that the trial drug is not used:
After the expiry date
After the retest date unless the trial drug is reanalyzed and its retest date extended.
This is to be closely monitored by the CRA.
6.9
Assessment of Investigational Medicinal Product Compliance
In this trial, subjects will receive trial treatment at the investigational site.  Well-trained medical 
staff will monitor and perform the trial drug administration.  The information of each trial drug 
administration including the date, time, and dose of trial drug will be recorded on the eCRF.  The 
Investigator will make sure that the information entered into the eCRF regarding drug 
administration is accurate for each subject.  Any reason for noncompliance should be documented.
For the once every week dosing regimen, noncompliance is defined as a subject missing 
> 2 infusion of trial treatment for nonmedical reasons (see Section 5.5.1).  If 2 infusions are missed 
and the interval between the subsequent infusion and the last administered treatment is longer than 
4 weeks for nonmedical reasons, the criteria of insufficient compliance are met as well.
For the every 2 weeks dosing regimen, noncompliance is defined as a subject missing > 1 infusion 
of trial treatment for nonmedical reasons (see Section 5.5.1).  If 1 infusion is missed and the 
interval between the subsequent infusion and the last administered treatment is longer than 4 weeks 
for nonmedical reasons, the criteria of insufficient compliance are met as well.
6.10
Blinding
This is an open-label trial; thus, trial treatment is not blinded.
Study procedures will be established to maintain data integrity in this open-label trial and to limit 
biased assessment of endpoints by:

Establishing an independent and blinded review of tumor images (IRC) (see Section 5.2.3), 
and

Regulating the flow of PD-L1 expression data between the laboratory site, the IWRS
vendor for the stratification, and the IDMC during study conduct.
6.11
Emergency Unblinding
Not applicable.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
94/154
6.12
Treatment of Overdose
An overdose is defined as any dose ≥ 10% over the intended dose for that particular administration 
as described in this clinical trial protocol (Section 5.1.3.1).  Any overdose must be recorded in the 
trial drug section of the eCRF.
For monitoring purposes, any case of overdose, whether or not associated with an AE (serious or 
nonserious), must be reported to the Sponsor’s Global Drug Safety department in an expedited 
manner using the appropriate reporting form (see Section 7.4.1.4).
There are no known symptoms of avelumab overdose to date.  The Investigator should use his or 
her clinical judgment when treating an overdose of the trial drug.
In the case of an overdose of chemotherapy, subjects should receive therapeutic granulocyte 
colony-stimulating factor per package insert or equivalent as soon as possible after the overdose is 
discovered.
6.13
Medical Care of Subjects after End of Trial
After a subject has stopped trial treatment, usual treatment will be administered, if required, in 
accordance with the trial site’s standard of care and generally accepted medical practice and 
depending on the subject’s individual medical needs.
Upon withdrawal from trial treatment, subjects may receive whatever care they and their 
physicians agree upon.  Subjects will be followed for survival and AEs as specified in 
Section 7.1.4.
7
Trial Procedures and Assessments
7.1
Schedule of Assessments
A complete Schedule of Assessments is provided in Table 1 to Table 6.
Prior to performing any trial assessments not part of the subject’s routine medical care, the 
Investigator will ensure that the subject or the subject’s legal representative has provided written 
informed consent according to the procedure described in Section 9.2.
7.1.1
Screening and Baseline Procedures and Assessments
During the Screening period and before any trial-related investigations and assessments are started, 
subjects will be asked to sign the ICF.  The Screening procedures and Baseline assessments will 
be completed within 28 days of signing the ICF before randomization.  Failure to establish 
eligibility within 28 days would result in screening failure and the subject will be excluded from 
the trial; however, subjects can be re-entered in the trial based on the Investigator’s judgment 
within 6 weeks of signing the ICF.  In this case, a new ICF will be required to be signed by the 
subject.  A new subject number will be assigned by the IWRS.  Procedures from Screening 
(Table 1, Table 2, Table 3, and Table 4) will need to be repeated to ensure that the subject is 


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
95/154
eligible, excluding PD-L1 tumor expression, ECG, HBV, HCV, urinalysis, adrenocorticotropic 
hormone (ACTH), free thyroxine (T4), and thyroid-stimulating hormone (TSH), and the tumor 
evaluation scans if the scans performed during the prior screening period will be within the 
protocol-specified randomization window of 28 days.
Potential exceptions for the 6-week rescreening window must be discussed with the study Medical 
Monitor.
Tumor tissue must be available within 10 calendar days after the subject has signed the ICF in 
order to establish the PD-L1 status of the tumor.  Tumor tissue can be archival tissue or resulting 
from a screening biopsy of the subject if no archival tissue is available (see Section 7.6 for details).  
Preferably, archived samples, if needed, should be less than 6 months old.  Criteria for determining 
the adequacy of tumor tissue are described in the Study Manual.  Subjects who undergo a biopsy 
specifically as part of the Screening assessments for this protocol will be permitted to participate 
in the protocol provided they meet all other inclusion criteria and if no exclusion criteria.
Randomization cannot occur until PD-L1 expression has been determined by an 
Investigational Use Only PD-L1 IHC pharmDx companion diagnostic test by Dako (IDE No.  
G150051 S 001) to be evaluated centrally. 
The subjects’ information that will be documented during Screening includes the demographic 
information (birth date, sex, and ethnicity) and the complete medical history, including the disease 
history (NSCLC), previous and ongoing medications with administration started before the 
informed consent signature), baseline medical condition.  The AE reporting period for safety 
surveillance and a concomitant medication recording period begins when the subject first signs an 
informed consent.  Moreover, an Emergency Medical Support card will be handed out at the 
Baseline assessments visit.
During Screening, subjects will undergo a complete physical examination, vital signs including 
recording of body height and weight, 12-lead ECG, and a determination of the ECOG PS 
(Appendix II).  Subjects will also complete patient-reported outcomes / quality of life assessments.
The Screening laboratory examination includes hematology, hemostaseology, full serum 
chemistry (including Full serum chemistry and core chemistry), and full urinalysis (dipstick and
microscopic evaluation).  Adrenocorticotropic hormone (ACTH), T4, and TSH will also be 
assessed at Screening for all subjects.  
During Screening, a serum β-human chorionic gonadotropin (β-hCG) pregnancy test will be 
performed for females of childbearing potential (local and central laboratory) and blood hepatitis 
B virus and hepatitis C virus will be performed (central laboratory) for all Screening subjects as 
these conditions are trial entry exclusion criteria (see Section 5.3.2).  Females who are 
postmenopausal are exempt from pregnancy testing.  Females are considered postmenopausal if 
they have age-related amenorrhea ≥12 consecutive months or if they have undergone 
hysterectomy or bilateral oophorectomy.  If necessary to confirm/assess postmenopausal status, 
FSH may be drawn at Screening with documented increased FSH > 40 mIU/mL).


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
9 6 / 1 5 4
T he t u m or e val uati o n (t y pe a n d sta gi n g, etc.) will be perf or me d usi n g C T sca n or M RI (if M RI is 
use d, C T of c hest is ma n dat or y ) or a n y ot her esta blis he d met h o ds (see Secti o n  7. 2. 5 f or details ).  
A brai n C T / M RI sca n is re q uire d at Baseli ne.  A bo ne sca n s h o ul d be d o ne at Scree ni n g as 
cli nicall y i n dicate d.
 
 
 
7. 1. 2
Tre at me nt Peri o d
I n t his trial, t he treat me nt wil l be gi ve n u ntil P D, si g nifica nt cli nical deteri orati o n (cli nical 
pr o gressi o n), u nacce pta ble t o xicit y, or a n y criteri o n f or wit h dra wal fr o m t he trial or trial dr u g is 
f ulfille d (see Secti o n 5. 5. 1 ).  F or s u bjects recei vi n g a vel u ma b, treat me nt ma y  co nti n ue past t he 
i nitial deter mi nati o n of disease pr o gressi o n acc or di n g t o R E CI S T 1. 1 if t he s u bject’s E C O G P S 
has re mai ne d sta ble, a n d if i n t he o pi ni o n of t he In vesti gat or, t he s u bject will be nefit fr o m 
c o nti n ue d treat me nt (see Secti o n 6. 2. 1) .  A d diti o nall y, s u bjects recei vi n g a vel u ma b w h o ha ve 
e x perie nce d a C R s h o ul d be treate d f or a mi ni m u m of 1 2 m o nt hs a n d/ or u ntil disease pr o gressi o n 
or u nacce pta ble t o xicit y, after c o nfir mati o n of res p o nse.  I n case a s u bject wit h a c o nfir me d C R 
rela pses after st o p pi n g treat me nt, d uri n g l o n g ter m f oll o w- u p, o ne re-i nitiati o n of treat me nt is 
all o we d at t he discreti o n of t he In vesti gat or a n d a gree me nt of t he me dical m o nit or .  I n or der t o be 
eli gi ble f or r e-treat me nt, t he s u bject m ust n ot ha ve e x perie nce d a n y t o xicit y that le d t o treat me nt 
disc o nti n uati o n of t he i nitial a vel u ma b t hera py.  S u bjects w h o re-i nitiate treatme nt will sta y on 
trial a n d will be treate d a n d m o nit ore d acc or di n g t o t he pr ot oc ol fr o m Visit 1, a n d t he “ u ntil 
pr o gressi o n” sc he d ule i n t he Sc he d ule of Assess me nts (see  Ta ble 1 t o Ta ble 3 ).
T he treat me nt s h o ul d start wit hi n 4 da y s after ra n d o mizati o n.  As t he pre me dicati o n f or p e metre xe d 
( oral f olic aci d, vita mi n B 1 2 i ntra m usc ular i njecti o n) will nee d t o be deli vere d i n t he wee k bef ore 
first d ose of c he m ot hera p y, t his pre me dicati o n is per mitte d t o be i nitiate d i n all s u bjects wit h 
n o n-s q ua m o us hist ol o g y after si g ni n g t he i nf or me d c o nse nt a n d pri or t o ra n d o mizati o n.  In t he 
e ve nt t hat a s u bject is s u bse q ue ntl y ra n d o mize d t o a vel u ma b or is scree n faile d, vita mi n B 1 2 a n d 
t he f olic aci d m a y  be disc o nti n ue d .  W hile o n trial treat me nt, s u bjects will be as ke d t o visit t he 
trial site eit her: 

O nce e ver y wee k or o nce e ver y 2 wee ks
f or s u bjects ra n d o mize d t o recei ve a vel u ma b (see 
Ta ble 1 a n d Ta ble 4 ).

O nce e ver y 3 wee ks f or s u bjects ra n d o mize d t o recei ve c he m ot hera p y , e xce pt f or ge mcita bi ne, 
w hic h is t o be a d mi nistere d o n D a y  1 an d Da y  8 of eac h 3 - wee k c ycle (see Ta ble 2 a n d Ta ble 3) .
If t he st u d y treat me nt is ter mi nate d bef ore disease pr o gressi o n, all assess me nts will c o nti n ue o n a 
6- wee k sc he d ule u ntil disease pr o gressi o n if n o ne w ca ncer treat me nt is i nitiate d a n d s u bjects are 
sta ble.
A ti me wi n d o w u p t o 3 da y s bef ore or 1 d a y  after t he sc he d ule d visit da y (-3/ + 1 d a y s) will be 
per mitte d f or all trial pr oce d ures f or s u bjects e nr olle d i n Ar m A , Ar m B a n d f or s u bjects i n Ar m C 
w hile recei vi n g a vel u ma b o nce e ve r y tw o wee ks. A ti me wi n d o w of 1 da y  bef ore or 1 d a y  after 
C CI


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
97/154
the scheduled visit day (-1/ +1 days) will be permitted for all trial procedures for subjects enrolled 
in Arm C while receiving avelumab once weekly.
Subjects will receive either:
Avelumab by IV infusion following premedication with an antihistamine and with paracetamol 
(acetaminophen) (for example, 25 to 50 mg diphenhydramine and 500 to 650 mg paracetamol 
[acetaminophen] IV or oral equivalent) approximately 30 to 60 minutes prior to each dose, once 
every week or once every 2 weeks, depending on randomization (see Section 6.2.1), or
Chemotherapy by IV infusion following pretreatment as applicable prior to each chemotherapy 
infusion (see Section 6.2.2).
During the treatment period, the following assessments will be performed (see Table 1, Table 2,
Table 3, and Table 4 for the detailed schedules): 
Patient-reported outcomes / quality of life assessments will be completed by the subject after 
randomization (before the first administration of the trial treatment) then prior to administration 
of trial treatment and before any trial-related procedures (including collection of biological 
samples) 
o Week 1 (treatment administration 1), Week 7 (treatment administration 4), and Week 13 
(treatment administration 7) for subjects receiving avelumab,
o Week 1 (treatment administration 1), Week 7 (treatment administration 3), and Week 13 
(treatment administration 5) for subjects receiving chemotherapy (pemetrexed, paclitaxel, 
cisplatin, carboplatin, gemcitabine)
o Every 6 weeks thereafter while on treatment for all subjects.
AEs and concomitant medications will be documented at each trial visit.
ECOG PS will be assessed at Day 1 (unless the Screening ECOG PS was performed within 
3 days prior to Day 1) and at each trial visit thereafter for Arm A and B, and at every other visit 
(ie, every 2 weeks) for Arm C.
Physical examinations will be performed at each visit until Week 13 and every 6 weeks 
thereafter.  A full physical examination should be performed at Screening and the EoT visit.  
Physical examinations at all other visits should be directed towards signs and symptoms.
Vital signs will be assessed at each visit until Week 13 (Week 16 or Week 17 [regimens 
containing gemcitabine only] in Arm B) and every 2 or 3 weeks (chemotherapy arm) thereafter
Body weight will be assessed every 2 weeks until Week 13 in Arms A and C and Week 16 or 
Week 17 (regimens containing gemcitabine only) in Arm B as indicated in the Schedule of 
Assessments and every 2 or 3 weeks (chemotherapy arm) thereafter.
ECGs are to be performed as clinically indicated in case of abnormalities such as increased 
heart rate above the subject’s baseline detected during the physical examination and/or vital 
signs measurements performed prior to avelumab treatment.


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
9 8 / 1 5 4

T he a vel u ma b a d mi nistrati o n s h o ul d n ot be wit h hel d i n t he is olate d sit uati o n of a n i ncrease d 
heart rate, u nless t he o verall e val uati o n, i ncl u di n g t he E C G, is s u g gesti ve of m y ocar ditis, i n 
w hic h case t he pr ot oc ol g ui deli nes (as o utli ne d i n Ta ble 1 0 ) s h o ul d be f oll o we d.

H e mat ol o g y a n d he m ostase ol o g y (e xce pt f or Ar m B o n Da y 8 of eac h c ycle: o nl y he mat ol o g y 
is t o be perf or me d) tests will be assesse d at eac h visit u p t o Wee k 1 3 a n d e ver y 2 or 3 wee ks
(c he m ot hera py ar m) t hereafter.  

F ull ser u m c he mistr y will be assesse d at Wee ks 
3, 5, a n d 1 3 f or s u bjects ra n d o mize d t o 
a vel u ma b i n Ar m A a n d at Wee ks 2, 4, 6, 8, 1 0, 1 2 a n d 1 3 f or s u bjects ra n d o mize d t o a vel u ma b 
i n Ar m C ; at Wee ks 4, 7, a n d 1 3 f or s u bjects ra n d o mize d t o c he m ot hera p y; a n d t he n e ver y 
6 wee ks t hereafter f or all s u bjects.  

C ore ser u m c he mistr y  will be assesse d at:
o
Wee ks
1, 7, 9, a n d 1 1, a n d t he n e ver y 2 wee ks ( w he n f ull ser u m c he mistr y is n ot 
sc he d ule d to be d o ne) t hereafter f or s u bjects recei vi n g a vel u ma b i n Ar m A;
o
Wee ks 1, 3, 5, 7, 9 , a n d 1 1, a n d t he n e ver y 2 wee ks ( w he n f ull ser u m c he mistr y is n ot 
sc he d ule d t o be d o ne) t hereafter f or s u bjects recei vi n g a vel u ma b i n Ar m C;
o
Wee ks 1, 1 0, a n d t he n e ver y 3 wee ks ( w he n f ull ser u m c he mistr y is n ot sc he d ule d t o be 
d o ne) t hereafter f or s u bjects recei vi n g pe metre xe d, cis plati n, car b o plati n, or paclita xel; 
o
Wee ks 
1, 2, 5, 8, 1 0, 1 1, 1 4, a n d e ver y 3 wee ks ( w he n f ull ser u m c he mistr y is n ot 
sc he d ule d t o be d o ne) t hereafter f or s u bjects recei vi n g ge mcita bi ne. 

F ull uri nal y sis ( di pstic k a n d micr osc o pic e val uati o n) at t he Scree ni n g a n d E n d - of-Treat me nt 
V isits a n d a basic uri nal ysis ( di pstic k) will be perf or me d at eac h treat me nt visit.  If t he basic 
uri nal y sis is a b n or mal, a f ull uri nal ysis s h o ul d be perf or me d.

A uri ne or ser u m β -h C G pre g na nc y  test will be perf or me d bef ore t he a d mi nistrati o n of t he trial 
dr u g e ver y 4 wee ks f or s u bjects recei vi n g a vel u ma b , or e ver y 3 wee ks f or s u bjects recei vi n g 
c he m ot hera p y f or fe males of c hil d beari n g p ote ntial.  Res ults of t he m ost rece nt pre g na nc y test 
s h o ul d be a vaila ble pri or t o t he ne xt d osi n g of trial dr u g.  T he pre g na nc y  test ma y be d o ne by a 
l ocal la b orat or y.

T u m or e val uati o n f or all s u bjects (see Secti o n  7. 3 ) will be perf or me d at Wee k 7 a n d t he n o nce 
e ver y 6 wee ks a n d e ver y 1 2 wee ks after 1 2 m o nt hs, u ntil disease pr o gressi o n.  T he s u bject ma y 
sta y on a 6 wee k sc he d ule if t he y c o nti n ue t u m or e val uati o ns i n t he a bse nce of pr o gressi o n a n d 
t here is n o start of f urt her a ntica ncer t hera py.

A C T H will be c ollecte d o nl y  at t he Baseli ne visit.  T4 a n d T S H will be c ollecte d at 
Scree ni n g / Baseli ne, e ver y 6 wee ks t hereafter d uri n g t he treat me nt p hase.
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
9 9 / 1 5 4
7. 1. 3
E n d of Tre at me nt
7. 1. 3. 1
E n d -of -Tre at me nt V isit
S u bjects m ust u n der g o E n d - of-Treat me nt visit after disc o nti n uati o n of I MP f or a n y reas o n.  This 
visit s h o ul d be perf or me d wit hi n 7 d a y s of t he decisi o n t o disc o nti n ue treat me nt, b ut bef ore a n y 
ne w t hera p y is starte d, if p ossi ble, w hic he ver occ urs earlier.  The E n d -of -Treat me nt visi t will 
c o m prise a f ull assess me nt f or safety, i m m u n o ge nicit y, a n d t u m or res p o nse as a p pr o priate, a n d 
will i ncl u de t he f oll o wi n g (see  Ta ble 1 t o Ta ble 6 ):

Patie nt- re p orte d o utc o mes / q ualit y of life assess me nts

A Es, c o nc o mita nt me dicati o ns, a n d E C O G P S

P h y sical e xa mi nati o n i ncl u di n g vital si g ns a n d b o d y wei g ht

1 2- lea d E C Gs

La b orat or y  he mat ol o g y, he m ostase ol o g y , f ull ser u m c he mistr y, a nd f ull uri nal y sis ( di pstic k a n d
micr osc o pic e val uati o n)

Uri ne or ser u m β -h C G pre g na nc y  test (i n fe males of c hil d beari n g p ote ntial)

T u m or e val uati o n ( o nl y t o be perf or me d if n o disease pr o gressi o n was d oc u me nte d pre vi o usl y)

O pti o nal t u m or bi o ps y

T 4, a n d T S H le vels 
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 0 / 1 5 4

Bl o o d sa m ples f or plas ma bi o mar kers f or s u bjects recei vi n g a vel u ma b .
7. 1. 4
S afet y F oll o w -u p
All s u bjects will ha ve a s u bse q ue nt visit sc he d ule d 3 0 da y s ( ±5 da y s) after t he last a d mi nistrati o n 
of trial treat me nt, f oll o we d b y  a 90 -d a y  tele p h o ne Safet y F oll o w - u p.  T he 3 0- da y  Safet y F oll o w -u p 
visit will i ncl u de t he f oll o wi n g assess me nts of safet y para meters:

Patie nt -re p orte d o utc o mes/ q ualit y of life assess me nts

A n y  S A E s a n d n o n -seri o us A Es will be d oc u me nte d.

O n g oi n g S A Es will be f oll o we d.

C o nc o mita nt me dicati o ns a n d pr oce d ures will be re p orte d.

P h y sical e xa mi nati o n

Vital si g ns meas ure me nts

B o d y wei g ht

E C O G P S

He mat ol o g y a n d he m ostase ol o g y

C ore ser u m c he mistr y

Uri nal y sis

β- H C G pre g na nc y  test

T 4 a n d T S H le vels
7. 1. 5
S afet y F oll o w -u p P h o ne C all
At 9 0 da ys ( ± 1 wee k) after t he last d ose of I M P, s u bjects will be c o ntacte d b y tele p h o ne t o c ollect 
i nf or mati o n o n ne w or o n g oi n g S A Es a n d treat me nt-relate d n o n-seri o us A Es.  A n y S A E assesse d 
as relate d t o st u d y treat me nt m ust be re p orte d w he ne ver it occ urs, irres pecti ve of t he ti me ela pse d 
si nce t he last a d mi nistrati o n of st u d y treat me nt.  S u bjects will als o be as ke d a b o ut a n y a ntit u m or 
t hera py.
7. 1. 6
L o n g -ter m F oll o w -u p
All S A Es o n g oi n g at t he S afet y Foll o w - u p p h o ne call m ust be m o nit ore d a n d f oll o we d u p b y  th e 
In vesti gat or u ntil sta bilizati o n or o utc o me is k n o w n, u nless t he s u bject is d oc u me nte d as “l ost t o 
f oll o w-u p.”   A n y S A E assesse d as relate d t o t he I M P m ust be re p orte d w he ne ver it occ urs, 
irres pecti ve of t he ti me ela pse d si nce t he last trial dr u g a d mi nistrati o n.
C CI


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 1 / 1 5 4
S u bjects wit h o ut P D acc or di n g t o R E CI S T 1. 1 at t he E n d - of-Treat me nt visit will be f oll o we d u p 
f or disease pr o gressi o n ( C T / M RI  sca ns e ver y 6 wee ks [ ± 1 wee k ] d uri n g t he first 1 2 m o nt hs of 
t he st u d y, a n d t he n e ver y 1 2 wee ks usi n g t he sa me pr oce d ur es a n d re vie w as w hile o n treat me nt) 
u p t o P D. T u m or e val uati o n at t he E n d -of -Treat me nt visit s h o ul d o nl y  be perf or me d if n o disease 
pr o gressi o n has bee n d oc u me nte d pre vi o usl y.   T he s u bject ma y  sta y o n a 6 wee k sc he d ule if t he y 
c o nti n ue t u m or e val uati o ns i n t he a bse nce of pr o gressi o n a n d t here is n o start of f urt her a ntica ncer 
t hera py.
After t he E n d - of-Treat me nt visit, s u bjects will be f oll o we d u p o n e ver y 12 w ee ks ( ± 1 w ee k) f or 
s ur vi val (i ncl u di n g assess me nt of a n y furt her t u m or t hera p y).  The s ur vi val f oll o w- u p will c o nti n ue 
u ntil 5 y ears after t he last s u bject recei ves t he last d ose of a vel u ma b.   U n der s o me circ u msta nces, 
t he s u bject m a y  n ot b e f oll o we d f or 5 years f or s ur vi val i n t his st u d y, f or e g, t he s u bjects ma y be 
offere d t o e nter i nt o a r oll- o ver st u d y, or t he Sp o ns or ma y  ter mi nate t he st u d y early.
7. 1. 7
Bl o o d Dr a ws f or Cli nic al Assess me nts
T he o verall a m o u nt of bl o o d t o be dra w n fr o m a si n gle s u bject wit h a b o d y  wei g ht ≥ 7 0 k g ( 1 5 4 l bs) 
m ust n ot e xcee d 1 2 0 m L i n a si n gle d a y  an d 5 5 0 m L  o ver a n 8- wee k peri o d f or safet y  la b orat or y 
testi n g, pre g na nc y  testi n g, 
 
7. 2
De m o gr a p hic a n d Ot her B aseli ne C h ar acteristics
7. 2. 1
De m o gr a p hic D at a
At t he Scree ni n g Visit , t he f oll o wi n g de m o gra p hic data will be c ollecte d: d ate of birt h , se x
( ge n der), race, a n d et h nicit y.
7. 2. 2
Di a g n osis of N o n- S m all Cell L u n g C a ncer
T he t u m or disease i nf or mati o n t hat will be d oc u me nte d a n d verifie d at t he Scree ni n g visit f or eac h 
s u bject i ncl u des:

Detaile d hist or y  of t he t u m or, i ncl u di n g hist o pat h ol o gical dia g n osis (i ncl u di n g d oc u me ntati o n 
of P D -L 1  ex pressi o n as deter mi ne d b y  a co m pa ni o n dia g n ostic test u n der de vel o p me nt a n d 
perf or me d ce ntrall y, Secti o n 7. 6 f or details), gra di n g, a n d sta gi n g i n acc or da nce wit h t he 
I nter nati o nal U ni o n A gai nst Ca ncer T u m or N o de Metastasis 
Classificati o n of Mali g na nt 
T u m ors at dia g n osis;

All 
t hera py use d f or pri or treat me nt of t he t u m or (i ncl u di n g s ur ger y, ra di ot hera py,  
c he m ot hera p y, a n d i m m u n ot hera py);

A n y  ot her c o n diti o ns t hat were 
treate d wit h 
c he m ot hera p y, ra diati o n t hera py, or 
i m m u n ot hera p y;

S m o ki n g hist or y ;

C urre nt ca ncer si g ns a n d s ym pt o ms a n d si de effects fr o m c urre nt a n d pre vi o us a nticancer 
treat me nts; a n d
C CI


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
102/154
Current cancer disease status.
7.2.3
Medical History
In order to determine the subject’s eligibility to the trial, a complete medical history of each subject 
will be collected and documented during Screening, which will include, but may not be limited to, 
the following:
Past and concomitant nonmalignant diseases and treatments
All medications (including herbal medications) taken and procedures carried out within 28 days 
prior to Screening
For the trial entry, all of the subjects must fulfill all inclusion criteria described in Section 5.3.1, 
and none of the subjects should have any exclusion criterion from the list described in 
Section 5.3.2.
7.2.4
Vital Signs and Physical Examination
Vital signs including body temperature, respiratory rate, heart rate (after 5-minute rest), and arterial 
blood pressure (after 5-minute rest) will be recorded at trial entry. 
A complete physical examination (including, in general, appearance, dermatological, head / neck, 
pulmonary, cardiovascular, gastrointestinal, genitourinary, lymphatic, musculoskeletal system, 
extremities, eyes [inspection and vision control], nose, throat, and neurologic status) will be 
performed and the results documented.
The ECOG PS will be documented during the Screening phase and at each scheduled visit (if the 
Screening ECOG PS was performed within 3 days prior to Day 1, it does not have to be repeated 
at Day 1).
Body weight and height (Screening only) will be recorded.
7.2.5
CT or MRI Scans for Tumor Assessment at Baseline
Baseline imaging will be performed within 28 days prior to randomization in order to establish 
baseline disease status of target and nontarget lesions according to RECIST 1.1.  Acceptable 
modalities include CT scans (chest, abdomen, and pelvis), CT chest with contrast together with 
MRI of the abdomen and pelvis, or positron emission tomography/CT scans.  The use of IV 
contrast is preferred unless there is a history of allergy or other risk in the opinion of the 
Investigator (chest X-ray is not acceptable and other imaging modalities may be performed at the 
discretion of the Investigator and as clinically indicated).  Bone scans should be performed if 
clinically indicated.  Baseline tumor burden should be determined as outlined in Section 7.3.  A 
brain CT/MRI scan is required at Screening if one has not been performed within 6 weeks prior to 
randomization.  In general, lesions detected at Screening/Baseline need to be followed using the 
same imaging methodology and preferably the same imaging equipment at subsequent tumor 
evaluation visits.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
103/154
7.2.6
Cardiac Assessments
A 12-lead ECG will be recorded at Screening and at the End-of-Treatment visit after the subject 
has been in a supine position breathing quietly for 5 minutes.  The ECG results will be used to 
evaluate the heart rate, atrial-ventricular conduction, QR and QT duration, and possible 
arrhythmias.  ECGs are to be performed as clinically indicated in case of abnormalities such as 
increased heart rate above the subject’s baseline, detected during the physical examination and/or 
vital signs measurements performed prior to avelumab treatment.
7.2.7
Clinical Laboratory Tests
Blood samples will be collected at Screening for clinical laboratory parameter evaluations.  These 
clinical laboratory test results will serve not only as the Baseline values for subsequent safety 
clinical laboratory evaluations during the trial, but will also help to make sure that each randomized 
subject fulfills all the trial entry criteria and does not meet any of the trial exclusion criteria for 
laboratory parameters as listed in Section 5.3.  Detailed description of laboratory assessments is 
provided in Section 7.4.3.
7.3
Efficacy Assessments
On study imaging will be performed every 6 weeks (±1 week) calculated from the randomization 
date and as clinically indicated and submitted for central radiology review.  The timing for imaging 
studies should follow calendar days and should not be adjusted for delays in cycle starts.  The 
CT/MRI scans will be performed and collected until disease progression is assessed by the 
Investigators according to RECIST 1.1.  For all subjects and if clinically feasible, a subsequent 
scan at least 4 weeks after initial assessment of progressive disease should be collected to confirm 
progression.
NOTE: Subjects who discontinue treatment for reasons other than radiological progression 
assessed according to RECIST 1.1, will continue to have efficacy assessments (CT/MRI scans) 
according to the protocol schedule until disease progression.
In case of avelumab treatment beyond progression, additional images should be collected in 
accordance with imaging schedule as long as the subject continues on avelumab therapy.
Radiographic images and physical findings (physical assessments) will be used by the 
Investigators for the local determination of disease progression and subject treatment decisions.  
Images will also be read centrally and reviewed by a blinded IRC.  The IRC will make a 
determination for tumor response and/or progression of disease according to RECIST 1.1. 
For each subject, tumor response assessment will be performed by CT scan or MRI (if MRI is 
used, chest CT is mandatory) imaging of the chest/abdomen/pelvis (plus other regions as 
specifically required) and other established assessments of tumor burden if CT/MRI imaging is 
insufficient for the individual subject.  All the scans performed at Baseline and other imaging 
performed as clinically required (other supportive imaging) need to be repeated at subsequent visits 
(except for brain scans, unless clinically indicated).  In general, lesions detected at Baseline need 


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
104/154
to be followed using the same imaging methodology and preferably the same imaging equipment 
at subsequent tumor evaluation visits.
A brain CT/MRI scan is required at Screening if not performed within 6 weeks prior to 
randomization.  Brain CT/MRI scans should be performed after Screening, if clinically indicated 
by development of new specific symptoms.  A bone scan should be done as clinically indicated at 
Screening and beyond.  For each subject, the Investigator will designate 1 or more of the following 
measures of tumor status to follow for determining response: CT or MRI images of primary and/or 
metastatic tumor masses, physical examination findings, and the results of other assessments.  All 
available images collected during the trial period will be considered and submitted for central 
radiological review.  The most appropriate measures to evaluate the tumor status of a subject 
should be used.  The measure(s) to be chosen for sequential evaluation during the trial must 
correspond to the measures used to document the progressive tumor status that qualifies the subject 
for randomization.  The tumor response assessment will be assessed and listed according to the 
Schedule of Assessments (see Table 1).
Treatment decisions will be made by the Investigator based on the Investigator’s assessment of 
tumor status (tumor response and disease progression).  Investigator’s assessment of objective 
tumor response to treatment will be performed according to RECIST v1.1.
For the study objectives of efficacy determination, tumor responses to treatment will be assigned 
by the IRC based on the evaluation of the response of target, non-target, and new lesions according 
to RECIST 1.1.
To assess objective response, the tumor burden at Baseline will be estimated and used for 
comparison with subsequent measurements.  At Baseline, tumor lesions will be categorized in 
target and nontarget lesions as described in RECIST 1.1 (1).
Results for these evaluations will be recorded with as much specificity as possible so that pre- and 
post-treatment results will provide the best opportunity for evaluating tumor response. 
Any CR or PR should be confirmed, preferably at the scheduled 6-week interval, but no sooner 
than 4 weeks after the initial documentation of CR or PR. Confirmation of PR can be confirmed 
at an assessment later than the next scheduled assessment after the initial documentation of PR.
The Investigator may perform scans in addition to a scheduled trial scan for medical reasons or if 
the Investigator suspects PD. Subjects who withdraw from the trial for clinical or symptomatic 
deterioration or for adverse events before objective documentation of PD will be requested to 
undergo appropriate imaging to confirm PD.  Every effort should be made to confirm a clinical 
diagnosis of PD by imaging.  After radiological progression of disease and if clinically feasible, a 
subsequent scan at least 4 weeks after initial assessment of progression should be collected to 
confirm progression.  If radiological progression is not confirmed, and there was no new anticancer 
therapy initiated, then the subject may resume or continue trial treatment and have their next scan 
according to the study schedule.  
There will also be an optional biopsy for avelumab subjects only. A de novo (ie, fresh biopsy) 
tumor sample should be collected at End of Treatment, unless clinically contraindicated, or after 


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
105/154
disease progression (if EOT occurred before progression). If after disease progression, the biopsy 
should be collected before the start of any new therapy.  
7.4
Assessment of Safety
The safety profile of the trial treatments will be assessed through the recording, reporting, and 
analyzing of baseline medical conditions, AEs, physical examination findings, including vital 
signs, and laboratory tests.
Comprehensive assessment of any apparent toxicity experienced by the subject will be performed 
throughout the course of the trial, from the time of the subject’s signature of informed consent.  
Trial site personnel will report any AE, whether observed by the Investigator or reported by the 
subject (see Section 7.4.1.2).  Given the intended mechanism of action of avelumab, particular 
attention will be given to AEs that may follow the enhanced T-cell activation, such as dermatitis, 
colitis, hepatitis, uveitis, or other immune-related reactions.  Ophthalmologic examinations should 
be considered, when clinically indicated, for signs or symptoms of uveitis.
The reporting period for AEs is described in Section 7.4.1.3.
The safety assessments will be performed according to the Schedule of Assessments (see Table 1,
Table 2, Table 3, and Table 4).
7.4.1
Adverse Events
7.4.1.1
Adverse Event Definitions
Adverse Events
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, regardless of causal relationship with this treatment.  An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product. 
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
The Investigator is required to grade the severity or toxicity of each AE.
Investigators will reference the NCI-CTCAE, v 4.03 (publication date: 14 June 2010), a descriptive 
terminology that can be used for AE reporting.
A general grading (severity/intensity; hereafter referred to as severity) scale is provided at the 
beginning of the above referenced document, and specific event grades are also provided.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
106/154
If a particular AE’s severity is not specifically graded by the guidance document, the Investigator 
is to use the general NCI-CTCAE definitions of Grade 1 through Grade 5 following his or her best 
medical judgment.
The 5 general grades are:
Grade 1 or Mild
Grade 2 or Moderate
Grade 3 or Severe 
Grade 4 or Life-threatening
Grade 5 or Death 
According to Sponsor convention, any clinical AE with severity of Grade 4 or 5 must also be 
reported as an SAE.  However, a laboratory abnormality of Grade 4, such as anemia or neutropenia,
is considered serious only if the condition meets one of the serious criteria described below.
If death occurs, the primary cause of death or event leading to death should be recorded and 
reported as an SAE.  “Fatal” will be recorded as the outcome of this specific event and death will 
not be recorded as separate event.  Only, if no cause of death can be reported (for example, sudden 
death, unexplained death), the death per se might then be reported as an SAE.
Investigators must also systematically assess the causal relationship of AEs to trial treatment using 
the following definitions.  Decisive factors for the assessment of causal relationship of an AE to 
the trial treatment include, but may not be limited to, temporal relationship between the AE and 
the trial treatment, known side effects of trial treatment, medical history, concomitant medication, 
course of the underlying disease, trial procedures.
Unrelated:
Not reasonably related to the trial treatment avelumab/chemotherapy.  The AE could 
not medically (pharmacologically/clinically) be attributed to the trial treatment under 
study in this clinical trial protocol.  A reasonable alternative explanation must be 
available.
Related:
Reasonably related to the trial treatment avelumab/chemotherapy.  The AE could 
medically (pharmacologically/clinically) be attributed to the trial treatment under 
study in this clinical trial protocol. 
Abnormal Laboratory Findings and Other Abnormal Investigational Findings
Abnormal laboratory findings and other abnormal investigational findings (for example, on an 
ECG trace) should not be reported as AEs unless they are associated with clinical signs and 
symptoms, lead to treatment discontinuation or are considered otherwise medically important by 
the Investigator.  If a laboratory abnormality fulfills these criteria, the identified medical condition 
(for example, anemia, increased ALT) must be reported as the AE rather than the abnormal value 
itself.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
107/154
Adverse Drug Reaction (ADR)
ADRs are defined in this study as any AEs suspected to be related to study treatment by the 
Investigator and / or Sponsor.
Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:
Results in death.
Is life-threatening.  (Note: The term “life-threatening” refers to an event in which the subject is 
at risk of death at the time of the event, not an event that hypothetically might have caused death 
if it was more severe.)
Requires inpatient hospitalization or prolongs an existing hospitalization.
Results in persistent or significant disability or incapacity.
Is a congenital anomaly or birth defect.
Is otherwise considered to be medically important.
Note: Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered as SAEs when, based upon appropriate medical judgment, they 
may jeopardize the subject or may require medical or surgical intervention to prevent one of the 
outcomes listed above.  Examples of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse.
For the purposes of reporting, any suspected transmission of an infectious agent via an IMP is also 
considered an SAE, as described in 7.4.1.4.
Events that Do Not Meet the Definition of an SAE
Elective hospitalizations to administer, or to simplify trial treatment or trial procedures (for 
example, an overnight stay to facilitate chemotherapy and related hydration therapy application) 
are not considered SAEs.  However, all events leading to unplanned hospitalizations or unplanned 
prolongation of an elective hospitalization (for example, undesirable effects of any administered 
treatment) must be documented and reported as SAEs.
Events Not to Be Considered as AEs/SAEs
Medical conditions present at the initial trial visit that do not worsen in severity or frequency during 
the trial are defined as Baseline Medical Conditions, and are not to be considered AEs.
AE/SAEs Observed in Association with Disease Progression
Disease progression recorded in the course of efficacy assessments only, but without any adverse 
signs or symptoms should not be reported as adverse events.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
108/154
However, if adverse signs or symptoms occur in association with disease progression then these 
should be recorded as AEs or reported as SAEs, if they meet criteria for seriousness.
Adverse Events of Special Interest
Any AE that is suspicious to be a potential irAE including infusion related reactions will be 
considered AEs of special interest (AESIs). 
7.4.1.2
Methods of Recording and Assessing Adverse Events
At each trial visit, the subject will be queried on changes in his or her condition.  During the 
reporting period, any unfavorable changes in the subject’s condition will be recorded as AEs, 
whether reported by the subject or observed by the Investigator. 
Complete, accurate, and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the eCRF.  
All SAEs must be additionally documented and reported using the appropriate report form as 
described in Section 7.4.1.4.
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates [and times when it is important to assess the time of AE onset relative to the 
recorded treatment administration time]), its severity, its causal relationship with the trial 
treatment, any other potential causal factors, any treatment given or other action taken, including 
dose modification or discontinuation of the trial drug, and its outcome.  In addition, serious cases 
should be identified and the appropriate seriousness criteria documented. 
Specific guidance can be found in the eCRF Completion and Monitoring Conventions.
7.4.1.3
Definition of the Adverse Event Reporting Period
The AE reporting period for safety surveillance begins when the subject is initially included in the 
trial (date of first signature of informed consent) and continues for all SAEs and treatment-related 
non-serious AEs through the study’s Safety Follow-up Phone Call, defined as 90 days (± 1 week) 
after the last IMP administration. 
Any SAE assessed as related to the trial treatment must be reported whenever it occurs, irrespective 
of the time elapsed since the last administration. 
7.4.1.4
Procedure for Reporting Serious Adverse Events
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (within a maximum of 24 hours after becoming aware of the event) inform the 
Sponsor or its designee using the SAE Report Form, following specific completion instructions.
In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone; 
in these cases, a SAE report form must be provided immediately thereafter.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
109/154
Relevant pages from the eCRF may be provided in parallel (for example, medical history, 
concomitant drugs).  Additional documents may be provided by the Investigator, if available (for 
example, laboratory results, hospital report, autopsy report).  In all cases, the information provided 
on the SAE Report Form must be consistent with the data about the event recorded in the eCRF.
The Investigator must respond to any request for follow-up information (for example, additional 
information, outcome, final evaluation, other records where needed) or to any question the
Sponsor/designee may have on the AE within the same timelines as those noted above for initial 
reports.  This is necessary to ensure prompt assessment of the event by the Sponsor or designee 
and (as applicable) to allow the Sponsor to meet strict regulatory timelines associated with 
expedited safety reporting obligations.
Requests for follow-up will usually be made via the responsible monitor, although in exceptional 
circumstances the Global Drug Safety department of the Sponsor may contact the Investigator 
directly to obtain clarification or to obtain further information or to discuss the event.
7.4.1.5
Safety Reporting to Health Authorities, Independent Ethics 
Committees/ Institutional Review Boards and Investigators
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations.
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (particularly deaths) involving trial subjects to the IEC/IRB that approved the 
trial.
In accordance with ICH GCP, the Sponsor/designee will inform the Investigator of “findings that 
could adversely affect the safety of subjects, impact the conduct of the trial or alter the IEC’s/IRB’s 
approval/favorable opinion to continue the trial.”  In particular and in line with respective 
regulations, the Sponsor/designee will inform the Investigator of AEs that are both serious and 
unexpected and are considered to be related to the administered product (“suspected unexpected 
serious adverse reactions” or SUSARs).  The Investigator should place copies of Safety Reports 
in the Investigator Site File.  National regulations with regard to Safety Report notifications to 
Investigators will be taken into account.
When specifically required by regulations and guidelines, the Sponsor/designee will provide 
appropriate Safety Reports directly to the concerned lead IEC/IRB and will maintain records of 
these notifications.  When direct reporting is not clearly defined by national or site-specific 
regulations, the Investigator will be responsible for promptly notifying the concerned IEC/IRB of 
any Safety Reports provided by the Sponsor/designee and of filing copies of all related 
correspondence in the Investigator Site File.
For trials covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities regarding 
the reporting of SAEs/SUSARs/Safety Issues will be carried out in accordance with that Directive 
and with the related Detailed Guidance documents.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
110/154
7.4.1.6
Monitoring of Subjects with Adverse Events
Adverse events are recorded and assessed continuously throughout the trial (see Section 7.4.1.3) 
and are assessed for final outcome at the 30-day Safety Follow-up visit.  After this visit, all SAEs
and all treatment-related non-serious AEs need to be documented through the study’s Safety 
Follow-up Phone Call, defined at 90 days (± 1 week) after the last IMP administration.  All SAEs 
ongoing at the 90-day Safety Follow-up phone call must be monitored and followed up by the 
Investigator until stabilization or until the outcome is known, unless the subject is documented as 
“lost to follow-up”.  Reasonable attempts to obtain this information must be made and documented.  
It is also the responsibility of the Investigator to ensure that any necessary additional therapeutic 
measures and follow-up procedures are performed. 
7.4.2
Pregnancy and In Utero Drug Exposure 
Should a woman become pregnant or suspect that she is pregnant while she or her partner is 
participating in this trial, the treating physician should be informed immediately.  Only pregnancies 
considered by the Investigator to be related to trial treatment (for example, resulting from a drug 
interaction with a contraceptive medication) are considered to be AEs.  However, all pregnancies 
with an estimated conception date during the period defined in Section 7.4.1.3 must be recorded 
by convention in the AE page/section of the eCRF. The same rule applies to pregnancies in female 
subjects and to pregnancies in female partners of male subjects.  The Investigator must notify the 
Sponsor/designee in an expedited manner of any pregnancy using the paper Pregnancy Report 
Form, which must be transmitted according to the same process as described for SAE reporting in 
Section 7.4.1.4.
Investigators must actively follow up, document, and report on the outcome of all these 
pregnancies, even if the subjects are withdrawn from the trial.
The Investigator must notify the Sponsor/designee of these outcomes using the Pregnancy Form.  
If an abnormal outcome occurs, the SAE Report Form will be used if the subject sustains an event 
and the Parent-Child/Fetus Adverse Event Report Form if the child/fetus sustains an event.
Any abnormal outcome must be reported in an expedited manner as described in Section 7.4.1.4, 
while normal outcomes must be reported within 45 days after delivery.
In the event of a pregnancy in a subject occurring during the course of the trial, the subject must 
be discontinued from trial medication immediately.  The Sponsor/designee must be notified 
without delay and the subject must be followed as mentioned above.
7.4.3
Clinical Laboratory Assessments
All laboratory samples that are detailed in the Schedule of Assessments (see Table 1 to Table 4) 
must be collected, and sent to the central laboratory for analysis.
Sample for complete blood count and core chemistry must be available and reviewed prior to dose 
administration.  Results of all central laboratory testing will be transferred to the clinical database.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
111/154
Urinalysis and Urine Pregnancy Testing will be done locally.
Local laboratory samples may be drawn, and if collected, are required to be collected in the eCRFs
as per eCRF completion guidelines, however, central laboratory samples must be collected in 
addition.
In the case of LFT elevations (AST, ALT and/or total bilirubin) requiring additional lab draws 
(according to guidelines set forth in Table 10 Management of irAEs), an unscheduled lab draw 
should be sent to the central laboratory for analysis.
The report of the results must be retained as a part of the subject’s medical record or source 
documents.  Blood samples for the full safety tests listed in Table 11 will be taken from nonfasted 
subjects during the Screening phase (28 days prior to randomization), during the treatment phase 
as specified in Table 11, Table 1 to Table 4, at the End-of-Treatment visit, and at the Safety 
Follow-up visit.  The ACTH, T4, TSH, and urinalysis will only be assessed at the time points 
defined in Table 11, Table 1, Table 2, and Table 3.  If confirmation of a subject’s postmenopausal 
status is necessary, an FSH level will also be performed at Screening, see Section 7.1.1.
Table 11
Required Full Laboratory Safety Tests
Full Chemistry
Core Chemistrya
Hematology
Albumin
Alkaline phosphatase
Absolute lymphocyte count
Alkaline phosphatase
ALT
ANC
ALT
AST
Hematocrit
Amylase
BUN/total urea
Hemoglobin
AST
Calcium
Platelet count
GGT
Chloride
RBC count
BUN / total urea
Creatinine
WBC count and differential count
Calcium
Glucose
RBC morphology
Chloride
Phosphorus / Phosphates
Reticulocytes
Cholesterol
Magnesium
MCH
Creatine kinase
Potassium
Mean corpuscular volume
Creatinine
Sodium
MCHC
CRP
Total bilirubin
Glucose
Amylase
Hemostaseology
LDH
Lipase
aPTT
Lipase
Creatine kinase
Prothrombin time / INR
Phosphorus / Phosphates
Magnesium
Basic Urinalysis (dipstick, including macroscopic 
appearance, bilirubin, blood, color, glucose, 
ketones, leukocyte esterase, nitrite, pH, protein, 
specific gravity, urobilinogen)
Full urinalysis (dipstick and microscopic evaluation) 
to be performed only at the Screening and 
End-of-Treatment visits and a basic urinalysis prior 
to each administration of the trial drug.
Potassium
Sodium
Total bilirubin


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
112/154
Full Chemistry
Core Chemistrya
Hematology
Total protein
Uric acid
Totality of binding ADAs
Triglycerides
ACTH (only at Baseline), TSH, and T4
To be assessed - according to schedule of 
assessments in Table 1, Table 2, Table 3, and 
Table 4.
Hormone
FSH (yes / no if applicable)
ACTH: adrenocorticotropic hormone; ADA: Anti-drug antibody; ALT: alanine aminotransferase; ANC: absolute 
neutrophil count; aPTT: activated partial thromboplastin time; AST: aspartate aminotransferase; BUN: blood urea 
nitrogen; CRP: C-reactive protein; FSH: follicle-stimulating hormone; GGT: gamma-glutamyltransferase;
INR: international normalized ratio; LDH: lactate dehydrogenase; MCH: mean corpuscular hemoglobin;
MCHC: mean corpuscular hemoglobin concentration; RBC: red blood cell; TSH: thyroid-stimulating hormone;
T4: free thyroxine; WBC: white blood cell.
a Core serum chemistries.
If a subject has a clinically significant abnormal laboratory test value that is not present at Baseline, 
the test will be repeated weekly and the subject will be followed until the test value has returned 
to the normal range or the Investigator has determined that the abnormality is chronic or stable.
7.4.4
Vital Signs, Physical Examination and Other Assessments
The ECOG PS will be assessed at Screening and at subsequent visits as indicated in the Schedule 
of Assessments (Table 1, Table 2, Table 3, and Table 4) and documented in the eCRF.
Body weight will be measured at Screening and at subsequent visits as indicated in the Schedule 
of Assessments (Table 1, Table 2, Table 3, and Table 4) and documented in the eCRF.  Body 
height will be measured at Screening only.
A physical examination will be conducted at Screening and at subsequent visits if indicated as 
indicated in the Schedule of Assessments (Table 1, Table 2, Table 3, and Table 4) and documented 
in the eCRF (detailed description in Section 7.2.4).  Results of the physical examination, including 
any abnormalities, will be documented in the eCRF.  Abnormal findings are to be reassessed at 
subsequent visits.
A 12-lead ECG will be recorded as indicated in the Schedule of Assessments (Table 1, Table 2, 
Table 3, and Table 4).  Vital signs including body temperature, respiratory rate, heart rate (after 
5-minute rest), and arterial blood pressure (after 5-minute rest) will be recorded at trial entry.
All newly diagnosed or worsening conditions, signs, and symptoms observed from Screening, 
whether related to trial treatment or not, are to be reported as AEs.
For female subjects of childbearing potential, a serum β-hCG pregnancy test will be carried out 
during the Screening phase.  A urine or serum β-hCG test will be performed before administration 
of trial drug (every 4 weeks for the avelumab arm or every 3 weeks for the comparator arm) during 
the treatment phase and at the End-of-Treatment visit.  Results of the most recent pregnancy test 


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 3 / 1 5 4
s h o ul d be a vaila ble pri or t o t he ne xt d osi n g of trial dr u g.  Su bjects w h o are p ost me n o pa usal are 
e xe m pt fr o m pre g na nc y testi n g.  Fe males are c o nsi dere d p ost me n o pa usal if t he y  ha ve a ge-relate d 
a me n orr hea ≥1 2 c o nsec uti ve m o nt hs or if t he y ha ve u n der g o ne h y sterect o my or bilateral 
o o p h orect o m y.  If necessar y  to c o nfir m/assess p ost me n o pa usal stat us, F S H ma y  be dra w n at 
Scree ni n g wit h d oc u me nte d i ncrease d F S H > 4 0 mI U/ m L.
C CI


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 4 / 1 5 4
C CI


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 5 / 1 5 4
C CI


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
116/154
7.7
Other Assessments
7.7.1
Patient-reported Outcomes/Quality of Life
Patient-reported outcomes / quality of life will be assessed by the EQ-5D-5L, EORTC QLQ-C30, 
and module QLQ-LC13.  Questionnaires will be completed by the subject at Screening (or on 
Day 1, if not done at Screening), Week 7, Week 13 prior to trial treatment administration, and then 
every 6 weeks thereafter while on trial treatment for subjects randomized to receive avelumab; and 
Screening (or on Day 1, if not done at Screening), Week 7, Week 13, and then every 6 weeks 
thereafter while on trial treatment for subjects randomized to receive chemotherapy.  
Patient-reported outcomes will also be assessed at the End-of-Treatment visit (details will be 
provided in the Study Manual) and Safety Follow-up Visit 30 Days after Last Treatment.  
The patient-reported outcomes / quality of life questionnaires should be completed by the subject 
prior to any of the other trial-related assessments being performed, that is, physical examinations, 
blood draws, trial treatment administration, etc.  Subjects will use a validated electronic tablet or 
validated site pad to record their responses to these questionnaires.  In rare and extenuating 
circumstances when an electronic tablet or site pad is not available or not working properly, 
collection on validated paper questionnaires may be allowed to ensure data are collected and not 
lost.
The EQ-5D-5L comprises 5 questions and a visual analogue scale.  The questionnaire is used to 
calculate the utility index, used in economic evaluations.  The 5 items are mobility, self-care, usual 
activities of daily living, pain/discomfort, anxiety/depression with 5 descriptive levels ranging 
from “no problem to…” to “extreme…/unable to do….”  The visual analogue scale ranges from 
0-100 where 0 is “the worst health you can imagine” and 100 is “the best health you can imagine.”  
The recall period is defined as “today.”
EORTC QLQ-C30 accesses the quality of life of cancer patients with 30 questions including the 
dimensions of activities of daily living, pain, fatigue, shortness of breath, appetite loss, nausea, 
vomiting, sleeping disturbances, diarrhea, difficulties to concentrate, anxiety and depression, 
memory loss, social activities, financial burden, impression of overall health and impression of 
overall quality of life.  Questions 1-28 are measured in a range from 1-4 where 1 represents “Not 
at All” and 4 represents “Very Much”, and questions 29-30 are measured in a range from 1-7 where 
1 represents “Very poor” and 7 represents Excellent.  The recall period is defined as “during the 
past week.”
The QLQ-LC13 comprises 13 questions incorporated into 1 multi-item scale designed to evaluate 
lung cancer symptoms such as dyspnea, different types of pain, cough, hemoptysis, dysphagia, 
sore mouth, alopecia, and peripheral neuropathy.  For each domain and item, a linear 
transformation is applied to standardize the raw score to a range from 0 to 100, with 
100 representing the best possible function / quality of life, and highest burden of symptoms for 
symptom domains and single items.  The recall period is defined as “during the past week.”
Data will be collected by the CRO and housed in a database.  Analysis of the questionnaires will 
be described in the SAP.


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 7 / 1 5 4
C CI


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 8 / 1 5 4
C CI


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 9 / 1 5 4
8. 3
E n d p oi nts
8. 3. 1
Pri m ar y E n d p oi nts
T he pri mar y  en d p oi nt s of t he trial are the P F S ti me or O S ti me.  The trial will be c o nsi dere d t o 
ha ve met its o bjecti ve if eit her or b ot h of t he pri mar y  e n d p oi nts are p ositi ve.
P F S is defi ne d as t he ti me fr o m date of ra n d o mizati o n u ntil date of t he first d oc u me ntati o n of P D 
or deat h d ue t o a n y ca use i n t he a bse nce of d oc u me nte d P D, w hic he ver occ urs first.   
T he P F S will be defi ne d acc or di n g t o R E CI S T 1. 1 a n d as a dj u dicate d b y  an I RC (see 
Secti o n 2. 3. 2 ).  Details o n deter mi nati o n of t he first disease pr o gressi o n date will be s pecifie d i n 
t he IR C c harter.
F or t he pri mar y  anal ys is P F S data will be ce ns ore d o n t he date of t he last a de q uate t u m or 
assess me nt f or s u bjects w h o d o n ot ha ve a n e ve nt ( P D or deat h), f or s u bjects w h o start ne w 
a ntica ncer treat me nt pri or t o a n e ve nt, or f or s u bjects wit h a n e ve nt after t w o or m ore missi n g 
t u m or assess me nts.  Su bjects w h o d o n ot ha ve a baseli ne t u m or assess me nt or w h o d o n ot ha ve 
a n y post -baseli ne t u m or assess me nts will be ce ns ore d o n t he date of ra n d o mizati o n u nless deat h 
occ urre d o n or bef ore t he ti me of t he sec o n d pla n ne d t u m or assess me nt, i n w hic h case t he deat h 
will be c o nsi dere d a n e ve nt.
S o me s u bjects ma y  start ne w a ntica ncer t hera py pri or t o d oc u me n te d disease pr o gressi o n.  For 
s uc h s u bjects, t he pr ot oc ol re q uires t u m or assess me nts t o be c o nti n ue d per sc he d ule of assess me nts 
C CI


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
120/154
through documented disease progression or death to enable conduct of a supportive analysis for 
PFS that will ignore (that is, not censor subjects at) start of new anticancer treatment. 
The OS is defined as the time from randomization to the date of death, regardless of the actual 
cause of the subject’s death.
For subjects who are still alive at the time of data analysis or who are lost to follow-up, OS time 
will be censored at the last recorded date that the subject is known to be alive (specified in the 
SAP) as of the data cut-off date for the analysis.
8.3.2
Secondary Endpoints
8.3.2.1
Best Overall Response
The BOR will be determined according to RECIST 1.1 (1) and as adjudicated by an IRC (see 
Section 2.3.2).  It is defined as the best response obtained among all tumor assessment visits after 
the date of randomization until documented disease progression or start of subsequent new 
anti-cancer therapy.  Details of determination of tumor response date at each time point will be 
provided in the IRC charter. 
For a BOR of PR or CR, confirmation of the response according to RECIST 1.1 will be required, 
preferably at the regularly scheduled 6-week assessment interval, but no sooner than 4 weeks after 
the initial documentation of CR or PR.  A BOR of SD requires that an overall response of SD has 
been determined at a time point at least 6 weeks after randomization.
The ORR is defined as the proportion of all randomized subjects with a confirmed BOR of PR or 
CR according to RECIST 1.1 and as adjudicated by the IRC.
The BOR according to Investigator assessment will be derived in the same way as the BOR 
according to the IRC.
8.3.2.2
Duration of Response
The duration of response according to RECIST 1.1, defined for each subject with a confirmed 
response as the time from the date of the first assessment demonstrating a CR or PR to date of the 
first assessment demonstrating PD or death within 12 weeks after the last tumor assessment, 
whichever occurs first.
8.3.2.3
Patient-reported Outcomes/Quality of Life (QoL) assessment
Changes in patient-reported outcomes / quality of life will be assessed by the EQ-5D-5L, EORTC 
QLQ-C30, and EORTC QLQ-LC13 questionnaires, as defined in the SAP.
8.3.3
Safety Endpoints
Safety endpoints include AEs, physical examination findings, laboratory assessments, vital signs, 
ECG parameters, and ECOG PS as described in Section 7.4.


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 1 / 1 5 4
8. 4
A n al ysis Sets
Scree ni n g A n al ysis Set
T he scree ni n g a nal ys is set i ncl u des all s u bjects w h o si g ne d t he I CF. 
F ull A n al ysis Set ( F A S)
T he F A S will i ncl u de all s u bjects w h o were ra n d o mize d t o trial treat me nt.  Anal y ses perf or me d 
o n t he F A S will ta ke i nt o acc o u nt s u bjects’ all ocati o n t o treat me nt gr o u ps as ra n d o mize d .
M o difie d F ull A n al ysis Set ( m F A S)
T he m o difie d F A S is defi ne d as t he F A S restricte d t o s u bjects w h o were ra n d o mly assi g ne d t o 
treat me nt acc or di n g t o C T P versi o n 4. 0 or later, after A r m C is acti vate d i n t he treat me nt all ocati o n.
P D -L 1 P ositi ve
T he i ncl usi o n criteria f or p ositi ve P D-L 1  is deter mi ne d b y  a Da k o P D-L 1  im m u n o hist oc he mistr y  
(I H C) p har m D x c o m pa ni o n dia g n ostic test, de vel o pe d f or t he p ur p ose of t his trial.  T he P D -L 1  
I H C assa y an d t he sc ori n g al g orit h m t o deter mi ne a n y, m o derate ,a n d hi g h P D -L 1 e x pressi o n stat us 
will be defi ne d pr i or t o c o n d ucti n g a n y statistical a nalys es. Details will be s pecifie d i n la b orat or y 
ma n ual a n d S A P .
T he a n y P D -L 1 + a nal ys is set will i ncl u de all s u bjects wit h a n y e x pressi o n P D -L 1 + t u m ors at a n y 
stai ni n g i nte nsit y w h o were ra n d o mize d t o trial treat me nt.
C CI


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 2 / 1 5 4
T he m o derate a n d hi g h e x pressi o n P D -L 1 + a nal ysis set will i ncl u de all s u bjects wit h m o derate 
e x pressi o n a n d hi g h e x pressi o n P D -L 1 + t u m ors at a n y stai ni n g i nte nsit y (i n t u m or cells) w h o were 
ra n d o mize d t o trial treat me nt.
T he hi g h e x pressi o n P D -L 1 + a nal ysis set will i ncl u de all s u bjects wit h hi g h e x pressi o n P D -L 1 + 
t u m ors at a n y stai ni n g i nte nsit y (i n t u m or cells) w h o were ra n d o mize d t o trial treat me nt.
S afet y A n al ysis Set   
T he Safet y a nal ys is set will i ncl u de all s u bjects w h o were a d mi nistere d at least 1 d ose of t he trial 
me dicati o n.  A nal ys es perf or me d o n t he Safet y a nal ysis set will c o nsi der s u bjects as treate d .
S u b gr o u p A n al ysis Sets 
A nal y sis of efficac y varia bles will als o be perf or me d o n s u b gr o u ps of i nterest, w hic h will be 
s pecifie d i n t he S A P.
P h ar m ac o k i netic A n al ysis Set
T he P K A nal y sis Set will i ncl u de s u bjects w h o were a d mi nistere d at least 1 d ose of t he trial 
me dicati o n a n d at least 1 q ua ntifia ble ser u m c o nce ntrati o n at a sc he d ule d P K ti me p oi nt p ost d ose . 
I m m u n o ge nicit y ( A D A) A n al ysis Set
All s u bjects w h o c o m plete at least 1 a d mi nistrati o n of a vel u ma b a n d w h o ha ve at least 1 vali d 
A D A res ult.
8. 5
Descri pti o n of St atistic al A n al yses
8. 5. 1
Ge ner al C o nsi der ati o ns
F ull details of t he pla n ne d a nal ys es will be descri be d i n t he trial S A P.
Pri m ar y a n al ysis p o p ul ati o n
T he pri mar y  a nalys is p o p ulati o n will be:

T he F A S p o p ulati o n f or Ar m A (a vel u ma b o nce e ver y 2 wee ks) a n d Ar m B
( S O C
c he m ot hera p y ) c o m paris o ns.

T he m F A S p o p ulati o n f or Ar m C ( a vel u ma b o nce a wee k f or 1 2 wee ks f oll o we d by a v el u ma b 
o nce e ver y  2 wee ks) a n d Ar m B ( S O C c he m ot hera pies ) c o m paris o ns.
Si g nific a nce le vel
T he o verall si g nifica nce le vel is 2. 5 % o ne- si de d. C o nfir mat or y  statistical tests are descri be d i n 
Secti o n 8. 5. 2 al o n g wit h pr oce d ures f or c o ntr olli n g t he fa mil y wise err or rate i n t he str o n g se nse. 
 All statistical tests c o m pari n g 
C CI


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
123/154
treatment arms will be performed one-sided. If confidence intervals are to be calculated, these will 
be two-sided with a confidence probability of 95%, unless otherwise specified. 
Sequence of Analyses
The planned sequence of analysis is displayed in Figure 2. Dates are exemplary cut-off dates.
Figure 2
Sequence of Analyses
OS: overall survival; PFS: progression free survival.
The data cut-off for the primary OS and PFS analysis will occur after the target number of 173 OS 
events for Arm C versus B comparison of the randomized subjects with high PD-L1 has been 
reached and at least 20 months follow-up after the randomization of the last subject in the study. 
Lan-de-Mets alpha spending with O’Brien-Fleming-like boundaries will be adopted for the 
currently observed event size at cut-off date for each treatment group comparison (see 
Section 8.5.2).
The PD-L1 IHC assay and the scoring algorithm to determine low, moderate, and high PD-L1 
expression status will be defined prior to conducting any statistical analyses.  Details will be 
specified in laboratory manual and statistical analysis plan.
Further details concerning interim analysis are included in Section 8.6.  
General Conventions
Baseline characteristics summary and the efficacy analysis will be performed on the FAS and 
mFAS population considering treatment Arms A, B and C.  Analyses performed on the FAS and 
mFAS will take into account subjects’ allocation to treatment groups as randomized.  Analyses 
performed on the safety population will consider subjects as treated.
All safety and efficacy endpoints will be summarized by treatment group.  
In order to provide overall estimates of treatment effects, data will be pooled across trial centers.  
The “center” factor will not be considered in statistical models or for subgroup analyses due to the 
high number of participating centers in contrast to the anticipated small number of subjects 
randomized at each center.
In general, descriptive summaries will be presented for the efficacy and safety variables collected.  
Continuous variables will be summarized using mean, standard deviation, minimum, median, and 
maximum.  Categorical variables will be summarized using frequency counts and percentages.    


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
124/154
Unless otherwise specified, the calculation of proportions will be based on the sample size of the 
population of interest.  Counts of missing observations will be included in the denominator and 
presented as a separate category if not otherwise specified in the SAP.
In general, the last measurement prior to randomization will serve as the baseline measurement.  
If such a value is missing, the last measurement prior to the first trial drug administration will be 
used as the baseline measurement.
Statistical analyses will be performed using SAS® version 9.3 or higher.
8.5.2
Analysis of Primary Endpoints
Primary Analysis
The primary statistical comparisons of Arm A vs Arm B will be performed with the FAS.  The 
primary statistical comparison of Arm C vs Arm B will be performed with the mFAS to ensure a 
randomized comparison of treatment arms that is not impacted by the time of randomization.
The primary endpoints of this trial are PFS and OS.  The primary analysis will compare the PFS
and OS time between the 2 investigational treatment groups (Arm A, Arm C) vs the control group 
(Arm B) independently, and will be performed using a one-sided stratified log rank test at the 
global = 0.025 (one-sided).  The stratification factors are those used for randomization as 
captured via the IWRS (NSCLC histology:  squamous versus non-squamous cell, and PD-L1 
tumor expression: low expression versus moderate versus high expression).  Missing PD-L1 
expression classification for subjects enrolled prior to Amendment 3 will be imputed from the 
results of the Dako PD-L1 immunohistochemistry (IHC) pharmDx companion diagnostic test.
A hierarchical testing strategy will be applied to test superiority of either avelumab regimen vs 
SOC chemotherapy for the primary endpoints PFS and OS. The FAS will be used for the 
comparisons of Arm A and Arm B and mFAS will be used for the comparison of Arm C and Arm 
B:
Hierarchy Step 1: PFS and OS in the high expression PD-L1+ population 
Hierarchy Step 2: PFS and OS in the moderate and high expression PD-L1+ population 
(including high expression PD-L1+ population) 
Hierarchy Step 3: OS in the any expression PD-L1+ population
A closed testing procedure will be used with weighted Bonferroni tests according to Hommel, 
Bretz, Maurer 2007 to account for multiplicity. For the closure test, it holds: an intersection 
hypothesis Hi can only be rejected if all intersection hypotheses implying HI can also be rejected 
by their local tests. 
The following procedure is used:
All hypotheses comparing Arm C vs Arm B get three times the weight of the hypotheses 
comparing Arm A vs Arm B, ie, weight ¾ and ¼.  Corresponding hypotheses for PFS and OS 
get different weights, ie, 2/3 for PFS and 1/3 for OS.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
125/154
Exception: 
as 
long 
as 
an 
hypothesis 
with 
PD-L1 
high 
expression 
(H0_1A,H0_2A,H0_1C,H0_2C) is included in an intersection hypothesis the corresponding 
hypotheses for PD-L1 moderate and high expression (H0_3A,H0_4A,H0_3C,H0_4C) and all 
hypotheses for any PD-L1+ (H0_6A,H0_6C ) get weight 0, as long as both hypotheses (PFS 
and OS) with PD-L1 moderate expression (H0_3A,H0_4A and H0_3C,H0_4C) is included in 
an intersection hypothesis the corresponding OS hypotheses for any PD-L1+ (H0_6A and 
H0_6C) get weight 0.
For hypotheses with interim analyses the corresponding significance levels at interim and final 
analysis are defined based on -spending approaches using local significance levels according 
to 1 and 2.
Sum of the weights for each intersection hypothesis is 1.
The following figure provides an exemplary overview of the statistical testing procedure.
Figure 3
Exemplary Inferential Testing Procedure 
OS: overall survival; PFS: progression free survival.
Note: Arm A vs Arm B should read p<0.00417
The statistical hypotheses are described below. The significance levels noted are the minimum 
significance levels that can to be used for the corresponding hypothesis. Depending on the already 
rejected hypothesis according to closed testing procedure above the local significance level might 
increase.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
126/154
Hierarchy Step 1: Comparisons for high expression PD-L1+ population
PFS for high expression PD-L1+ in the FAS: Arm A versus B comparison at α = 0.00417 or 
above according to closed testing procedure
H0_1A: 1A(t) = 1h1B(t), 1h ≥ 1, versus H1_1A: 1B(t)=h1C(t), 1h < 1,
OS for high expression PD-L1+ in the FAS: Arm A versus B comparison at α = 0.00208 or 
above according to closed testing procedure
H0_2A: 2A(t) = 2h2B(t), 2h ≥ 1, versus H1_2A: 2A(t)=2h2B(t), 2h < 1,
PFS for high expression PD-L1+ in the mFAS: Arm C versus B comparison at α = 0.0125
or above according to closed testing procedure
H0_1C: 1C(t) = 1h1B(t), 1h ≥ 1, versus H1_1C: 1B(t)=1h1B(t), 1h < 1,
OS for high expression PD-L1+ in the mFAS: Arm C versus B comparison at α = 0.00625
or above according to closed testing procedure
H0_2C: 2C(t) = 2h2B(t), 2h ≥ 1, versus H1_2C: 2C(t)=2h2B(t), 2h < 1,
If local significant results are obtained in Hierarchy Step 1, inferential testing will proceed to 
corresponding hypotheses in Hierarchy Step 2.
Hierarchy Step 2: Comparisons for moderate and high expression PD-L1+ population
PFS for moderate and high expression PD-L1+ in the FAS: Arm A versus B comparison at 
α = 0.00417 or above according to closed testing procedure
H0_3A: 3A(t) = 3m3B(t), 3m ≥ 1, versus H1_3A: 3A(t)=3m3B(t), 3m < 1,
OS for moderate and high expression PD-L1+ in the FAS: Arm A versus B comparison at 
α = 0.00208 or above according to closed testing procedure
H0_4A: 4A(t) = 4m4B(t), 4m ≥ 1, versus H1_4A: 2A(t)=4m4B(t), 4m < 1,
PFS for moderate and high expression PD-L1+ in the mFAS: Arm C versus B comparison 
at α = 0.00125 or above according to closed testing procedure
H0_3C: 3C(t) = 3m3B(t), 3m ≥ 1, versus H1_3C: 3C(t)=3m3B(t), 3m < 1,
OS for moderate and high expression PD-L1+ in the mFAS: Arm C vs B comparison at 
α = 0.00625 or above according to closed testing procedure
H0_4C: 4C(t) = 4m4B(t), 4m ≥ 1, versus H1_4C: 4C(t)=4m4B(t), 4m < 1,
If local significant results are obtained for Hierarchy 2, inferential testing will proceed to 
corresponding hypotheses in Hierarchy 3.
Hierarchy Step 3: Comparisons for low expression PD-L1+ population: 


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
127/154
OS for low expression PD-L1+ in the FAS: Arm A versus B comparison at α = 0.00208 or 
above according to closed testing procedure
H0_6A: 6A(t) = 6ll6B(t), 6l ≥ 1, versus H1_6A: 6A(t)=6l6B(t), 6l < 1,
OS for any expression PD-L1+ in the mFAS: Arm C vs B comparison at α = 0.00625 or 
above according to closed testing procedure
H0_6C: 6C(t) = 6ll6B(t), 6l ≥ 1, versus H1_6C: 6C(t)=6l6B(t), 6l < 1,
Interim analyses are planned for PFS and OS based on required OS events and minimum follow-up 
time of 10 months for the high expression PD-L1+ population.  Interim and final analysis for PFS
and OS will be conducted at the same time.  Alpha will be spent according to Lan-DeMets with 
O’Brien-Fleming-like boundaries with the local significance level at the first hierarchy step.  
Further details are given in Section 8.6.
The treatment effect will be estimated using a Cox’s Proportional Hazard model stratified by the 
randomization strata to calculate the HR and its CI with a confidence level in line with the local 
significance level. In addition 95% CIs will be provided.  Each stratum will define a separate
baseline hazard function.  Ties will be handled by replacing the proportional hazards model by the 
discrete logistic model.
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment group together 
with a summary of associated statistics including the median PFS and OS time with two-sided 
95% CIs.  In particular, the PFS rate at 6, 9, 12 and 15 months and OS rate at 12, 18, 24 and 
30 months will be estimated with corresponding CIs.  The CIs for the median will be calculated 
according to Brookmeyer and Crowley (41) and the CIs for the survival function estimates at the 
time points defined above will be derived using the log-log transformation according to 
Kalbfleisch and Prentice (42).  The estimate of the standard error will be computed using 
Greenwood’s formula.
The proportional hazards assumption for the primary analysis will be visually checked by plotting 
log(-log[survival]) versus log(time) by treatment arm. The frequencies of event types and reasons 
for censoring will be assessed by treatment arm in terms of descriptive statistics.
Sensitivity analyses will be detailed in the SAP.
Time of Follow-Up for PFS
A Kaplan-Meier plot will be created for both treatment groups to compare the duration of 
follow-up for PFS using the following censoring rules.


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 8 / 1 5 4
T a ble 1 4
Ce ns ori n g R ules f or D ur ati o n of Pr o gressi o n Free S ur vi v al F oll o w -u p
D at e of E v e nt / C e n s ori n g
C e n s ori n g
S u bj e ct s ali v e a n d wit h o ut di s e a s e 
pr o gr e s si o n
Ti m e fr o m r a n d o mi z ati o n t o l a st d at e k n o w n t o b e 
pr o gr e s si o n fr e e ( a c c or di n g t o I R C)
N o 
S u bj e ct s w h o pr o gr e s s e d or di e d 
Ti m e fr o m r a n d o mi z ati o n t o d at e of P D or d e at h
Y e s
I R C: I n d e p e n d e nt R e vi e w C o m mitt e e; P D: pr o gr e s si v e di s e a s e.
8. 5. 3
A n al ysis of Sec o n d ar y E n d p oi nts
Ot her s ec o n dar y efficac y a nalys es o n B O R will be perf or me d o n t he F A S a n d m F A S a nal ysis set
res pecti vely f or t he P D -L 1 a nal ys is sets.  Details will be pr o vi de d i n t he trial S A P. 
Ti me of f oll o w -u p will be calc ulate d fr o m t he ra n d o mizati o n date a n d t he date t he s u bject was last 
k n o w n t o be ali ve .  F or s u bjects w h o die d, t i me of f oll o w -u p will be ce ns ore d o n t he date of deat h. 
A Ka pla n -Meier 
pl ot will be create d f or b ot h treat me nt gr o u ps t o c o m pare t he d urati o n of 
f oll o w- u p.
F or t he sec o n dar y en d p oi nt a nal ysis of B O R acc or di n g t o R E CI S T 1. 1 a n d as a dj u dicate d b y  the 
I R C, the O R R i n ter ms of ha vi n g a c o nfir me d B O R of C R or P R will be calc ulate d al o n g wit h
c orres p o n di n g t w o-si de d e xact Cl o p per -Pears o n CI s acc or di n g t o l ocal si g nifica nce le vel a n d 9 5 % 
CI  for t he 2 treat me nt gr o u ps. T he C oc hra n -Ma ntel -Hae nszel test will be perf or me d wit h t he 
ra n d o mizati o n strata ta ke n i nt o acc o u nt t o c o m pare t he O R R bet wee n t he 2 treat me nt gr o u ps.
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 9 / 1 5 4
C CI


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 0 / 1 5 4
8. 5. 5
A n al ysis of S afet y E n d p oi nts
T he e xte nt of e x p os ure t o trial dr u gs (a vel u ma b or c he m ot hera p y) will be c haracterize d b y  durati o n 
( wee ks), n u m ber of a d mi nistrati o ns, c u m ulati ve d ose, d ose i nte nsity, relati ve d ose i nte nsity ( act ual 
d ose gi ve n / pla n ne d d ose), a n d n u m ber of d ose dela y s.
Safet y  anal ys es will be perf or me d o n t he Safet y a nal ysis set.  Th e safety e n d p oi nts will be ta b ulate d 
usi n g descri pti ve statistics.
Safet y  assess me nts will be base d o n re vie w of t he i nci de nce of A Es i ncl u di n g A E SIs, A D Rs, a n d 
c ha n ges i n vital si g ns, E C Gs, b o d y  wei g ht, a n d la b orat or y val ues ( he mat ol o g y an d ser u m 
c he mistr y) .
T he o n -treat me nt peri o d is defi ne d as t he ti me fr o m t he first trial dr u g a d mi nistrati o n t o t he last 
dr u g a d mi nistrati o n date + 3 0 d a y s or t he earliest date of s u bse q ue nt a ntica ncer dr u g t hera p y mi n us 
1 da y , w hic he ver occ urs first, u nless ot her wise state d.
A Es
All A Es will be c o de d acc or di n g t o t he Me d D R A.  Se verit y of A Es will be gra de d usi n g t he 
N CI -C T C A E v 4. 0 3 t o xicit y  gra di n g scale. 
T he i nci de nce of T E A Es, re gar dless of attri b uti o n, a n d T E A Es defi ne d as p ossi bl y  relate d t o trial 
treat me nt will be s u m marize d b y  Preferre d Ter m a n d S yste m Or ga n Class f or eac h treat me nt ar m, 
a n d descri be d i n ter ms of i nte nsit y an d relati o ns hi p t o trial treat me nt.  Treat me nt-e mer ge nt A Es 
are t h ose e ve nts wit h o nset dates occ urri n g d uri n g t he o n- treat me nt peri o d or if t he w orse ni n g of 
a n e ve nt is d uri n g t he o n -treat me nt peri o d.  An y  AEs wit h a n o nset or w orse ni n g date after t he 
o n- treat me nt peri o d will be re p orte d se parately.
All pre mat ure ter mi nati o ns will be s u m marize d b y  pri mar y reas o n f or treat me nt disc o nti n uati o n / 
w it h dra wal.
L a b or at or y v ari a bles 
La b orat or y  res ults will be classifie d b y  gra de acc or di n g t o N CI -C T C A E v 4. 0 3.  The w orst 
o n- treat me nt gra des d uri n g t he treat me nt peri o d will be s u m marize d.  Shifts i n t o xicit y gra di n g 
fr o m ra n d o mizati o n t o hi g hest gra de d uri n g t he o n-treat me nt peri o d will be dis pla ye d.  Res ults f or 
varia bles t hat are n ot part of N CI -C T C A E will be prese nte d as bel o w, wit hi n, or a b o ve n or mal 
C CI


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 1 / 1 5 4
li mits.  Onl y  su bjects wit h p ost -Baseli ne la b orat or y val ues will be i ncl u de d i n t hese a nal ys es.  
F urt he r details of a nal yses f or all t he la b orat or y para meters will be pr o vi de d i n t he S A P. 
P h ysic al e x a mi n ati o n (i ncl u di n g vit al si g ns a n d 1 2 -le a d E C Gs)
P h y sical e xa mi nati o n data, i ncl u di n g vital si g ns ( b o d y te m perat ure, res pirat or y rate, heart rate, a n d 
bl o o d press ure) a n d 1 2 -lea d E C Gs rec or de d acc or di n g t o t he Sc he d ule of Assess me nts (Ta ble 1 t o 
Ta ble 4 ) will be prese nte d. 
F urt her details of safet y a nal yses will be pr o vi de d i n t he S A P .
8. 5. 6
S u b gr o u p A n al yses
S u b gr o u p a nal ys es will be perf or me d o n t he pri mar y  en d p oi nt s a n d sec o n dar y efficac y en d p oi nts 
wit h t he s u b gr o u ps, w hic h will be s pecifie d i n t he S A P.  F or P F S a n d O S a nal yses, t he H R a n d its 
c orres p o n di n g 9 5 % CI  will be c o m p ute d per s u b gr o u p le vel.  To assess t he heter o ge neit y of 
treat me nt effects acr oss t he s u b gr o u p le vels, a C o x re gressi o n m o del will be fitte d wit h t he e ve nt 
ti me as t he de pe n de nt varia ble; s u b gr o u p, treat me nt, a n d wit h a n d wit h o ut t he treat me nt-b y -
s u b gr o u p i nteracti o n as e x pla nat or y varia bles.  A p -val ue f or t he i nteracti o n test ( Li keli h o o d Rati o 
test) will be pr o vi de d t o get her wit h t he H R a n d c orres p o n di n g 9 5 % CI  of t he i nteracti o n m o del 
para meter.   F or t he sec o n dar y en d p oi nt of B O R, a nal o g o us a nal ys es will be perf or me d usi n g a 
l o gistic re gressi o n m o del.
S u b gr o u p a nal ysis t o e x pl ore t he effect size bet wee n Ar m A a n d Ar m B will be perf or me d wit h 
t he F A S, a n d m F A S f or Ar m C a n d Ar m B.
8. 6
I nteri m A n al ys is
I nteri m a nal ys es are pla n ne d after recr uit me nt ha ve bee n c o m plete d f or P F S a n d O S base d o n 
re q uire d e ve nts f or t he hi g h e x pressi o n P D -L 1  po p ulati o n.  Interi m a nal ys is f or P F S a n d O S wil l 
be c o n d ucte d base d o n re q uire d n u m ber of e ve nts f or Ar m B a n d C i n t he hi g h e x pressi o n P D -L 1 + 
p o p ulati o n. La n -De Mets α- s pe n di n g wit h O’ Brie n -Fle mi n g -li ke b o u n daries will be c o nsi dere d
gi ve n t he l ocal si g nifica nce le vels at t he first h ierarc hy ste p. T he e xact ti mi n g a n d t he e ve nt size 
will be c o nfir me d i n t he S A P.   N o f utilit y  a nalys is is pla n ne d.
T he i nteri m a nal ys is will test t he h y p ot heses f or P F S: H 0 _ 1 A, H 0 _ 1 C, H 0 _ 3 A, H 0 _ 3 C a n d t he hy p ot heses 
f or O S: H 0 _ 2 A, H 0 _ 2 C, H 0 _ 4 A, H 0 _ 4 C, H 0 _ 6 A, H 0 _ 6 C after t he re q uire d n u m ber of O S e ve nts f or t he i nteri m
a nal ys is f or Ar m C + B ha ve bee n reac he d a n d 1 0 m o nt hs ha ve ela pse d fr o m t he last s u bject
ra n d o mize d f or t he hi g h e x pressi o n P D-L 1  a nalys is set i n m F A S (see  Ta ble 1 6) .
Pri mar y  P F S a n d O S a nal y ses will be c o n d ucte d after t he re q uire d n u m ber of O S e ve nts f or Ar m 
C + B ha ve bee n reac he d a n d at least 2 0 m o nt hs ha ve bee n ela pse d fr o m last s u bject ra n d o mize d 
f or t he hi g h e x pressi o n P D-L 1 a nal ys is set i n m F A S. T he c urre nt pla n c o nsi ders
C CI


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
132/154

130 OS events for Arm C and B and a minimum follow-up of 10 months to determine the 
cut-off date for the interim PFS and OS analyses.

173 OS events and a minimum follow-up of 20 months for the final PFS and OS analyses.
Table 16 describes the expected number of events, information fraction, the associated cumulative 
alpha spending and the corresponding expected efficacy boundaries, under proportional hazard 
assumptions. The actual numbers in particular for the Arm A and B could vary as the event size at 
the planned cut-off dates is unknown. The alpha levels are however fixed according to Lan-DeMets 
α-spending with O’Brien-Fleming-like boundaries. Details will be confirmed in the SAP.
Table 16
Interim Analyses
Primary Inferential 
Analyses
(high expression PD-L1)
Expected 
number of 
events
Information 
fraction
Cumulative alpha 
spent
Efficacy boundary 
HR
IA – PFS 
Arm A vs. B (FAS)
228
91%
0.0026994
0.69
Arm C vs. B (mFAS)
146
84%
0.0063969
0.66
Final PFS
Arm A vs. B (FAS)
250
100%
0.004170
0.71
Arm C vs. B (mFAS)
174
100%
0.012500
0.70
IA – OS
Arm A vs. B (FAS)
214
83%
0.0007241
0.64
Arm C vs. B (mFAS)
130
75%
0.001609
0.60
Final OS
Arm A vs. B (FAS)
258
100%
0.002080
0.69
Arm C vs. B (mFAS)
173
100%
0.006250
0.68
FAS: full analysis set, HR: hazard ratio, IA: interim analysis, mFAS: modified full analysis set, OS: overall survival, 
PFS: progression free survival.
An IDMC will be formed and will be responsible for periodic evaluations of the trial including 
interim analyses and PFS and OS event monitoring. Details of the IDMC mission, composition, 
and operations will be provided in the IDMC charter.
9
Ethical and Regulatory Aspects
9.1
Responsibilities of the Investigator
The Investigator is responsible for the conduct of the trial at his / her site.  He / she will ensure that 
the trial is performed in accordance with the clinical trial protocol and with the ethical principles 
that have their origin in the Declaration of Helsinki, as well as with the ICH Note for Guidance on 
GCP (ICH Topic E6, 1996) and applicable regulatory requirements.  In particular, the Investigator 
must ensure that only subjects who have given their informed consent are included in the trial.


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 3 / 1 5 4
Acc or di n g t o U nite d States C o de of Fe deral Re g ulati o ns Part 5 4. 2 (e), f or trials c o n d uct e d i n a n y 
c o u ntr y that c o ul d res ult i n a pr o d uct s u b missi o n t o t he U nite d States F o o d a n d Dr u g 
A d mi nistrati o n f or mar keti n g a p pr o val a n d c o ul d c o ntri b ute si g nifica ntl y  t o t he de m o nstrati o n of 
efficac y an d safet y of a n I MP ( w hic h are c o nsi dere d “c o vere d clinical trials” b y  the F D A), t he 
I n vesti gat or a n d all s u bi n vesti gat ors are o bli ge d t o discl ose a n y fi na ncial i nterest w hic h t he y, t heir 
s p o uses or t heir de pe n de nt c hil dre n m a y  ha ve i n t he S p o ns or or t he S p o ns or’s pr o d uct u n der st u d y. 
T his i nf or mati o n is re q u ire d d uri n g t he trial a n d f or 1 2 m o nt hs f oll o wi n g c o m pleti o n of t he trial.
9. 2
S u bject I nf or m ati o n a n d I nf or me d C o nse nt
A n u nc o n diti o nal prere q uisite f or a s u bject’s partici pati o n i n t he trial is his / her writte n i nf or me d 
c o nse nt.  The s u bject’s writte n i nf or me d c o nse nt t o partici pate i n t he trial m ust be gi ve n bef ore 
a n y trial-relate d acti vities are carrie d o ut.   A se parate s pecific 
 I CF will be pr o vi de d t o s u bjects 
w h o are willi n g t o partici pate i n t his o pti o nal pr oce d ure, w hic h refers t o t he e xtract i o n a n d a nal ysis 
of ger mli ne D N A fr o m bl o o d i n or der t o better u n dersta n d h o w ge ne(s) ma y affect t he efficac y of 
a vel u ma b.
A de q uate i nf or mati o n m ust t heref ore be gi ve n t o t he s u bject b y  the I n vesti gat or bef ore i nf or me d 
c o nse nt is o btai ne d (a pers o n desi g na te d b y  the I n vesti gat or m a y  gi ve t he i nf or mati o n, if per mitte d 
b y  local re g ulati o ns).  A su bject i nf or mati o n s heet i n t he l ocal la n g ua ge a n d pre pare d i n acc or da nce 
wit h t he N ote f or G ui da nce o n G C P (I C H T o pic E 6, 1 9 9 6) will be pr o vi de d b y t he S p o ns or f or the 
p ur p ose of o btai ni n g i nf or me d c o nse nt.  In a d diti o n t o pr o vi di n g t his writte n i nf or mati o n t o a 
p ote ntial s u bject, t he I nvesti gat or or his / her desi g nate will i nf or m t he s u bject ver ball y  of all 
perti ne nt as pects of t he trial.  The la n g ua ge use d i n d oi n g s o m ust be c h ose n s o t hat t he i nf or mati o n 
ca n be f ull y a n d rea dil y u n derst o o d b y la y  pers o ns. 
De pe n di n g o n nati o nal re g ulati o ns, a pers o n ot her t ha n t he I n vesti gat or m a y  inf or m t he s u bject 
a n d si g n t he I CF, as a b o ve.
W here t he i nf or mati o n is pr o vi de d b y  t he I n vesti gat or, t he I C F m ust be si g ne d a n d pers o nall y 
date d b y t he s u bject a n d t he I n vesti gat or. 
T he si g ne d a n d date d declarati o n of i nf or me d c o nse nt will re mai n at t he I n vesti gat or’s site, a n d 
m ust be safel y arc hi ve d b y  the I n vesti gat or s o t hat t he f orms ca n be retrie ve d at a n y ti me f or 
m o nit ori n g, a u diti n g, a n d i ns pecti o n p ur p oses.  A co p y  of t he si g ne d a n d date d i nf or mati o n a n d 
I CF s h o ul d be pr o vi de d t o t he s u bject pri or t o partici pati o n.  Whe ne ver i m p orta nt ne w i nf or mati o n 
bec o mes a vaila ble t hat ma y  be rele va nt t o t he s u bject’s c o nse nt, t he writte n s u bject i nf or mati o n 
s heet a n d a n y ot her writte n i nf or mati o n pr o vi de d t o s u bjects will be re vise d b y  the S p o ns or or 
desi g nee a n d be s u b mitte d a gai n t o t he I E C / I RB f or re vie w a n d fa v ora ble o pi ni o n.  T he a gr ee d, 
re vise d i nf or mati o n will be pr o vi de d t o eac h s u bject i n t he trial f or si g ni n g a n d dati n g.  The 
I n vesti gat or will e x plai n t he c ha n ges t o t he pre vi o us versi o n.
9. 3
S u bject I de ntific ati o n a n d Pri v ac y
A u ni q ue s u bject n u m ber will be assi g ne d t o eac h s u bject at i ncl usi o n b y  the I WR S s yste m, 
i m me diatel y after i nf or me d c o nse nt has bee n o btai ne d.  This n u m ber will ser ve as t he s u bject’s 
i de ntifier i n t he trial as well as i n t he cli nical trial data base.
C CI


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
134/154
The subject’s data collected in the trial will be stored under this number.  Only the Investigator 
will be able to link the subject’s trial data to the subject via an identification list kept at the site.  
The subject’s original medical data that are reviewed at the site during source data verification by 
the Clinical Trial Monitor, audits, and Health Authority inspections will be kept strictly 
confidential.
Data protection and privacy regulations will be observed in capturing, forwarding, processing, and 
storing subject data.  Subjects will be informed accordingly and will be requested to give their 
consent on data handling procedures in accordance with national regulations.
9.4
Emergency Medical Support and Subject Card
Subjects randomized into this clinical trial will be provided with Emergency Medical Support 
cards during their trial participation, which will be furnished by the Sponsor or designee.  The 
Emergency Medical Support card is based on the need to provide clinical trial subjects with a way 
of identifying themselves as participating in a clinical trial, and subsequently to give health care 
providers access to the information about this participation that may be needed to determine the 
course of the subject’s medical treatment.
This service is designed to provide information to health care providers who are not part of the 
clinical trial.
Clinical trial Investigators, who are already aware of the clinical trial protocol and treatment, have 
other means of accessing the necessary medical information for the management of emergencies 
occurring in their subjects.
The first point of contact for all emergencies will be the clinical trial Investigator caring for the 
affected subject.  The Investigator agrees to provide his or her emergency contact information on 
the card for this purpose.  If the Investigator is available when an event occurs, she or he will 
answer any questions.  Any subsequent action will follow the standard processes established for 
the Investigators.
In cases where the Investigator is not available, Merck KGaA / EMD Serono R&D or designee 
will provide the appropriate means to contact a Sponsor physician.  This includes the provision of 
a 24-hour contact number at a call center, whereby the health care providers will be given access 
to the appropriate Sponsor physician to assist with the medical emergency and to provide support 
for the subject concerned.
9.5
Clinical Trial Insurance and Compensation to Subjects
Insurance coverage will be provided for each country participating to the trial.  Insurance 
conditions shall meet good local standards, as applicable.
9.6
Independent Ethics Committee or Institutional Review Board
Prior to commencement of the trial at a given site, the clinical trial protocol will be submitted 
together with its associated documents (such as the ICF) to the responsible IEC / IRB for its 


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
135/154
favorable opinion / approval.  The written favorable opinion / approval of the IEC / IRB will be 
filed in the Investigator Site File, and a copy will be filed with the CRO.
The trial must not start at a site before the Sponsor or designee has obtained written confirmation 
of favorable opinion / approval from the concerned IEC / IRB.  The IEC / IRB will be asked to 
provide documentation of the date of the meeting at which the favorable opinion / approval was 
given, and of the members and voting members present at the meeting.  Written evidence of 
favorable opinion / approval that clearly identifies the trial, the clinical trial protocol version, and 
the Subject Information and ICF version reviewed should be provided.  Where possible, copies of 
the meeting minutes should be obtained.
Amendments to the clinical trial will also be submitted to the concerned IEC / IRB before 
implementation in case of substantial changes (see Section 10.5).  Relevant safety information will 
be submitted to the IEC / IRB during the course of the trial in accordance with national regulations 
and requirements.
9.7
Health Authorities
The clinical trial protocol and any applicable documentation (for example, Investigational 
Medicinal Product Dossier, Subject Information and Informed Consent Form) will be submitted 
or notified to the Health Authorities in accordance with all local and national regulations for each 
site.
10
Trial Management
10.1
Case Report Form Handling
The Investigator or designee will be responsible for entering trial data in the eCRF provided by 
the CRO and follow the data entry guidelines.  It is the Investigator’s responsibility to ensure the 
accuracy of the data entered in the eCRFs and to sign the case report forms.
The data will be entered into a validated database.  The CRO will follow the standards of the 
Sponsor in the database design and data structure.  The CRO will be responsible for data review 
and processing, in accordance with the CRO’s data management procedures.  Database lock will 
occur once quality control procedures and quality assurance procedures (if applicable) have been 
completed.  Copies of the eCRFs will be provided to the Investigators at the completion of the 
trial.
10.2
Source Data and Subject Files
The Investigator must keep a file (medical file, original medical records) on paper or electronically 
for every subject in the trial.  It must be possible to identify each subject by using this subject file.  
This file will contain the demographic and medical information for the subject listed below and 
should be as complete as possible. 
Subject’s full name, date of birth, sex, race, height, weight
Medical history and concomitant diseases


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
136/154
Prior and concomitant therapies (including changes during the trial)
Trial identification, that is, the Sponsor trial number for this clinical trial, and subject number
Dates for entry into the trial (informed consent) and visits to the site
Any medical examinations and clinical findings predefined in this clinical trial protocol
All AEs
Date that the subject left the trial including any reason for early withdrawal from the trial or 
IMP (if applicable).
Additionally, any other documents containing source data must be filed.  This includes original 
printouts of data recorded or generated by automated instruments, photographic negatives, X-rays, 
CT or MRI scan images, ECG recordings, laboratory value listings, etc.  Such documents must 
include at least the subject number and the date when the procedure was performed.  Information 
should be printed by the instrument used to perform the assessment or measurement, if possible.  
Information that cannot be printed by an automated instrument will be entered manually.  Medical 
evaluation of such records should be documented as necessary and the documentation signed and 
dated by the Investigator.
10.3
Investigator Site File and Archiving
The Investigator will be provided with an Investigator Site File upon initiation of the trial.  This 
file will contain all documents necessary for the conduct of the trial and will be updated and 
completed throughout the trial.  It must be available for review by the Monitor, and must be ready 
for Sponsor audit as well as for inspection by Health Authorities during and after the trial, and 
must be safely archived for at least 15 years (or per local requirements or as otherwise notified by 
the Sponsor) after the End of Trial.  The documents to be archived include the Subject 
Identification List and the signed subject ICFs.  If archiving of the Investigator Site File is no 
longer possible at the site, the Investigator must notify the Sponsor.
All original subject files (medical records) must be stored at the site (hospital, research institute, 
or practice) for the longest possible time permitted by the applicable regulations, and / or as per 
ICH GCP guidelines, whichever is longer.  In any case, the Investigator should ensure that no 
destruction of medical records is performed without the written approval of the Sponsor.
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities
This trial will be monitored in accordance with the ICH Note for Guidance on GCP (ICH Topic 
E6, 1996).  The Clinical Trial Monitor will perform visits to the trial site at regular intervals.
Representatives of the Sponsor’s Quality Assurance unit or a designated organization, as well as 
Health Authorities, must be permitted to inspect all trial-related documents and other materials at 
the site, including the Investigator Site File, the completed eCRFs, the trial drug, and the subjects’ 
original medical records / files.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
137/154
The clinical trial protocol, each step of the data capture procedure, and the handling of the data, 
including the final clinical trial report, will be subject to independent quality assurance activities.  
Audits may be conducted at any time during or after the trial to ensure the validity and integrity of 
the trial data.
10.5
Changes to the Clinical Trial Protocol
Changes to the clinical trial protocol will be documented in written protocol amendments.  Major 
(substantial, significant) amendments will usually require submission to the Health Authorities and 
to the relevant IEC / IRB for approval or favorable opinion.  In such cases, the amendment will be 
implemented only after approval or favorable opinion has been obtained.
Minor (nonsubstantial) protocol amendments, including administrative changes, will be filed by 
the Sponsor and at the site.  They will be submitted to the relevant IEC / IRB or to Health 
Authorities only where requested by pertinent regulations.
Any amendment that could have an impact on the subject’s agreement to participate in the trial 
requires the subject’s informed consent prior to implementation (see Section 9.2).
10.6
Clinical Trial Report and Publication Policy
10.6.1
Clinical Trial Report
After completion of the trial, a clinical trial report will be written by the Sponsor in consultation 
with the coordinating Investigator following the guidance in ICH Topic E3.
10.6.2
Publication
The first publication will be a publication of the results of the analysis of the primary endpoint(s) 
that will include data from all trial sites.
The Investigator will inform the Sponsor in advance about any plans to publish or present data 
from the trial.  Any publications and presentations of the results (abstracts in journals or 
newspapers, oral presentations, etc.), either in whole or in part, by Investigators or their 
representatives will require presubmission review by the Sponsor.
The Sponsor will not suppress or veto publications, but maintains the right to delay publication in 
order to protect intellectual property rights.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
138/154
11
References Cited in the Text
1. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47.
2. Ferlay J, Foucher ES, Tieulent J, et al. Cancer Incidence and Mortality Patterns in Europe: 
Estimates for 40 countries in 2012. Euro J of Canc 2013; 49:1374-1403.
3. http//seer.cancer.gov/statfacts/html/lung.html.
4. Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung 
cancer. BMJ 1995;311(7010):899-909.
5. NSCLC Collobarative Group 1995. Reference available upon request.
6. www.nccn.org
7. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: 
a potential mechanism of immune evasion. Nat Med 2002; 8:793-800. [Erratum, Nat Med 
2002;8:1039.
8. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate 
anti-tumor immunity. Curr Opin Immunol 2012;24:207-12.
9. Iwai Y, Ishida M, Tanaka Y, et al. Involvement of PD-L1 on tumor cells in the escape from 
host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA 
2002;99:12293-97.
10. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (Anti-PD-
1) in melanoma. N Engl J Med 2013;369:134-44.
11. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients 
with advanced cancer. N Engl J Med 2012;366(26):2455-65.
12. Velcheti V, Schalper KA, Carvajal DE, et al. Programmed death ligand-1 expression in non-
small cell lung cancer. Lab Invest 2014;94:107-16.]
13. Chen YB, Mu CY, Huang JA. Clinical significance of programmed death-1 ligand-1 
expression in patients with non-small cell lung cancer: a 5-year-follow-up study. Tumori 
2012;98(6):751-55.
14. Brahmer J, Reckamp K, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell 
non-small-cell lung cancer. N Engl J Med 2012;ePub May 31 2015.
15. Latchman Y, Wood CR, Chernova T, et al. PD-L1 is a second ligand for PD-1 and inhibits T 
cell activation. Nat Immunol 2001;2(3):261-68.
16. Gettinger SN, Shepherd F, Antonia J, et al. First-line nivolumab (Anti-PD-1; BMS-936558, 
ONO-4538) monotherapy in advanced NSCLC; safety, efficacy and correlation of outcomes 
with PD-L1 status. J Clin Oncol 2014 (suppl; abstr 8024):32-5s
17. (ASCO 2016; abstract 9036).
18. Gettinger et al. Nivolumab Monotherapy for First-Line Treatment of Advanced Non–Small-
Cell Lung Cancer. J.Clin.Oncology; Vol 34, No 25, September 1 2016.
19. Hui et al. Long Term OS for patients with advanced NSCLC. Enrolled in KEYNOTE-001. 
ASCO 2016.
20. Guidance for Industry, Clinical Trial Endpoints for the Approval of Non-Small Cell Lung 
Cancer Drugs and Biologics. Center for Drug Evaluation and Research (CDER), US 
Department of Health and Human Services, Food and Drug Administration. 2011.
21. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity 
in solid tumors: Immune-related response criteria. Clin Cancer Res 2009;15:7412-20.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
139/154
22. Eberhard DA, Johnson BE, Amler LC, et al. Mutations in the epidermal growth factor receptor 
and in KRAS are predictive and prognostic indicators in patients with non-small cell lung 
cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Onc 2005; 
2 :5900-09.
23. Mok TS, Wu Y, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary 
adenocarcinoma. N Engl J Med 2009;361 :947-57.
24. Shaw AT, Varghese AM, Solomon FJ, et al. Pemetrexed-based chemotherapy in patients with 
advanced, ALK-positive non-small cell lung cancer. Annals of Oncology 2013;24:59-66.
25. Wahbah M, Boroumand N, Castro C, et al. Changing trends in the distribution of the histologic 
types of lung cancer: a review of 4439 case. Ann Diagn Pathol 2007; 11:89-96.
26. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus 
gemcitabine with cisplatin plus pemetrexed in chemotherapy-naïve patients with advanced 
stage non-small cell lung cancer. J Clin Oncol 2008. Jul 20; 26(21):3543-51. Epub 2008 
May 27.
27. Fossella FV, DeVore R, Kerr RN, et al. Randomized Phase II trila of docetaxel versus 
vinorelbine or ifsofamide in subjects with advanced non-small-cell lung cancer previously 
treated with platinum-containing chemotherapy. J Clin Oncol 2000; 18:2354-62. 
28. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus 
docetaxel in subjects with non-small-cell lung cancer previously treated with chemotherapy. J 
Clin Oncol 2004; 22:1589-97.
29. Shepherd FA, Pereira JR, Ciuleanu T, et al. Erlotinib in previously treated non-small cell lung 
cancer previously treated with chemotherapy. N Engl J Med 2005; 353:123-32.
30. Peterson P, Park K, Fossella F, et al. Is pemetrexed more effective in adenocarcinoma and large 
cell lung cancer than in squamous cell carcinoma? A retrospective analysis of a phase III trial 
of pemetrexed vs. docetaxel in previously treated patients with advanced non-small cell lung 
cancer (NSCLC). J Thorac Oncol 2007; 2:S851 (abstr. P2-328).
31. Kawase A, Yoshida J, Ishii G, et al. Differences between squamous cell carcinoma and 
adenocarcinoma of the lung: are adenocarcinoma and squamous cell carcinoma prognostically 
equal? Jpn J Clin Oncol 2012; 42:189-95.
32. FDA (2009, draft) Guidance for Industry: Assay Development for Immunogenicity Testing of 
Therapeutic Proteins.
33. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-
small cell lung cancer. N Eng J Med 2006: 355: 2542-50.
34. Patel JD, Socinski MA, Garon EB, et al. PointBreak: A randomized phase III study of 
pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and 
bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance 
bevacizumab in patients with stage IIIB or IV nonsquamous non-small cell lung cancer. J Clin 
Oncol 2013;31(34):4349-57.
35. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line 
treatment for European patients with advanced EGFR mutation-positive non-small-cell 
lungcancer (EURTAC): a multicentre, open-label, randomized phase 3 trial. Lancet Oncol 
2012;13:239-46.
36. Carboplatin Summary of Product Characteristics.
37. Cisplatin Summary of Product Characteristics.
38. Gemcitabine Summary of Product Characteristics.
39. Pemetrexed Summary of Product Characteristics.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
140/154
40. Paclitaxel Summary of Product Characteristics.
41. Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics, 
1982, 38:29-41.
42. Kalbfleisch JD, Prentice, RL (1980). The Statistical Analysis of Failure Time Data. John Wiley 
and Sons: NY.
43. http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
141/154
12
Appendices


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
142/154
Appendix I:
Signature Pages and Responsible Persons for the Trial


C CI
P P D
P P D
P P D
P P D
P P D


P P D
P P D
P P D
C CI


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 5 / 1 5 4
Si g n at ure P a ge – Pri nci p al I n vesti g at or
Tri al Title
A P hase III o pe n -la bel, m ultice nter trial of a vel u ma b
(M S B 0 0 1 0 7 1 8 C) vers us plati n u m -base d d o u blet as a 
first-li ne of treat me nt of rec urre nt or Sta ge I V P D -L 1 + 
n o n- s mall cell l u n g ca ncer
I N D N u m ber
E u dr a C T N u m ber
2 0 1 5- 0 0 1 5 3 7- 2 4
Cli nic al 
Tri al 
Pr ot oc ol 
D ate 
/ 
Versi o n
0 3 Ja n uar y 2 0 1 9 / Versi o n 6. 0
Ce nter N u m ber
Pri nci p al I n vesti g at or
I, t he u n dersi g ne d, a m res p o nsi ble f or t he c o n d uct of t he trial at t his site a n d affir m t hat I 
u n dersta n d a n d will c o n d uct t he trial acc or di n g t o t he cli nical trial pr ot oc ol, a n y a p pr o ve d pr ot oc ol 
a me n d me nts, I nt er nati o nal C o u ncil f or Har m o nisati o n G o o d Cli nical Practice ( T o pic E 6) a n d all 
a p plica ble Healt h A ut h orit y re q uire me nts a n d nati o nal la ws.
I als o affir m t hat I u n dersta n d t hat Healt h A ut h orities ma y re q uire t he S p o ns ors of cli nical trials t o 
o btai n a n d s u p pl y details a b o ut o w ners hi p i nterests i n t he S p o ns or or I nvesti gati o nal Me dici nal 
Pr o d uct a n d a n y  ot her fi na ncial ties wit h t he S p o ns or. T he S p o ns or will use a n y s uc h i nf or mati o n 
s olel y for t he p ur p ose of c o m pl yi n g wit h t he re g ulat or y re q uire me nts. I t heref ore a gree t o s u p pl y 
t he S p o ns or wit h a n y necessar y  inf or mati o n re gar di n g o w ners hi p i nterest a n d fi na ncial ties 
i ncl u di n g t h ose of my s p o use a n d de pe n de nt c hil dre n, a n d t o pr o vi de u p dates as necessar y t o meet 
Healt h A ut h orit y  re q uire me nts.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g nat ure
Date of Si g nat ure
Na me, aca de mic de gree:
F u ncti o n / Title:
I nstit uti o n:
A d dress:
Tele p h o ne n u m ber:
Fa x n u m ber:
E -mail a d dress:
C CI


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 6 / 1 5 4
S p o ns or Res p o nsi ble Pers o ns n ot N a me d o n t he C o ver P a ge
Na me, aca de mic de gree:
F u ncti o n / Title:
I nstit uti o n:
Merc k K Ga A
A d dress:
Fra n kf urter Str. 2 5 0 
6 4 2 9 3 Dar msta dt, Ger ma n y
Tele p h o ne n u m ber:
Fa x n u m ber:
 
E- mail a d dress:
Na me, aca de mic de gree:
F u ncti o n / Title:
Pri nci pal Cli nical Trial Lea d
I nstit uti o n:
Merc k K Ga A
A d dress:
Fra n kf urter Str. 2 5 0
6 4 2 9 3 Dar msta dt, Ger ma n y
Tele p h o ne n u m ber:
Fa x n u m ber:
E- mail a d dress:
P P D
P P D
P P D
P P
D
P P D
P P D
P P D
P P D
P P D


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
147/154
Appendix II: Eastern Cooperative Oncology Group Performance Status
ECOG PSa
Grade
ECOG
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, for example, light house work, office work
2
Ambulatory and capable of all self-care, but unable to carry out any work activities; up and about > 
50% of waking hours
3
Capable of only limited self-care, confined to bed or chair > 50% of waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to bed or chair
5
Dead
ECOG PS=Eastern Cooperative Oncology Group Performance Status.
a
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and Response 
Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5: 649-55. 


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
148/154
Appendix III:Guidance on contraception
Birth control methods considered as highly effective.
According to the Clinical Trials Facilitation Group (CTFG) “Recommendations related to 
contraception and pregnancy testing in clinical trials” methods that can achieve a failure rate of 
less than 1% per year when used consistently and correctly are considered as highly effective birth 
control methods, such as:
- combined (estrogen and progesterone containing) hormonal contraception associated with 
inhibition of ovulation1 (oral, intravaginal, transdermal)
- progesterone-only hormonal contraception associated with inhibition of ovulation1 (oral, 
injectable, implantable2)
- intrauterine device (IUD)2
- intrauterine hormone-releasing system (IUS)2
- bilateral tubal occlusion2
- vasectomized partner2,3
- sexual abstinence4
1Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method
2Contraception methods in the context of this guidance are considered to have low user dependency
3Vasectomised partner is a highly effective birth control method provided that the partner is the sole sexual partner of 
the woman of childbearing potential trial participant and that the vasectomized partner has received medical 
assessment of the surgical success
4In the context of this guidance sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the subject.


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 9 / 1 5 4
A p pe n di x I V: 
Pr ot oc ol A me n d me nts Hist or y
T he i nf or mati o n f or t he c urre nt a me n d me nt is o n t he title pa ge.
A m e n d me nt 4. 0
T his is t he f o urt h a me n d me nt t o t he ori gi nal pr ot oc ol.  
T he k e y  reas o ns ( maj or a n d a d mi nistrati ve c ha n ges) f or t his a me n d me nt are s u m marize d bel o w:

T o u p date t he n u m ber of sites w here t he st u d y will be c o n d ucte d a n d pla n ne d trial peri o d

M o ve
i n Sec o n dar y O bjecti ve s wit h relate d c ha n ge i n Sec o n dar y E n d p oi nts t o E x pl orat or y 
O bjecti ves a n d E n d p oi nts : 
Sec o n dar y O bjecti ve s: T o c haracterize p har mac o ki netics ( P K) of a vel u ma b a n d i n di vi d ual 
dr u g e x p os ures base d o n s parse P K sa m pli n g a n d to c haracterize t he i m m u n o ge nicit y of 
a vel u ma b.
T he sec o n dar y e n d p oi nts f or t he trial: P K of a vel u ma b a n d i m m u n o ge nicit y of a vel u ma b.

T o u p date t he  
 f or t he st u dy

T o u p date t he P D -L 1 t u m or e x pressi o n le vel fr o m a n y  t o l o w

T o re m o ve refere nce t o c o- pri mar y  e n d p oi nts a n d u p date t o pri mar y e n d p oi nts

T o clarif y t hat pre me dicati o n f or a vel u ma b is ma n dat or y f or t he first 4 i nf usi o ns o nl y

T o u p date t he sc he d ules of assess me nt t o matc h t he b o d y of t he pr ot oc ol

T o clarif y t he ti mi n g of S A E c ollecti o n

T o i ncl u de c ollecti o n of f urt her a ntit u m or t hera py at F oll o w- u p

T o clarif y t he nat ure of p h ysical e xa mi nati o n assess me nts

T o u p date t he re q uire me nts o n E C G assess me nts

T o clarif y t he c ollecti o n of T 4 a n d T S H

T o clarif y t hat bl o o d  
 sa m ples will n ot be c ollecte d at sites i n C hi na

T o u p date t he na me of t he C R O fr o m Q ui ntiles t o 

T o u p date t he i nf or mati o n o n pac ka gi n g, distri b uti o n a n d s u p pl y  of cli nical s up plies

T o re m o ve t he deter mi nati o n of date of disease pr o gressi o n b y t he I R C
P P D
C CI
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 0 / 1 5 4

T o u p date o n g oi n g cli nical st u dies i n a vel u ma b

T o u p date t he ma na ge me nt of a d verse dr u g reacti o ns

T o u p date i ncl usi o n criteri o n 8 t o i ncl u de ne oa dj u va nt c he m ot hera p y a n d clarificati o n o n pri or 
t h oracic ra diati o n t hera p y

T o u p date e xcl usi o n criteri o n 9 f or clarit y

T o clarif y i n e xcl usi o n criteri o n 1 8 t hat car diac arr h yt h mia ma y be seri o us a n d u nc o ntr olle d

T o u p date te xt o n ma na ge me nt f or disease pr o gressi o n d ue t o brai n metastasis

T o clarif y  t u m or e val uati o n f or s u bjects w h o c o nti n ue a vel u ma b t hera py be y o n d pr o gressi o n

T o all o w l ocal ster oi d i njecti o ns as per mitte d me dicati o ns

T o u p date pr o hi bite d me dici nes t o clarif y  tar gete d b o ne lesi o ns

T o i ncl u de details o n i m m u n ot hera p y as pr o hi bite d me dici nes

T o u p date treat me nt m o dificati o ns f or s y m pt o ms of i nf usi o n -relate d reacti o ns

T o re m o ve se vere h y perse nsiti vit y  reacti o ns, fl u-li ke s ym pt o ms a n d t u m or l ysis s yn dr o me as 
t he y are n o l o n ger a p plica ble f or t his pr ot oc ol

T o u p date t he ma na g e me nt of i m m u ne-relate d a d verse e ve nts

T o u p date t he pr ot oc ol te xt a n d sc he d ule of assess me nts f or c o nsiste nc y

T o i ncl u de i nf or mati o n o n t he ma n dat or y  use of ta blets

T o u p date t he bi ostatist icia n res p o nsi ble f or t he st u d y

T o c orrect mi n or gra m matical err ors, a d mi nistrati ve c ha n ges, a n d c orrect i nc o nsiste ncies 
bet wee n pr ot oc ol secti o ns.
Rati o nale f or Maj or C ha n ge s

After i m ple me ntati o n of Pr ot oc ol Versi o n 4. 0, 3 6 s u bjects were err o ne o usl y ra n d o mize d 
acc or di n g t o Pr ot oc ol Versi o n 3. 0 ( Ar m A a n d Ar m B i n a 1: 1 rati o i nstea d of Ar m A, Ar m B 
a n d Ar m C i n a 1: 2: 2 rati o).  Of t hese, 1 5 s u bjects are e x pecte d t o bel o n g t o t he hi g h P D -L 1  
e x pressi o n gr o u p.  In or der t o reac h t he re q uire d n u m bers of eve nts i n d ue ti me, t hese 3 6 
s u bjects will be re place d.  This i ncreases t he n u m ber of s u bjects t o b e ra n d o mize d fr o m 
ori gi nall y 1 0 9 5 t o 1 1 3 1 (t o ac hie ve 4 8 4 hi g h P D -L 1 e x pressi o n s u bjects i nstea d of 4 6 9). T he 
e x pecte d n u m ber of scree ne d s u bjects i ncrease d t o u p t o 3 1 0 0.

T he n u m ber of sites a n d trial d urati o n were u p date d base d o n c urre nt e nr oll me nt.

Ma na ge me nt of A D Rs was u p date d t o a d here t o t he c urre nt g ui deli nes i n t he I B.
C CI
C CI


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 1 / 1 5 4

T o u p date pr ot oc ol te xt t o a v oi d a m bi g uit y o n t u m or assess me nts f or s u bjects u ntil disease 
pr o gressi o n wit h or wit h o ut treat me nt.

T o clarif y  ma na ge me nt of disease pr o gressi o n d ue t o brai n metastases.
A d diti o nal c ha nges were i nc or p orate d i nt o t he pr ot oc ol base d o n t he res ults of c urre nt a vel u ma b 
st u dies a n d t o u p date pr ot oc ol secti o ns base d o n i nc o nsiste ncies bet wee n te xt a n d sc he d ules of 
assess me nts .
A m e n d me nt 3. 0
T his is t he t hir d a me n d me nt t o t he ori gi nal pr ot oc ol.  
T he ke y  reas o ns ( maj or a n d a d mi nistrati ve c ha n ges) f or t his a me n d me nt are s u m marize d bel o w:

A d diti o n of a ne w st u d y ar m ( A R M C): A vel u ma b 1 0 m g/ k g a d mi nistere d o nce wee kl y ( Q 1 W) 
f or 1 2 c o nsec uti ve wee ks, f oll o we d b y a vel u ma b of 1 0 m g/ k g o nce e ver y 2 weeks ( Q 2 W) .

C ha n ge i n Pri mar y  O bjecti ve wit h relate d c ha n ge i n Pri mar y E n d p oi nts:

Pri mar y  Objecti ve: T o de m o nstrate s u peri ority wit h re gar d t o o verall s ur vi val ( O S) or 
pr o gressi o n free s ur vi val ( P F S) of a vel u ma b vers us plati n u m -base d d o u blet, base d o n 
a n i n de pe n de nt re vie w c o m mittee assess me nt as per R E CI S T 1. 1, i n N S C L C s u bjects 
wit h hi g h e x pressi o n P D -L 1 + t u m ors.

T he pri mar y  co- e n d p oi nts f or t he trial: P F S or O S i n s u bjects wit h hi g h e x pressi o n o n 
P D -L 1 + t u m ors.

C ha n ges t o sec o n dar y  e n d p oi nts

T o de m o nstrate s u peri orit y wit h re gar d t o O S i n N S C L C s u bjects wit h m o derate -t o-hi g h 
e x pressi o n P D -L 1 + t u m ors; O S i n N S C L C s u bjects wit h a n y ex pressi o n P D -L 1 + 
t u m ors; P F S i n N S C LC s u bjects wit h m o derate -t o- hi g h e x pressi o n P D-L 1 + t u m ors.

I ncrease d  
 f or t he a d diti o nal ar m

A d de d a n i nitial safet y e val uati o n peri o d f or a vel u ma b 1 0 m g/ k g a d mi nistere d e ver y  wee k

T o u p date t he me dical lea d res p o nsi ble f or t he st u d y

T o u p date t he a p pr o xi mate n u m ber of sites i n t he U S A

T o u p date t he pla n ne d trial peri o d of t he st u d y

T o clarif y the ti mi n g of t he E n d - of-Treat me nt, Safet y  Foll o w - u p a n d L o n g -ter m F oll o w -u p 
visits

T o u p date Safet y F oll o w -u p t o i ncl u de a 3 0 -d a y  F oll o w-u p visit a n d a 9 0 -da y  F oll o w-u p p h o ne 
call

T o re d uce t he fre q ue nc y of assess me nt of vital si g ns, wei g ht, pre g na nc y  testi n g, t u m or 
e val uati o n, a n d A C T H assess me nts
C CI


A vel u m a b
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer
E M R 1 0 0 0 7 0 - 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 2 / 1 5 4

T o u p date t he Sc he d ule of Assess me nts a n d rele va nt secti o ns i n t he pr ot oc ol t o re m o ve A N A, 
A N C A, R F, a n d 

T o u p date t he Sc he d ule of Assess me nts a n d rele va nt secti o ns i n t he pr ot oc ol f or 
sa m ples 
a n d A D A sa m ples calc ulate d f or t he ne w ar m, Ar m C

T o i ncl u de t he c ollecti o n of  
 sa m ples

T o u p date i ncl usi o n criteri o n 3 t o clarif y  ty pe a n d n u m ber of t u m or tiss ue sli des c ollecte d

T o u p date i ncl usi o n criteri o n 6 t o clarif y t he sta ge of metastatic ca ncer

T o u p date i ncl usi o n criteri o n 1 5 t o u p date i nf or mati o n o n hi g hl y  effecti ve c o ntrace pti o n 
met h o ds

T o clarif y  t he defi niti o n of s ur vi val f oll o w-u p

T o u p date t he i nf or mati o n o n ra di o gra p hic c o nfir mati o n of disease pr o gre ssi o n

T o clarif y  la b orat or y f or c ollecti o n of ser u m f or pre g na nc y testi n g

T o u p date all o we d c he m ot hera p y re gi me ns

T o use ra n d o mizati o n wit hi n t he pr ot oc ol te xt a n d re m o ve e nr oll me nt f or c o nsiste nc y an d 
clarit y

T o c orrect mi n or gra m matical err ors, a d mi nistrati ve c ha n ges, a n d c orrect i nc o nsiste ncies 
bet wee n pr ot oc ol secti o ns.
Rati o nale f or C ha n ges

A ne w st u d y ar m ( Ar m C) was a d de d t o test wee kl y  ad mi nistrati o n of a vel u ma b, w hic h is 
h y p ot hesize d t o i m pr o ve efficac y  wit h mar gi nal i m pact o n safety.

I n or der t o assess, if hi g her e x p os ure t o a vel u ma b offers t he a bilit y t o i m pr o ve t he 
cli nical o utc o mes f or s u bjects wit h rec urre nt/ metastatic N S C L C, a 3r d ar m was 
pr o p ose d t o t he o n g oi n g t w o ar ms of t he trial. T he a d diti o n of A vel u ma b 1 0 m g/ k g I V 
o nce a wee k f or 1 2 we e ks f oll o we d b y  avel u ma b 1 0 m g / k g I V ev er y  tw o wee ks 
t hereafter pr o vi des t he a bilit y in a ra n d o mize d c o ntr olle d setti n g t o assess if t his 
sc he d ule is m ore efficaci o us a n d yet  safer f or s u bjects wit h P D -L 1  positi ve N S C L C 
vers us a plati n u m base d d o u blet sta n dar d of care c he m ot hera p y.

I n ad diti o n t he c o nti n uati o n of t he o n g oi n g t w o ar ms will c o nti n ue t o e val uate if 
a vel u ma b 1 0 m g/ k g I V e ver y 2 wee ks is als o m ore efficaci o us a n d ye t safer t ha n t he 
sta n dar d of care plati n u m base d d o u blet c he m ot hera p y i n s u bjects wit h P D -L 1 p ositi ve 
rec urre nt/ metastatic N S C L C.

T he pri mar y  a nalys is patie nt p o p ulati o n was c ha n ge d fr o m s u bjects wit h a n y e x pressi o n of P D -
L 1 + t u m ors t o t h ose wit h hi g h e x pressi o n of P D -L 1 + t u m ors beca use s u bjects wit h i ncrease d 
e x pressi o n of P D -L 1 + t u m ors ha ve de m o nstrate d i m pr o ve d cli nical o utc o mes wit h a vel u ma b 
treat me nt c o m pare d wit h s u bjects wit h l o wer e x pressi o n of P D-L 1 + t u m ors.

T he c o -pri mar y  e n d p oi nt of o verall s ur vi val ( O S) was a d de d t o pr o gressi o n free s ur vi val ( P F S) 
t o e val uate t he l o n g ter m im pact of a vel u ma b o n patie nt s ur vi val.
C CI
C CI
C CI


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
153/154
Secondary endpoints will be evaluated by different levels of PD-L1 expression because of its 
effect on clinical outcomes that has been hypothesized and shown in previous studies.
The sample size was modified to include Arm C and support the enrollment of the necessary 
number of subjects with high expression of PD-L1 under the study statistical assumptions and 
population prevalence of approximately 7/3.
An initial safety evaluation was included in a cohort of 6 subjects to evaluate the safety of 
weekly administration prior to enrolling subjects in Arm C. A second safety evaluation will be 
performed once 20 subjects have completed at least 4 weeks of treatment in Arm C.
Amendment 2.0
This is the second amendment to the original protocol.  
The key reasons (major and administrative changes) for this amendment are summarized below:
For protocol clarification, adding text to the Schedule of Assessments and Sections 7.1.4, 
7.4.1.3, 7.4.1.6, and 7.4.1.6, indicating that all SAEs and all non-serious treatment-related AEs 
need to be documented.
To change inclusion criteria 15, indicating that male subjects are advised not to father a child 
during the 6 months after treatment with chemotherapy.
To specify in exclusion criteria 18, that cisplatin should not be used in patients with hearing 
impairment.
Amendment 1.0
To ensure consistency of safety assessments throughout the avelumab program.
To streamline Section 3.3.1 and refer the Investigator to the IB for the most current safety 
information from prior clinical studies.
For protocol clarification, to add Day 8 assessments (i.e., physical examination, vital signs 
measurements, weight measurement, ECOG, hematology, core chemistry, urine β-HCG 
pregnancy test) for each cycle of treatment for subjects receiving gemcitabine in the 
chemotherapy arm. A separate Schedule of Assessments table was created for these subjects 
(Table 3).
To specify that eligible subjects for the chemotherapy arm use effective contraception for at 
least 6 months after ceasing participation in the trial, to be consistent with the SmPCs for 
chemotherapy-treated patients. This differs from the original protocol, in which subjects in both 
treatment arms were to use effective contraception 30 days prior and 2 months after trial 
participation.
To inform the investigators that subjects who have a CR while receiving avelumab may be 
treated (after confirmation of response and at the discretion of the Investigator) for a minimum 
of 12 months and/or until disease progression or unacceptable toxicity.


Avelumab
Avelumab in First-line Non-Small Cell Lung Cancer
EMR100070-005
C O N F I D E N T I A L
I N F O R M A T I O N
154/154
To change the time points for assessment of ACTH, ANA, ANCA, RF, TSH, and T4 from 
Week 13, Week 25, and if clinically indicated to Screening, End-of-Treatment, and Safety 
Follow-up visits, for consistency with other avelumab protocols.
To remove the requirement for collection of AEs and concomitant medications between visits 
by weekly telephone contact, as this may not be feasible.

SAP_001.pdf: 
A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 /1 0 2  
 
 
 
St atistic al A n al ysis Pl a n   
Cli nic al Tri al Pr ot oc ol 
I de ntific ati o n N o. 
E M R 1 0 0 0 7 0 -0 0 5  
Title:  
A 
P hase III 
o pe n -la bel, 
m ultice nter trial 
of a vel u ma b 
( M S B 0 0 1 0 7 1 8 C) vers us plati n u m-base d  d o u blet as a first li ne 
treat me nt of rec urre nt or Sta ge I V P D-L 1 + n o n -s mall cell l u n g 
ca ncer  
Tri al P h ase  
P hase III  
I n vesti g ati o n al Me dici n al 
Pr o d uct(s)  
A vel u ma b   
Cli nic al Tri a l Pr ot oc ol 
Versi o n  
0 3 J a n uar y 2 0 1 9/ Versi o n 6. 0  
St atistic al A n al ysis Pl a n 
A ut h or  
 
St atistic al A n al ysis Pl a n  
D ate a n d Versi o n  
1 2 Oct o ber  2 0 2 1 /Versi o n  6 . 0 
St atistic al A n al ysis Pl a n 
Re vie wers  
, 
 
, Se ni or E x pert Statisticia n  
,  
 Me dical Res p o nsi ble  
 
 
, 
 
, 
 
,  
 Bi ostatistics Pr o gra m Lea d  
 
 
, 
 
 
 
C o nfi de nti al  
T his d oc u me nt is t he pr o pert y of Merc k K Ga A, Dar msta dt, Ger ma n y, or o ne of its affiliate d c o m pa nies.  
It is i nte n de d f or restricte d use o nl y a n d ma y n ot - i n f ull or part - be passe d o n, re pr o d uce d, p u blis he d or use d wit h o ut e x press 
per missi o n of Merc k K Ga A, Dar msta dt, Ger ma n y or its affiliate .  
C o p yri g ht © 2 0 1 9  b y M erc k K G a A, D ar mst a dt, Ge r m a n y or its affili ate. All ri g hts reser ve d.  
Gl o bal Versi o n I D: 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
C CI
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 /1 0 2  
 
 
A p pr o v al P a ge   
 
I nte gr ate d A n al ysis Pl a n: E M R 1 0 0 0 7 0 -0 0 5  
A P hase III o p e n -la b el, m ultice nter trial of a v el u ma b ( M S B 0 0 1 0 7 1 8 C) vers us plati n u m -base d 
d o u blet as a first li ne treat me nt of rec urre nt or Sta ge I V P D -L 1 + n o n -s mall cell l u n g ca ncer 
A p pr o val of t he I A P b y all Merc k Data A nal ysis Res p o nsi ble has t o be d oc u me nte d wit hi n 
E L D O R A D O v ia e Si g n at ure. Wit h t he a p pr o val, t he Merc k res p o nsi ble f or eac h of t he a n al ysis 
als o ta kes res p o nsi bilit y t hat all re vie wers’ c o m me nts are a d dresse d a de q uat el y.  
B y usi n g e Si g n at ure, t he si g nat ur e will a p pear at t he e n d of t he d oc u me nt.  
 
 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 /1 0 2  
 
 
 
1  
T a ble of C o nte n ts  
A p pr o val Pa ge  
 ..............................................................................................................2  
1  
Ta ble of C o nte nts  ..................................................................................3  
2  
List of A b bre viati o ns a n d Defi niti o n of Ter ms  ....................................7  
3  
M o dificati o n Hist or y  ..........................................................................1 0  
4  
P ur p ose of  t he Statistical A nal ysis Pla n .............................................1 0  
4. 1  
C ha n ges t o Pre vi o us Versi o n  ..............................................................1 0  
5  
S u m mar y of Cli nical Tri al Feat ures  ...................................................1 5  
6  
/ Ra n d o mizati o n ...............................................................1 9  
6. 2  
Ra n d o mizati o n  ....................................................................................2 1  
7  
O ver vie w of Pla n ne d A nal yses  ...........................................................2 1  
7. 1  
Se q ue nce of A nal yses  .........................................................................2 2  
7. 2  
I nteri m A nal ysis ..................................................................................2 3  
7. 3  
Fi nal A nal ysis  .....................................................................................2 5  
7. 4  
F oll o w -u p a n al ysis  ..............................................................................2 5  
8  
C ha n ges t o t he Pla n ne d A nal ys es i n t he Cli nical Trial Pr ot oc ol  ........2 6  
8. 1  
C O VI D -1 9 I m pa ct  ..............................................................................2 6  
8. 2  
Dis p ositi o n of S u bjects a n d Disc o nti n uati o ns  ....................................2 7  
9  
A nal ysis Sets  .......................................................................................2 8  
1 0  
Ge neral S pecificati o ns f or Statistical A nal yses  ..................................3 5  
1 1  
Trial S u bjects  ......................................................................................4 5  
1 1. 1  
Pr ot oc ol De viati o ns  ............................................................................4 5  
1 2  
De m o gra p hics a n d Ot her Baseli ne C haracteristics  .............................4 5  
1 2. 1  
De m o gra p hics  .....................................................................................4 5  
1 2. 2  
Me dical Hist or y  ..................................................................................4 6  
1 2. 3  
Ot her Baseli ne C haracteristics  ............................................................4 7  
1 2. 3. 1  
Disease C haracteristics  .......................................................................4 7  
1 2. 3. 2  
Pri or A nti -Ca ncer T h era pies  ...............................................................4 8  
1 2. 3. 3  
P D -L 1 E x pressi o n Stat us a n d Bas eli ne Bi o mar kers  ...........................4 9  
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 /1 0 2  
 
 
1 3  
Pre vi o us or C o nc o mita nt Me dicati o ns/ Pr oce d ures  .............................4 9  
1 3. 1  
Pri or a n d C o nc o mita nt Me dicati o ns/ Pr oce d ures  ................................4 9  
1 3. 2  
S u bse q ue nt A nti -Ca ncer T hera pies/ Pr oce d ures  .................................5 0  
1 4  
Treat me nt C o m plia nce a n d E x p os ure  .................................................5 1  
1 5  
E n d p oi nt E val uati o n  ...........................................................................5 5  
1 5. 1  
Pri mar y E n d p oi nt A nal ys es  ................................................................5 6  
1 5. 1. 1  
Hierarc hical testi n g  .............................................................................5 6  
1 5. 1. 2  
Pr o gressi o n Free S ur vi val  ...................................................................5 8  
1 5. 1. 3  
O verall S ur vi val  ..................................................................................6 1  
1 5. 1. 4  
Se nsiti vit y A nal ys es of Pri mar y E n d p oi nts  ........................................6 2  
1 5. 1. 5  
S u b gr o u p A n al ysis of Pri mar y E n d p oi nts  ..........................................6 4  
1 5. 1. 6  
Ti me of F oll o w -U p  .............................................................................6 5  
1 5. 2  
Sec o n dar y E n d p oi nt A nal yses  ............................................................6 5  
1 5. 2. 1  
C o nfir me d Best O v erall Res p o nse  ......................................................6 5  
1 5. 2. 2  
Healt h -Relate d Q ualit y of Lif e  ...........................................................6 8  
1 5. 2. 3  
Se nsiti vit y A nal ys es of Sec o n dar y Efficac y E n d p oi nts  ......................7 2  
1 5. 2. 4  
S u b gr o u p A n al ysis o n Sec o n dar y Efficac y E n d p oi nts  .......................7 3  
1 5. 3  
Ot her E n d p oi nt A nal yses  ....................................................................7 4  
1 5. 3. 1  
Pr o gressi o n -free s ur vi val o n ne xt-li ne t hera p y ( P F S 2) ......................7 4  
1 5. 3. 2  
D urati o n of Res p o nse  .........................................................................7 5  
1 6  
Safet y E val uati o n  ................................................................................7 9  
1 6. 1  
A d verse E v e nts  ...................................................................................7 9  
1 6. 1. 1  
All A d verse E v e nts  .............................................................................8 1  
1 6. 1. 2  
A d verse E v e nts Lea di n g t o Per ma ne nt Treat me nt Disc o nti n uati o n  ...8 3  
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 /1 0 2  
 
 
1 6. 2  
Deat hs, Ot her Seri o us A d verse E ve nts, a n d Ot her Si g nifica nt 
A d verse E v e nts  ...................................................................................8 4  
1 6. 2. 1  
Deat hs  .................................................................................................8 4  
1 6. 2. 2  
Seri o us A d verse E v e nts  ......................................................................8 4  
1 6. 2. 3  
Ot her Si g nifica nt A d verse E ve nt  ........................................................8 5  
1 6. 3  
Cli nical La b orat or y E val uati o n  ...........................................................8 7  
1 6. 3. 1  
He mat ol o g y a n d C he mistr y Para meters  .............................................8 7  
1 6. 3. 2  
Ot her La b orat or y Para meters  ..............................................................9 0  
1 6. 4  
Vital Si g ns  ..........................................................................................9 0  
1 6. 5  
Ot her Safet y or T olera bilit y E val uati o ns  ............................................9 1  
1 6. 5. 1  
E C G  ....................................................................................................9 1  
1 6. 5. 2  
E C O G Perf or ma n ce Stat us  .................................................................9 2  
1 7  
Refere n ces  ...........................................................................................9 5  
1 8  
A p pe n dices  .........................................................................................9 6  
 
 
 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 /1 0 2  
 
 
T a ble of T a bles  
Ta ble 2  
I nteri m A nal yses .................................................................................2 4  
Ta ble 3  
A nal ysis Sets b y P D -L 1 stat us  ............................................................3 1  
Ta ble 4  
Statistical A nal ysis b y A nal ysis Set  ...................................................3 1  
Ta ble 5  
O utc o me a n d e v e nt dates f or P F S a n d d urati o n of res p o nse 
a nal ys es  ...............................................................................................5 9  
Ta ble 6  
Best O verall Res p o nse W he n C o nfir mati o n of C R/ P R Is Re q uir e d ...6 6  
Ta ble 7  
Sc ori n g r ul es f or E O R T C Q L Q -C 3 0 a n d Q L Q -L C 1 3  ........................6 9  
Ta ble 8:  
O utc o me a n d e v e nt dates f or T U D D a nal yses  ....................................7 2  
Ta ble 9  
O utc o me a n d e v e nt dates f or P F S 2 a nal ysis  .......................................7 4  
Ta ble 1 0  
 Cate g ories a n d Preferre d Ter ms f or Tier 1 E ve nts  ............................8 0  
Ta ble 1 1  
P ote ntiall y Cli nicall y Si g nifica nt A b n or malities criteria f or E C G  .....9 2  
Ta ble 1 2  
Al g orit h m f or t he Deri v ati o n of A D A Res ults  ...................................9 3  
Ta ble 1 3  
S u bjects C haracterize d base d o n A D A Res ults  ..................................9 3  
Ta ble 1 4  
Al g orit h m f or t he Deri v ati o n of n A b Res ults  .....................................9 3  
Ta ble 1 5  
S u bjects C haracterize d base d o n n A b Res ults  ....................................9 4  
Ta ble 1 6  
Criteria f or i nf usi o n r elat e d reacti o ns  ...............................................1 0 2  
 
Gl o bal Versi o n I D: C CI
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 /1 0 2  
 
 
2  
L ist of A b bre vi ati o ns a n d Defi niti o n of Ter ms  
A D A  
A nti -dr u g a nti b o d y  
A E(s)  
A d verse e ve nt(s)  
A E SI  
A d verse e ve nt of s pecial i nterest  
A L K  
A na plastic l y m p h o ma ki nase  
A L T  
Ala ni ne a mi n otra nsferas e  
A N C  
A bs ol ute ne utr o p hil c o u nt  
a P T T 
Acti vate d partial t hr o m b o plasti n ti me  
A S T  
As partate a mi n otra nsferase  
A T C  
A nat o mical T hera pe utic C he mical  
B MI  
B o d y mass i n de x  
B O R  
Best o verall res p o nse  
B S A  
B o d y S urface Area  
C e oi 
C o nce ntrati o n o bser ve d i m me diatel y at t he e n d of i nf usi o n  
CI  
C o nfi de nce i nter val(s)  
CI P D  
Cli nicall y  i m p orta nt pr ot oc ol de viati o ns 
C M H  
C oc hra n -Ma nt el -Hae nszel  
C PI  
C hec k p oi nt i n hi bit ors 
C P K  
Creati ne Ki nase  
C R  
C o m plete res p o nse  
C R F  
Case Re p ort F or m  
C S R  
Cli nical St u d y Re p ort  
C T  
C o m p ute d t o m o gra p h y  
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts  
Ctr o u g h  
C o nce ntrati o n 
o bser ve d 
i m me diatel y 
b ef ore 
ne xt 
d osi n g 
(c orres p o n di n g t o pre-d ose or tr o u g h c o n ce ntr ati o n f or 
m ulti ple 
d osi n g)  
D B P  
Diast olic bl o o d press ure  
E AI R  
E x p os ure A dj uste d I n ci de nce Rate  
E C G  
Electr ocar di o gra m  
E C O G P S  
Easter n C o o perati ve O nc ol o g y Gr o u p Perf or ma n ce Stat us  
e C D F 
E m pirical c u m ulati ve distri b uti o n f u ncti o n  
e C R F 
Electr o nic case re p ort f or m  
e DI S H  
E val uati o n of Dr u g -I n d u ce d Seri o us He p at ot o xicit y 
E E A  
E ur o pea n E c o n o mic Area  
E G F R  
E pi der mal gr o wt h f act or rece pt or  
E O R T C  
E ur o pea n Or ga nizati o n f or Researc h a n d Treat me nt of Ca ncer  
E Q -5 D  
E ur o Q O L fi ve di me nsi o ns q uesti o n naire  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 /1 0 2  
 
 
E ur o Q O L  
E ur o pea n Q u alit y of Life  
F A S  
F ull A nal ysis Set  
F U  
F oll o w -u p  
G C P  
G o o d Cli nical Practice  
G G T  
Ga m ma -gl uta m yl tra nsferase  
H B  
He m o gl o bi n  
H R  
Hazar d rati o  
H R Q o L  
Healt h -Relate d Q ualit y of Lif e  
I C F 
I nf or me d c o ns e nt f or m  
I C H 
I nter nati o nal C o nfere nce o n Har m o nisati o n 
I D M C 
I n d e pe n de nt Data M o nit ori n g C o m mittee 
I H C 
I m m u n o hist oc he mistr y 
I R C 
I n d e pe n de nt Re vi e w C o m mittee 
I N R 
I nter nati o nal n or malize d rati o 
I P D 
I m p ort a nt Pr ot oc ol De viati o ns 
ir A E 
I m m u ne-relat e d a d verse e ve nt  
I R R 
I nf usi o n relate d reacti o n 
I V 
I ntr a ve n o us 
I T T 
I nte nti o n-t o-treat 
IW R S  
I nteracti ve we b res p o nse s yste m 
L D H  
Lactate d e h y dr o ge n ase  
L L N  
L o w er li mit of n or mal  
L L O Q  
L o w er Li mit of Q ua ntitati o n  
M C H  
Mea n c or p us c ular h e m o gl o bi n  
M C H C  
Mea n c or p us c ular h e m o gl o bi n c o nce ntrati o n  
M CI C  
Mi ni mal Cli nicall y I m p orta nt C ha n ge  
M C V  
Mea n C or p usc ular V ol u me  
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
M M R M  
Mi x e d -effect m o del r e peate d meas ures  
M RI  
Ma g n etic res o n a nce i ma gi n g  
n A b  
Ne utralizi n g a nti b o d y 
N CI  
Nati o nal Ca ncer I nstit ute  
N E  
N o n -e val ua bl e  
N S C L C  
N o n -s mall cell l u n g ca n cer 
O R R  
O bjecti ve res p o ns e rat e  
O S  
O verall s ur vi val  
P D  
Pr o gressi ve disease  
P D -1  
Pr o gra m me d deat h 1  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 /1 0 2  
 
 
P D -L 1  
Pr o gra m me d deat h li ga n d 1  
P F S  
Pr o gressi o n -free s ur vi val 
P K  
P har mac o ki netic(s)  
P L T  
Platelet c o u nt  
P R  
Partial res p o nse  
P R O(s)  
Patie nt -Re p orte d O utc o me(s)  
P T  
Preferre d ter m  
Q L Q -C 3 0  
Q ualit y of Lif e Q uesti o n naire -C ore 3 0 ite ms  
Q L Q -L C 1 3  
Q ualit y of Lif e Q uesti o n naire -L u n g ca ncer 1 3 -ite m m o d ule  
Q O L  
Q ualit y of Lif e  
R B C  
Re d bl o o d cell  
R E CI S T 1. 1  
Res p o nse E val uati o n Criteria i n S oli d T u m ors versi o n 1. 1  
R M S T  
Restricte d Mea n S ur vi val Ti me  
R P S F T  
Ra n k Preser vi n g Str uct ur al Fail ure Ti me  
S A E  
Seri o us a d verse e ve nt  
S A P  
Statistical A nal ysis Pla n  
S B P  
S yst olic bl o o d press ure  
S D  
Sta ble disease  
S D G  
Sta n dar dize d Dr u g Gr o u pi n g  
S O C  
S yste m Or ga n Class  
T E A E  
Treat me nt -e mer ge nt a d v erse e v e nt  
T M B  
T u m or M utati o nal B ur de n  
T U D D  
Ti me U ntil Defi niti ve Deteri orati o n  
U L O Q  
U p per Li mit of Q ua ntitati o n  
U L N  
U p per li mit of n or mal  
V A S  
Vis ual a nal o g ue scale  
U S A  
U nite d States  
 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 0 /1 0 2  
 
 
3  
M o dific ati o n Hist or y   
U ni q u e I d e ntifi er f or 
S A P V er si o n  
D at e of S A P V er si o n  
A ut h or  
C h a n g e s fr o m t h e Pr e vi o u s 
V er si o n  
1. 0  
1 4 J ul y 2 0 1 5  
 
N/ A Fir st v er si o n  
2. 0  
2 7  J ul y 2 0 1 7  
  
S e e S e cti o n 4. 1  C h a n g e s t o 
Pr e vi o u s V er si o n  
3. 0  
1 1  F e br u ar y 2 0 1 9  
  
S e e S e cti o n 4. 1  C h a n g e s t o 
Pr e vi o u s V er si o n  
4. 0  
2 3  M a y 2 0 1 9  
  
S e e S e cti o n 4. 1  C h a n g e s t o 
Pr e vi o u s V er si o n  
5. 0  
0 5 A u g 2 0 2 1  
 
S e e S e cti o n 4. 1  C h a n g e s t o 
Pr e vi o u s V er si o n  
6. 0  
1 2 O ct 2 0 2 1  
  
S e e S e cti o n 4. 1  C h a n g e s t o 
Pr e vi o u s V er si o n  
4  
P ur p ose of t he St atistic al A n al ysis Pl a n   
T he p ur p ose of t his statistical a nal ysis pla n ( S A P) is t o d oc u me nt tec h nical a n d detaile d 
s pecificati o ns f or t he i nt eri m a n d fi nal a n al ysis of data c ollecte d f or pr ot o c ol E M R 1 0 0 0 7 0 -0 0 5 . 
Res ults of t he a nal yses d escri be d i n t his S A P will be i ncl u de d i n t he Cli nical St u d y Re p ort ( C S R ). 
A d diti o nall y, t he  pla n ne d a nal yses i de ntifie d i n t his S A P ma y 
be i ncl u de d i n re g ulat or y 
s u b missi o ns or f ut ure m a n uscri pts. A n y p ost-h oc, or u n pla n ne d a nal yses perf or me d t o pr o vi d e 
res ults f or i ncl usi o n i n t h e C S R b ut n ot i de ntifie d i n t his pr os pecti ve S A P will be clearl y i d e ntifie d 
i n t he C S R .  
T he S A P is base d u p o n S ecti o n 8 ( Statistics) of t he trial pr ot oc ol a n d is pre pare d i n c o m plia nce 
wit h I C H E 9. V ersi o n 5 . 0 was create d base d o n t he pr ot oc ol versi o n 6 . 0 d ate d 0 3 J a n uar y 2 0 1 9 .  
4. 1  
C h a n ges t o Pre vi o us Versi o n   
Versi o n 6 . 0 
T he f oll o wi n g c ha n ges are ma de i n versi o n 6 . 0 of t he S A P: 
1.  U p date o n  P har mac o ki netics S ecti o n 1 5. 3. 5 .  
a. P K Data Ha n dli n g  secti o n a d de d (1 5. 3. 5. 1 )  
b.  P rese nti n g P K c o n ce ntr ati o n data i n Listi n gs, Ta bl es a n d Fi g ures a d d e d ( 1 5. 3. 5. 2 )  
2.  U p date 
o n  P o p ulati o n 
P har mac o metric 
A nal ysis 
S ecti o n 1 5. 3. 6 : refere n ce t o 
P har mac o metric M o d eli n g A n al ysis Pla n re gar di n g a n al ysis a n d a nal ysis set.  
3.  A D A cate g ories d escri b e d i n Ta ble 1 3  i n Secti o n 1 6. 5. 3  I m m u n o ge nicit y were u p d ate d. 
T he 
defi niti o ns of “ Treat me nt i n d uce d ”, “ Treat me nt -i n d uce d 
Tra nsie nt p ositi ve”, 
Gl o bal Versi o n I D: 
P P D
P P D
P P D
P P D
P P D
P P D
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 1 /1 0 2  
 
 
“ Treat me nt -i n d uce d Persiste nt p ositi ve”, a n d “Treat me nt e m er ge nt ” were a d de d a n d/ or  
u p date d . 
4.  n A b  cate g ories des cri be d i n Ta ble 1 5  i n Secti o n 1 6. 5. 3  I m m u n o ge ni cit y were u p date d. T h e 
defi niti o ns of “ Treat m e nt i n d uce d ”, “ Treat m e nt -i n d uce d 
Tra nsie nt p ositi ve”, a n d 
“ Treat me nt -i n d uce d Persiste nt p ositi ve” were u p d ate d .  
Versi o n 5. 0  
T he f oll o wi n g c ha n ges are ma de i n versi o n 5. 0 of t he S A P:  
1.  A d de d Secti o n 8. 1  t o descri be d t he s u m mar y of t he i m pact of t he C O VI D-1 9 pa n de mic o n 
t he st u d y a n d ad d e d a refere nce t o p ote ntial s u m maries of C O VI D-1 9 vacci n ati o ns ( Secti o n 
1 3. 1 )  
2.  A d de d s u b gr o u ps base d o n t u m or m utati o nal b ur de n t o Secti o n 8. 2 . 
3.  A d de d descri pti o n of statistical o ut p uts t hat will be re peate d f or J a pa n ese s u bjects t o 
Secti o n 8. 2 . 
4.  A d diti o n of i nstr ucti o ns t o Secti o n 1 0  f or creati o n of a n a vera ge w he n d u pli cate ce ntr al la b 
meas ure me nts e xist wit h t he sa me visit, sa m ple c ollecti o n date, a n d sa m ple c ollecti o n ti me.  
5.  U p dates t o Healt h -Re late d Q ualit y of Lif e a n a l ys es ( Secti o n 1 5. 2. 2 ). 
a. C ha n ge d t he de n o mi nat or f or c o m plia nce a n d c o m pleti o n s u m maries t o t he n u m ber 
i n t he F A S, M F A S, or s u bset base d o n P D-L 1 e x pressi o n stat us.   
b.  Clarif y t h e des cri pti ve st atistics will be pr o vi de d f or visits wit h ≥ 1 0 s u bj ects i n 
eac h tr eat me nt gr o u p  
c. F or M M R M a n al ysis, cl arif y t h at meas ure me nts after treat me nt disc o nti n uati o n ca n 
be i ncl u de d.   
d.  F or T U D D a nal yses, refer t o Mi ni mal Cli nicall y I m p or t a nt C ha n g ( M CI C) rat h er 
t ha n 
Mi ni m u m I m p orta nt 
Differe nce ( MI D) i n t he defi niti o n of defi niti ve 
deteri orati o n. 
Als o, clarif y t hat d eteri or ati o n is c o nfir m e d b y n o f urt her 
i m pr o ve me nt of H R Q o L sc ore  e x cee di n g M CI C ma g nit u de at ne xt assess me nt  or 
n o f urt her  a vaila ble H R Q o L dat a d ue t o deat h , occ urri n g wit hi n 2 sc he d ule d P R O 
assess me nts .  A ta ble was a d de d t o descri be e ve nt a n d ce ns ori n g r ules. Fi nall y, 
re m o ve t he s e nte nce t hat defi niti ve deteri orati o n m ust be wit hi n 5 da ys after 
treat me nt disc o nti n uati o n t o be c o nsi dere d f or a n al ysis.  
6.  U p date d descri pti o n of e DI S H pl ot  i n Secti o n 1 6. 3. 1  t o i n dicate t hat pea k t otal bilir u bi n 
(/ U L N) will be dis pla ye d rat her t ha n t he bilir u bi n (/ U L N) res ult t hat was c o nc urre nt wit h 
t he pea k A L T or A S T. 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 2 /1 0 2  
 
 
7.  U p date T a ble 1 6  t o i n dicate t hat a n I R R i de ntifie d as a si g n or s y m pt o m is re q uire d t o h a ve 
s h o ul d ha ve res ol ve d o n t he da y of o nset or t he ne xt da y  rat h er t ha n wit hi n 2 da ys of o nset. 
Versi o n 4. 0  
T he f oll o wi n g c ha n ges are ma de i n versi o n 4 . 0 of t he S A P: 
1.  A d de d t he m o difie d safet y a n al ysis set t o Secti o n 8. 2  a n d a d de d s pecific ta bles w hic h will 
be pr o d uce d f or t his a nal ysis set i n Secti o n 1 6 . 
2.  A d de d  te xt t o descri be i m p utati o n r ules f or la b orat or y res ults re p orte d as < L L O Q or 
> U L O Q t o Secti o n 1 0 . 
3.  A d de d  i nstr ucti o ns t o Secti o n 1 0  f or selecti o n of rec or ds f or s u m maries of l a b assess me nts 
b y visit w he n m ulti ple assess me nts are a vaila ble f or a s pecifi c visit.  
4.  A d de d t w o f urt her s u b gr o u ps t o Secti o n 8. 2 . 
Versi o n 3. 0  
T he f oll o wi n g c ha n ges are ma de i n versi o n 3. 0 of t he S A P:  
1.  T he f oll o wi n g s ecti o ns w ere u p date d t o ali g n wit h pr ot oc ol v 6. 0. C ha n ges t o t he pr ot oc ol 
i ncl u de d re vis o ns t o ass u m pti o ns o n P F S dr o p-o ut rate. Als o, t he sc h e d uli n g of i nteri m a n d 
pri mar y a nal ysis of P F S a n d O S were  c ha n ge d t o ha ve i nteri m a n d pri mar y a nal ysis of b ot h 
e n d p oi nts at t he sa m e ti me deter mi ne d b y t he n u m ber of O S e ve nts a n d mi ni m u m -f oll o w-
u p ti me . 
a. Secti o n 5  S u m mar y of Cli nical Trial Feat ures , 
b.   Secti o n 6. 1  Sa m ple Size ,  
c. Secti o n 6. 2  Ra n d o mizati o n . 
d.  Secti o n 7  O ver vie w of Pla n ne d A nal ys es, i ncl u di n g  all s u bsecti o ns  
e. Secti o n 1 5  E n d p oi nt E val uati o n  
2.  I n v ari o us secti o ns of t he d oc u me nt, c ha n ges were ma de t o i n dicate t hat t here will be o ne 
i nteri m a nal ysis a n d o n e pri mar y a nal ysis of O S a n d P F S. 
3.  Secti o n 8. 2  A nal ysis Sets:  
a. T he m o difie d f ull a nal ysis set ( m F A S) defi niti o n was u p date d t o acc o u nt f or t he 3 6 
s u bjects ra n d o mize d acc or di n g t o t he o ut date d pr ot oc ol versi o n .  
b.  S u b gr o u ps d efi ne d b y t h e prese n ce or a bs e nce of li ver metastas es, b o ne met astases, 
visceral metastas es, a n d ple ural eff usi o n at baseli ne were a d de d.  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 3 /1 0 2  
 
 
4.  Secti o n 1 2. 3. 1  - Sta ge at i nitial dia g n osis a n d st u d y e ntr y were a d d e d t o t he list of disease 
c haracteristics  
5.  Secti o n 1 5. 1. 2  Pr o gressi o n Free S ur vi val:  
a. A d de d clarificati o n re gar di n g t he i nter val use d t o deter mi ne w he n s u bjects misse d 
t w o sca ns i nt o Ta ble 5 . 
b.  Cate g orize d ce ns ori n g reas o ns as a d mi nistrati ve a n d n o n -a d mi nistrati ve  
6.  Secti o n 1 5. 3. 1  Pr o gressi o n -free sur vi val o n ne xt -li ne t hera p y ( P F S 2) a d d e d  
7.  Secti o n 1 5. 1. 4  Se nsiti vit y A nal yses of t he Pri mar y E n d p oi nt: T h e f oll o wi n g a nal yses were 
a d de d:  
a. P F S w here s u bjects are n ot ce ns ore d b ase d o n t heir s u bse q ue nt a nti -ca ncer 
treat me nt. 
b.  P F S i n treate d s u bjects, i. e. safet y a nal ysis set.  
8.  Secti o n 1 6. 1  te xt was a d d e d t o descri be t he 3-tier a p pr oac h to s u m marize a n d a nal yz e A Es  
9.  Secti o n 1 6. 2. 3  Ot her Si g nifica nt A d verse E ve nts was u p date d  t o i n dicate t hat ir A Es are 
i de ntifie d base d o n a list of Me d D R A P Ts a n d ot her q ualif yi n g criteria (f or details see 
A p pe n di x V ); relate d ir A E were d elete d fr o m t he ir A E a nal ysis.  
Versi o n 2. 0  
T he  f oll o wi n g c ha n ges are ma de i n versi o n 2. 0 of t he S A P: 
1.  T he ter m “I nt e nti o n -t o-Treat (I T T) a n al ysis s et” was u p date d as “ F ull a n al ysis set ( F A S)” 
t hr o u g h o ut t his d oc u me nt (t he defi niti o n re mai ns t he sa me) p er pr ot oc ol v ersi o n 4. 0; 
2.  Per -pr ot oc ol ( P P) a nal ysis  set a n d a nal ysis were delete d as n o P P a nal ysis will be 
perf or me d o n t his st u d y per pr ot oc ol versi o n 4. 0;  
3.  M o difie d F ull A nal ysis Set ( m F A S) was a d de d f or t he s pecific c o m paris o n of Ar m B vs. 
Ar m C, d ue t o t he a d diti o n of Ar m C i n t he st u d y a n d t he fact t h at recr uit me nt of patie nts 
i n Ar m C starte d after recr uit me nt of patie nts i n Ar m A a n d Ar m B; 
4.  Secti o n 5  S u m mar y of Cli nical Trial Feat ur es was u p date d per pr ot oc ol versi o n 4. 0, i n 
partic ular t o prese nt t he a d diti o n of t he t hir d ar m (a vel u ma b ar m C) a n d t he c ha n ge i n st u d y 
e n d p oi nts ( pri mar y e n d p oi nts Pr o gressi o n Free S ur vi val –  P F S  –  a n d O verall s ur vi val –  
O S);  
5.  Secti o n 6. 1  Sa m ple Size was u p date d f or t he t otal n u m ber of ra n d o mize d s u bjects  t o be 
1 0 9 5, base d o n u p date d calc ulati o n per pr ot o c ol versi o n 4. 0;  
6.  Secti o n 6. 2  Ra n d o mizati o n was u p date d t o a d d ra n d o mizati o n strat a of P D -L 1 t u m o r 
e x pressi o n le vel s at baseli ne per pr ot oc ol v ersi o n 4. 0;  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 4 /1 0 2  
 
 
7.  Secti o n 7  O ver vie w of Pla n ne d A nal ys es was u p date d t o i ncl u de i nteri m a nal ys es a n d 
O’ Brie n -Fle mi n g b o u n d aries base d o n a La n -De M ets al p ha s pe n di n g f u ncti o n t hat acc o u nt 
f or t he act ual n u m ber of P F S  e ve nts i n s u bjects wit h hi g h P D-L 1 +  e x pressi o n t u m ors at t he 
i nteri m a n d t he fi nal a n al ysis; data c ut -off dat e f or t he i nteri m a n d t he fi nal a nal ysis was 
u p date d as pr e -s pecifie d date base d o n a pre -s pecifie d e x pecte d n u m ber of e ve nts; 
8.  Secti o n 8. 2  Healt h -Relate d Q ualit y of Life ( H R Q o L ) a n al ysis set a n d m o difie d  H R Q o L 
a nal ysis s et were a d d e d; S u b gr o u p of P D -L 1 + + stat us Yes/ N o was re place d b y s u b gr o u p 
P D -L 1 +  E x pressi o n  le vel L o w/ M o derate/ Hi g h ; Safet y C o h ort a nal ysis set was a d de d ; 
9.  Secti o n 1 0  Ge neral S pecificati o ns f or Statistical A nal yses was u p date d;  Refere n ce t o 
listi n gs f or safet y c o h ort was a d de d; 
1 0.  Secti o n 1 1. 1  Pr ot oc ol De viati o ns was u p date d wit h sta n dar d te xt;  cli nicall y i m p orta nt 
pr ot oc ol de viati o ns ( CI P Ds) were a d d e d;  
1 1.  Secti o n 1 2. 1  De m o gra p hics –  a ge gr o u ps a n d re gi o n classificati o n were  u p date d;  
1 2.  Secti o n 1 3. 1  Pri or a n d 
C o nc o mita nt 
Me dicati o ns/ Pr oce d ures, defi niti o n of pri or 
me dicati o ns was u p date d;  
1 3.  Secti o n 1 3. 2  S u bse q ue nt A nti -Ca ncer T h era pies/ Pr oce d ures was  u p dat e d wit h m ore 
details;  
1 4.  Secti o n 1 4  Treat me nt C o m plia nce a n d E x p os ure was u p dat e d t o a d d calc ulati o ns f or 
a vel u ma b ar m C;  
1 5.  Secti o n s 1 5. 1  Pri mar y E n d p oi nt A nal yse s a n d 1 5. 2  Sec o n dar y E n d p oi nt A nal ys es  w ere  
u p date d t o refl ect c ha n ges of st u d y e n d p oi nts per pr ot oc ol versi o n 4. 0; 
1 6.  Secti o n 1 5. 1. 4  Se nsiti vit y A nal yses was u p date d t o i ncl u de Restricte d Mea n S ur vi val Ti me 
( R M S T) as a n alter nate met h o d t o esti mate t he effect siz e f or ti me-t o-e v e nt e n d p oi nts i n 
case pr o p orti o nal h azar ds as s u m pti o ns ca n n ot b e h ol d. A d diti o nal se nsiti vit y a nal ysis was 
a d de d;  
1 7.  Secti o n 1 5. 2. 1  Best O verall Res p o nse  ( B O R) was u p date d t o clarif y t u m or assess me nt after 
start of a n y f urt her a nti-ca ncer will n ot be i nc l u de d i n B O R deri vati o n; Ta ble 6  was u p date d  
t o cite t he ori gi n al B O R deri vati o n ta ble fr o m Eis e n ha user, et al.;  
1 8.  Secti o n 1 5. 2. 2  Healt h Relate d Q ualit y of Life was u p date d t o i ncl u de m ore d etails o n t he 
q uesti o n naires  sc ori n g s yste m; c o m plia nce, ti me u ntil defi niti ve deteri or ati o n ( T U D D) 
a nal ysis, a n d a d diti o nal s u m mar y a n al ysis i ncl u di n g fi g ures were a d de d;  det ails o n a nal ysis 
s u m mar y of sc he d ule d a n d u nsc he d ule d visits were a d de d;  
1 9.  Secti o n 1 5. 3. 5  Descri pti ve P har mac o ki netic  (P K ) A nal ysis was u p d ate d base d o n P K tea m 
i n p ut; 
2 0.  Secti o n 1 6. 1  A d vers e E v e nts, defi niti o n of i m m u ne-rel ate d A E (ir A E) a n d I nf usi o n-relate d 
reacti o ns (I RRs)  was u p d ate d; details of p o oli n g t he sa me A E wit h differe nt t o xicit y gra de, 
o utc o me or seri o us ness rec or de d as differe nt e ntries o n t he e C R F were a d d e d;  
2 1.  Secti o n 1 6. 2. 3  Ot her Si g nifica nt A d verse E ve nts was u p date d  t o a d d descri pti o n of  
I m m u ne-relat e d a d verse e ve nt (ir A Es) a n d I R Rs; 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 5 /1 0 2  
 
 
2 2.  Secti o n 1 6. 2. 4  I m m u n o ge nicit y S u b gr o u p A nal ysis of A d verse E ve nts was a d de d; 
2 3.  Secti o n 1 6. 3. 1  He mat ol o g y a n d C h e mistr y Para m eters was u p d ate d;  
2 4.  Secti o n 1 6. 5. 3  I m m u n o ge nicit y d etails were a d de d f or t he i m m u n o ge nicit y data a nal ysis; 
2 5.  A p pe n di x II was u p dat e d t o  i ncl u de i m p orta nt pr ot oc ol de viati o ns b y pr o gra m mi n g c hec k 
a n d me dical r e vie w ; 
2 6.  A p pe n di x III Pre -s pecifie d Searc h List of Me d D R A Preferre d Ter m f or I m m u ne Relate d 
A d verse E ve nts w as re m o ve d fr o m t his S A P. A versi o n -c o ntr olle d s earc h list will be 
a vaila ble i n S p o ns or’s M A R V E L s yste m ; 
2 7.  A p pe n di x III w as a d d e d t o i ncl u de t he scree ns h ot of E O R T C Q L Q -C 3 0 versi o n 3. 0 sc ori n g 
s yste m; 
2 8.  A p pe n di x I V w as a d de d t o i ncl u de t he scree ns h ot of E O R T C Q L Q -C 3 0 -L C 1 3 L u n g 
Ca ncer M o d ule s c ori n g s yste m;  
2 9.  A p pe n di x V  was a d de d t o i ncl u de “ Descri pti o n of t he Case Re vie w f or Assess me nt of 
I m m u ne-Relate d A Es ”  a n d detaile d i nf or mati o n f or I R R . 
5  
S u m m ar y of Cli nic al Tri al Fe at ures   
 
Tri al o bjecti ves  
Pri m ar y o bjecti ve  
T he pri mar y o bjecti ve is t o de m o nstrate s u peri orit y wit h re gar d t o o verall 
s ur vi val ( O S) or pr o gressi o n -free s ur vi val (P F S ) of a vel u ma b vers u s 
plati n u m -base d d o u blet, base d o n a n I n d e pe n de nt Re vie w C o m mittee 
assess me nt  as per R E CI S T 1. 1,  i n N S C L C s u bjects wit h hi g h e x pressi o n P D -
L 1 + t u m ors . 
Sec o n d ar y o bjecti ves  
Sec o n dar y o bje cti ves are as f oll o ws:  
•  T o de m o nstrate s u peri orit y wit h re gar d t o O S or P F S base d o n a n 
i n de pe n de nt re vie w c o m mittee assess me nt per R E CI S T 1. 1 i n N S C L C 
s u bjects wit h m o derate a n d hi g h e x pressi o n P D-L 1 + t u m ors  
•  T o de m o nstrate s u peri orit y wit h re gar d t o O S i n N S C L C s u bjects wit h 
a n y e x pressi o n P D -L 1 + t u m ors  
•  T o c o m parati vel y assess t he o bjecti ve res p o nse rate ( O R R) b y R E CI S T 
1. 1 of a vel u ma b vers us c he m ot hera p y i n hi g h, m o derate a n d hi g h, a n d 
a n y e x pressi o n P D -L 1 + t u m ors  
•  T o deter mi ne d urati o n of res p o nse of a vel u ma b vers us c he m ot hera p y T o 
c o m pare t he patie nt -re p orte d o utc o mes / q ualit y of life w he n treate d wit h 
a vel u ma b vers us c h e m ot hera p y usi n g t he E ur o pea n Q ualit y of Life 
(E ur o Q O L) 5 -di me nsi o ns q uesti o n naire ( E Q -5 D)  a n d t he E ur o pea n 
Or ga niz ati o n f or Res earc h a n d Treat me nt of Ca ncer ( E O R T C) Q L Q -C 3 0 
a n d m o d ule Q L Q -L C 1 3  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 6 /1 0 2  
 
 
•  T o deter mi ne t he safet y a n d t olera bilit y of a vel u ma b  
E x pl or at or y o bjecti ves  
Tri al desi g n a n d 
pl a n  
Met h o d ol o g y: T his is a m ultice nter, i nter nati o nal, ra n d o mize d, o pe n -la bel, 
P hase III trial i n c he m ot hera p y-n aï ve (first li ne) metastatic  or rec urre nt 
( Sta ge I V) N S C L C s u bjects c o m pari n g a vel u ma b t o first-li ne plati n u m-
base d  c he m ot hera p y. T he trial c o nsists of a 2 8 -da y s cree ni n g peri o d, 
f oll o we d b y t he treat me nt p hase (wit hi n 4 da ys aft er ra n d o mizati o n).  
T o ac hie ve t he tar get e nr oll me nt of 4 8 4  s u bjects ra n d o mize d wit h hi g h 
e x pressi o n P D -L 1 + t u m ors,  a p pr o xi matel y 1 1 3 1  eli gi ble s u bjects will be 
ra n d o mize d wit h a n y e x pressi o n P D-L 1 + t u m ors a n d  a p pr o xi matel y 3 1 0 0 
s u bjects will be scree ne d f or st u d y p artici pati o n. 
S u bjects will be ra n d o ml y all ocate d  i nt o t he 3 st u d y ar ms as f oll o ws: 
•  Ar m A: A vel u ma b at a d ose of 1 0 m g/ k g as a 1 -h o ur ( -1 0/ + 2 0 mi n utes) 
i ntra ve n o us (I V) i nf usi o n o nce e v er y 2 wee ks u ntil disease pr o gressi o n or 
u nacce pta ble t o xicities, or  
•  Ar m B: I n vesti gat or’s c h oice plati n u m c o ntai ni n g c h e m ot hera p y re gi me n 
t o be a d mi nistere d i n 3-wee k c ycl es u p t o a ma xi m u m of 6 c ycles of I V 
Gl o bal Versi o n I D: 
C CI
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 7 /1 0 2  
 
 
i njecti o n u ntil disease pr o gressi o n or u nacce pta ble t o xicities c o nsisti n g of 
o ne of t he f oll o wi n g:  
o  f or patie nts w h ose t u m or is of n o n-s q ua m o us hist ol o g y: 
▪ pe metre x e d ( 5 0 0 m g/ m 2) i n c o m bi nati o n wit h 
cis plati n ( 7 5 m g/ m 2 a d mi nistere d o n Da y 1 of eac h 
c ycle) or car b o plati n ( A U C 6  m g/ m L  x mi n  
a d mi nistere d o n Da y 1 of eac h c ycle).  
o  f or patie nts w h ose t u m or is of s q ua m o us hist ol o g y: 
▪ paclita xel ( 2 0 0 m g/ m 2) pl us car b o plati n ( A U C 6 
m g/ m L  x mi n  a d mi nistere d o n Da y 1 of eac h c ycl e) ; 
or  
▪ ge m cita bi ne ( 1 2 5 0 m g/ m 2 a d mi nistere d o n Da y 1 
a n d Da y 8) pl us cis plati n ( 7 5 m g/ m 2); or  
▪ ge m cita bi ne ( 1 0 0 0 m g/ m 2 a d mi nistere d o n Da y 1 
a n d Da y 8) pl us car b o plati n ( A U C 5  m g/ m L  x mi n).  
•  Ar m C: A vel u ma b at a d ose of 1 0 m g/ k g as a 1 -h o ur ( -1 0/ + 2 0 mi n utes) 
I V i nf usi o n e ver y wee k f or 1 2 c o nsec uti ve wee ks, f oll o we d b y a vel u ma b 
at a d ose of 1 0 m g/ k g o nce e v er y 2 wee ks u ntil disease pr o gressi o n or 
u nacce pta ble t o xicities  
S u bjects will be ra n d o ml y all ocate d t o o ne of t h e 3 treat me nt ar ms, i nitiall y 
i nt o Ar m A a n d Ar m B i n a 1: 1 rati o. T he all ocati o n rati o c ha n ge d  t o 1: 2: 2 
( Ar m A: Ar m B: Ar m C) o nce t he I D M C rec o m me n de d, J ul y 2 0 1 7, t he 
a vel u ma b o nce a wee k d osi n g re gi me n  t o be i ncl u de d i n t he ra n d o mizati o n 
sc he me after t he i nitial safet y e val u ati o n of a v el u ma b 1 0 m g/ k g e ver y wee k 
i n a c o h ort of 6 s u bjects.  
N S C L C hist ol o g y (s q ua m o us vers us n o n -s q ua m o us cell) will be use d as 
stratificati o n fact ors f or ra n d o mizati o n. T he P D-L 1 t u m or e x pressi o n le vel 
at baseli ne ( l o w e x pressi o n vers us 
m o derate e x pressi o n vers us hi g h 
e x pressi o n) will be s u p ple me nte d as ra n d o mizati o n strata f or t h e 1: 2: 2 
ra n d o mizati o n sc he me. 
T u m or meas ur e me nts b y c o m p ute d t o m o gra p h y ( C T) s ca n or ma g n etic 
res o na nce i ma gi n g (M RI) will be perf or me d e ver y 6  wee ks f or t he first 1 2 
m o nt hs a n d e ver y 1 2 wee ks t hereafter t o deter mi ne res p o nse t o treat me nt.  
Res p o nse will be e v al uate d usi n g t he Res p o nse E val uati o n Criteria i n S oli d 
T u m ors versi o n  1. 1 ( R E CI S T 1. 1) . 
Treat me nt wit h a vel u m a b 
will c o nti n ue u ntil disease pr o gressi o n or 
u nacce pta ble t o xicit y. S u bjects recei vi n g a v el u ma b w h o ha ve e x perie nce d a 
c o m plete res p o nse ( C R) s h o ul d be treate d f or a mi ni m u m of 1 2  m o nt hs 
a n d/ or u ntil disease pr o gressi o n or u nacce pta bl e t o xicit y , after c o nfir mati o n 
of res p o nse.  I n case a s u bject wit h a c o nfir me d C R rela pses after st o p pi n g 
treat me nt, o ne re-i nitiati o n of treat me nt is all o we d at t he discreti o n of t h e 
I n v esti gat or a n d a gree me nt of t he me dical m o nit or. 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 8 /1 0 2  
 
 
Treat me nt wit h c he m ot h era p y wil l c o nti n ue u ntil disease pr o gressi o n or 
u nacce pta ble t o xicit y or after t he c o m pleti o n of 6 c ycl es of c he m ot hera p y.  
S u bjects wit h n o n -s q ua m o us hist ol o g y are a ut h ori ze d t o c o nti n ue t o recei ve 
pe metre x e d as a mai nte na nce t hera p y aft er 4 c ycl es of plati n u m -ba se d 
c he m ot hera p y if t h eir dis ease h as n ot pr o gress e d, or i n acc or da nce wit h t he 
pe metre x e d l ocal la bel. N o ot her mai nte na n ce t h era p y is per mitte d .  
Decisi o ns re gar di n g me dical ma na ge m e nt of s u bj ects will be ma de b y t he 
I n v esti gat or; h o we ver, t he pri mar y a n d sec o n dar y e n d p oi nt deter mi nati o ns 
(res p o nse a n d pr o gressi ve disease [ P D]) will be acc or di n g t o t he ce ntr al 
i ma gi n g assess me nt a n d re vie w b y a bli n de d I n de p e n de nt 
Re vie w 
C o m mittee ( I R C). 
A d verse e v e nts ( A Es) will be assesse d t hr o u g h o ut t he trial a n d e val uate d 
usi n g t he Nati o nal Ca ncer I nstit ute ( N CI) C o m m o n Tec h n ol o g y Criteri a 
versi o n f or A d v erse E v e nts versi o n 4. 0 3 ( C T C A E v  4. 0 3).   
Peri o dic e val uati o ns of t he trial data will be c o n d ucte d  b y a n I n d e pe n d e nt 
Data 
M o nit ori n g C o m mittee (I D M C) t o e ns ure s u bject safet y, a n d t he 
vali dit y a n d scie ntific m erit of t he trial.  
•  E n d -of -Tre at me nt visit : wit hi n 7 da ys fr o m t he decisi o n t o disc o nti n ue, 
or bef ore t he start of a n y ot her a nti ne o plastic t h era p y i ncl u di n g a f ull 
safet y e val uati o n f or s u bj ects t hat h a ve disc o nti n ue d treat me nt d ue t o a n 
A E, a n d  
•  F oll o w -u p p h ase : Safet y F oll o w-u p visit 3 0 da ys ( ± 5 da ys) aft er t he last 
a d mi nistrati o n of trial treat me nt, f oll o we d b y a 9 0 -da y tel e p h o ne Safet y 
F oll o w -u p ( ± 1 wee k), a n d L o n g -ter m F oll o w-u p e ver y 1 2 wee ks ( ± 1 
wee k).  
Pl a n ne d n u m ber 
of s u bjects  
A p pr o xi matel y 3 1 0 0 s u bj ects will be scree ne d. Accr ual will pr ocee d u p t o a 
tar get n u m ber of a p pr o xi matel y 1 1 3 1  s u bjects ra n d o mize d 
wit h a n y 
e x pressi o n P D -L 1 + t u m ors i n or der t o o btai n at least 4 8 4  s u bjects 
ra n d o mize d wit h hi g h e x pressi o n P D L 1 + t u m ors. T his is base d o n t he 
esti mati o n t hat a m o n g s u bjects wit h a n y e x pressi o n P D -L 1 + t u m ors, 
a p pr o xi matel y 4 5 % of t h e m wi ll ha ve hi g h e x pressi o n P D-L 1 t u m ors . 
Pri m ar y 
e n d p oi nt 
T he pri mar y e n d p oi nt s f or t he trial are P F S  a n d O S. P F S is  defi ne d as t he 
ti me fr o m date of ra n d o mizati o n u ntil date of t he first d oc u me ntati o n of P D 
as deter mi ne d b y t h e I R C ( per R E CI S T 1. 1) or deat h  d ue t o a n y ca us e i n t he 
a bse nce of d o c u me nte d P D, w hic he ver o cc urs first . O S is defi ne d as t he ti me 
fr o m ra n d o mizati o n t o t h e date of d eat h, re gar dless of t he act ual ca us e of t he 
s u bject’s deat h. 
Sec o n d ar y/  
 
e n d p oi nts 
T he sec o n d ar y e n d p oi nts i ncl u de:  
•  B O R acc or di n g t o R E CI S T 1. 1 a n d as a dj u dicate d b y t he I R C  
•  D urati o n of res p o ns e acc or di n g t o R E CI S T 1. 1  
•  P atie nt-re p orte d o utc o mes/ q ualit y of life (assesse d b y t he E Q-5 D 5 L, 
a n d t he E O R T C Q L Q -C 3 0, a n d m o d ule Q L Q -L C 1 3 q uesti o n naires)  
Gl o bal Versi o n I D: C CI
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 9 /1 0 2  
 
 
•  S afet y e n d p oi nts (i ncl u di n g A Es, cli nical la b orat or y assess me nts, 
vital si g ns, 
p h ysical 
e x a mi nati o n, 
electr o car di o gra m [ E C G] 
para meters, a n d E C O G P S).  
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 0 /1 0 2  
 
 
Gl o bal Versi o n I D: C CI
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 1 /1 0 2  
 
 
6. 2  
R a n d o miz ati o n   
Q ualifie d s u bjects will be ra n d o ml y all ocate d t o t he treat me nt gr o u ps t o recei v e a vel u ma b 
1 0  m g/ k g o nce e v er y 2 wee ks ( Ar m A) or c he m ot hera p y ( Ar m B) or a vel u ma b 1 0 m g/ k g o nce a 
wee k f or 1 2 c o ns ec uti ve we e ks, f oll o we d b y a vel u ma b at a d ose of 1 0 m g/ k g o n ce e ver y 2 wee ks 
( Ar m C), usi n g str atifie d per m ute d bl oc k ra n d o mizati o n via t he I W R S. 
S u bjects will be ra n d o ml y all ocate d, i nitiall y i nt o Ar m A a n d Ar m B i n a 1: 1 rati o.   
After t he i nitial safet y e v al uati o n  of a v el u ma b 1 0 m g/ k g e v er y wee k i n a c o h ort of 6 s u bjects  wa s 
c o n d ucte d, t he I D M C rec o m me n de d t o ha ve t he a vel u ma b o nce a wee k d osi n g re gi me n i ncl u de d 
i n t he ra n d o mizati o n sc he me, c ha n gi n g the all ocati o n rati o t o 1: 2: 2 a m o n gst t he t hree ar ms ( Ar m 
A: Ar m B : Ar m C). T his safet y c o h ort of 1 0  s u bj ects ( 4 a d diti o nal s u bjects were e nr olle d i n t he 
safet y c o h ort after t he i nitial 6) treate d wit h a vel u ma b 1 0 m g/ k g o nce a wee k f or 1 2 c o nsec uti ve 
wee ks, f oll o we d b y a vel u ma b at a d ose of 1 0 m g/ k g o n ce e ver y 2 wee ks w as n ot c o nsi dere d f or 
t he ra n d o mizati o n pr ocess. 
T he N S C L C hist ol o g y (s q ua m o us vers us n o n -s q ua m o us cell) will be use d as stratificati o n fact or 
f or ra n d o mizati o n. T he P D-L 1 t u m or e x pressi o n le vel at baseli ne ( l o w e x pressi o n vers us m o derat e 
e x pressi o n vers us hi g h e x pressi o n) will be s u p ple me nte d as ra n d o mizati o n strata f or t he 1: 2: 2 
ra n d o mizati o n sc he me. T he p ur p ose of str atificati o n is t o e ns ure bala nce d distri b uti o n of fact ors 
wit h p ote ntial pr o g n ostic or pre dicti ve i m pact of res p o nse fact ors bet w ee n treat me nt ar ms.  
Ra n d o mizati o n will occ ur u p o n c o m pleti o n of t he Scree ni n g pr oce d ures a n d d eter mi nati o n of 
s u bject eli gi bilit y, usi n g a stratifie d per m ute d bl oc k ra n d o mizati o n via I W R S as descri be d i n 
Secti o n 6. 3 of t he st u d y cli nical pr ot oc ol.  
7  
O ver vie w of Pl a n ne d  A n al yses   
T his S A P c o vers t he a nal ys es f or efficac y a n d safet y base d o n t h e data c ut -off date s f or t he i nteri m 
a n d fi nal a n al yses. Statistical a nal yses will be perf or me d usi n g clea ne d e C R F data , ce ntr al 
la b orat or y data as well as data of t u m or assess me nt res ults  a dj u dicate d b y t he I n de pe n d e nt Re vie w 
C o m mittee (I R C)  a n d Healt h -relate d q ualit y of life ( H R Q o L) dat a a n d bi o mar ker data , w hic h are 
c ollecte d b y a n e xter nal ve n d or.  
N o data base ca n be l oc ke d a n d n o ra n d o mizati o n c o de or P D -L 1 stratificati o n s h o ul d be u n bli n de d 
u ntil t his S A P has bee n a p pr o ve d . 
All data will be i ncl u de d u p t o a pr os pecti vel y det er mi ne d cli nical c ut -off d ate.  
T he data c ut -off f or t he i nteri m a n d t he fi nal a nal ysis will be pr os pecti vel y d eter mi ne d base d o n 
e ve nt pr ojecti o n pr o vi de d b y t he u n bli n de d tea m. F or t he i nteri m P F S a n d O S a nal ysis, t he cli nical 
c ut-off d ate will b e t he d ate o n w hic h a p pr o xi matel y 1 3 0  O S e v e nts  f or ar ms C a n d B are e x pecte d  
i n hi g h e x pressi o n P D -L 1 + s u bjects  base d o n t he e ve nt pr ojecti o ns perf or me d b y t he u n bli n de d 
tea m, a n d a mi ni m u m f oll o w -u p of 1 0 m o nt hs . F or t he fi nal P F S a n d fi n al O S a nal ysis, t he cli nical 
c ut-off d ate will b e t he d ate o n w hic h a p pr o xi matel y 1 7 3  O S e v e nts  for ar ms C a n d B  are e x pecte d 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 2 /1 0 2  
 
 
i n hi g h e x pressi o n P D-L 1 + s u bjects  base d o n t he e ve nt pr ojecti o ns perf or me d b y t he u n bli n de d 
tea m, a n d a mi ni m u m f oll o w -u p of 2 0  m o nt hs .  
Si nce t he o bser ve d n u m b er of e ve nts at t he i nteri m a nal ysis ma y n ot b e e x actl y e q ual t o t he pla n ne d 
1 3 0 O S  e ve nts  i n hi g h e x pressi o n P D-L 1 + s u bjects , t he efficac y b o u n dar y will be u p date d base d 
o n t he act ual n u m ber of o bser ve d e v e nts usi n g t he pre -s pecifie d al p h a-s pe n di n g f u ncti o n. T h e 
o bser ve d Z -test statistic at t he i nteri m a nal ysis will be c o m pare d wit h t he u p date d efficac y 
b o u n dar y. F or t he fi nal a nal ysis, if t he n u m ber of O S  e ve nts de viates fr o m t he tar get n u m ber of 
1 7 3  O S  e ve nts  i n hi g h e x pressi o n P D-L 1 + s u bjects , t he fi nal a nal ysis criteria will be deter mi ne d, 
ta ki n g i nt o acc o u nt t he act ual al p ha s p e nt at t he i nt eri m a n al ysis a n d t he act ual ass ociati o n b et wee n 
t he t w o test z-scales as s pecifie d i n Ta ble 2 , Secti o n 7. 2  s o t hat t he o verall o ne-si de d si g nifi ca nce 
le vel is c o ntr olle d at 0. 0 2 5.  
Si nce t he f or mal effic ac y b o u n daries will be us e d at t he i nteri m a nal ysis f or t he statistical testi n g 
of P F S  or O S , a statisticall y si g nifica nt fi n di n g at t he i nteri m will be i nte n de d t o clai m s u peri orit y.  
T he pla n ne d a n al yses i ncl u de:  
•  A n i nteri m P F S a n d O S a nal ysis  
•  A fi nal P F S a n d O S a nal ysis  
•  A f oll o w -u p a nal ysis  
A  se parate S A P c o v ers t he peri o dic safet y re vie w a n d i nteri m P F S  a n d O S  a nal ysis b y t he 
I n d e pe n de nt Data M o nit ori n g C o m mittee (I D M C). 
Se parate or s u p ple me ntal a nal ysis pla ns mi g ht be writte n t o c o ver:  
•  T he a nal ysis f or P o p P K, e x p os ure/efficac y a n d e x p os ure/safet y d ata t o s u p p ort t he 
S u m mar y  of Cli nical P har mac ol o g y  w he n a p pr o priate  
•  A d diti o nal a nal yses of p atie nt re p orte d o utc o mes ( P R O)  (i.e. E Q-5 D, E O R T C Q L Q -C 3 0 
a n d E O R T C Q L Q -L C 1 3)  
7. 1  
Se q ue nce of A n al ys es  
T he f oll o wi n g a nal yses will be perf or me d d uri n g t his trial. As t he  d ata c ut -off d ate f or b ot h t he 
i nteri m effic ac y a n d pri mar y a n al ys e s will be pr os pecti vel y deter mi ne d bas e d o n e ve nt pr ojecti o n 
pr o vi de d  b y t he u n bli n de d tea m, t he act ual n u m ber of O S  e ve nts m a y sli g htl y differ fr o m t he 
pla n ne d n u m ber as i n dicate d bel o w.  
•  I nteri m P F S a n d O S a nal ysis:   
o  T his a nal ysis will be perf or me d after a p pr o xi matel y 1 3 0 O S  e ve nts (7 5 %) ha v e 
bee n o bser ve d i n hi g h e x pressi o n P D -L 1 + s u bject s a n d a mi ni m u m f oll o w -u p of 1 0 
m o nt hs  i n ar ms B a n d C ( m F A S).  
•  Fi nal P F S a n d O S a nal ysis: 
Gl o bal Versi o n I D: C CI
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 3 /1 0 2  
 
 
o  T hi s a nal ysis will be perf or me d after a p pr o xi matel y 1 73  O S e ve nts ( deat h) ha v e 
bee n o bser ve d i n hi g h e x pressi o n P D -L 1 + s u bjects  a n d a mi ni m u m f oll o w -u p of 2 0 
m o nt hs  i n ar ms B a n d C ( m F A S) . 
T here will be a partial data base l oc k f or b ot h t he i nteri m a n d pri mar y a n al yse s.  
T here will be o n g oi n g p eri o dic safet y re vi e w s b y t he I D M C. Details are pr o vi de d i n t he I D M C 
c harter a n d t he I D M C S A P.  
7. 2  
I nteri m A n al ysis  
T his i nteri m a nal ysis will i ncl u de t he a n al ysis of t he P F S a n d O S pri mar y e n d p oi nt s, sec o n dar y 
e n d p oi nt s i ncl u di n g B OR , a n d safet y.  Descri pti ve statistics will a ls o be re p orte d i ncl u di n g s u bject 
dis p ositi o n, de m o gra p hics, me dical hist or y a n d ot her bas eli ne c h aracteristi cs, al o n g wit h safet y 
i nf or mati o n (a d vers e e ve nts, deat hs, a n d cli nical l a b orat or y e val uati o n) . 
A n I D M C will be f or me d a n d will be res p o nsi ble f or peri o dic safet y e val u ati o ns of t he trial as well 
as t he e val uati o n of t h is i nteri m efficac y a nal ysis. T he I D M C will c o nsist of a gr o u p of fi ve e x perts 
w h o will be neit her partici pa nts i n t he trial n or e m pl o yees of t he S p o ns or of t his trial, n or t he 
i n de pe nde nt statistical pr o vi der w h o is n ot a v oti n g me m ber of t he I D M C. A n I D M C c harter 
pr o vi de s details a b o ut t he c o n d uct of t he I D M C meeti n g a n d decisi o n ma ki n g r ules.  
T he i nteri m a n al ysis will test t he h y p ot heses f or P F S: H 0 _ 1 A, H 0 _ 1 C, H 0 _ 3 A, H 0 _ 3 C a n d t he h y p ot heses 
f or O S: H 0 _ 2 A, H 0 _ 2 C, H 0 _ 4 A, H 0 _ 4 C, H 0 _ 6 A, H 0 _ 6 C after t he re q uire d n u m ber of O S e ve nts f or t he i nteri m 
a nal ysis f or Ar m  C + B h a ve b ee n reac he d a n d 1 0 m o nt hs ha ve ela ps e d fr o m t he last s u bject 
ra n d o mize d f or t he hi g h e x pressi o n P D-L 1 a n al ysis  set i n m F A S (see Ta bl e 2 ). 
Pri mar y P F S a n d O S a nal ys es will be c o n d ucte d after t he re q uir e d n u m ber of O S e ve nts f or Ar m 
C + B ha ve b ee n reac h e d a n d at least 2 0 m o nt hs h a ve bee n ela pse d fr o m last s u bject ra n d o mize d 
f or t he hi g h e x pressi o n P D-L 1 a nal ysis set i n m F A S.  T he c urre nt pla n c o nsi ders  
•  1 3 0 O S e ve nts f or Ar m C a n d B a n d a mi ni m u m f oll o w -u p of 1 0 m o nt hs t o deter mi ne t he 
c ut-off dat e f or t he i nteri m P F S a n d O S a nal ys es.  
•  1 7 3 O S e v e nts a n d a mi ni m u m f oll o w -u p of 2 0 m o nt hs f or t h e fi nal P F S a n d O S a n al ys es.  
Ta ble 2  descri bes t he e x pecte d n u m ber of e ve nts, i nf or mati o n fracti o n, t he ass ociate d c u m ulati ve 
al p ha s pe n di n g a n d t h e c orres p o n di n g e x pecte d efficac y b o u n d aries, u n d er pr o p orti o nal hazar d 
ass u m pti o ns. T he act ual n u m bers i n partic ular f or t he Ar m A a n d B c o ul d var y as t he e ve nt siz e at 
t he pla n ne d c ut-off dates is u n k n o w n. T he al p ha le vels are h o we ver fi x e d acc or di n g t o La n -De M ets 
α -s pe n di n g wit h O’ Brie n-Fle mi n g -li ke b o u n daries.   
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 4 /1 0 2  
 
 
 T a ble 2  
I nteri m A n al yses    
Pri m ar y I nf er e nti al 
A n al y s e s  
( hi g h e x pr e s si o n P D-L 1)  
E x p e ct e d 
n u m b er of 
e v e nt s  
I nf or m ati o n 
fr a cti o n 
C u m ul ati v e al p h a 
s p e nt  
Effi c a c y b o u n d ar y 
H R  
I A –  P F S  
 
 
 
 
Ar m A v s. B ( F A S)  
2 2 8  
9 1 %  
0. 0 0 2 6 9 9 4  
0. 6 9  
Ar m C v s. B ( m F A S)  
1 4 6  
8 4 %  
0. 0 0 6 3 9 6 9  
0. 6 6  
Fi n al P F S  
 
 
 
 
Ar m A v s. B ( F A S)  
2 5 0  
1 0 0 %  
0. 0 0 4 1 7 0  
0. 7 1  
Ar m C v s. B ( m F A S)  
1 7 4  
1 0 0 %  
0. 0 1 2 5 0 0  
0. 7 0  
I A –  O S  
 
 
 
 
Ar m A v s. B ( F A S)  
2 1 4  
8 3 %  
0. 0 0 0 7 2 4 1  
0. 6 4  
Ar m C v s. B ( m F A S)  
1 3 0  
7 5 %  
0. 0 0 1 6 0 9  
0. 6 0  
Fi n al O S  
 
 
 
 
Ar m A v s. B ( F A S)  
2 5 8  
1 0 0 %  
0. 0 0 2 0 8 0  
0. 6 9  
Ar m C v s. B ( m F A S)  
1 7 3  
1 0 0 %  
0. 0 0 6 2 5 0  
0. 6 8  
F A S: f ull a n al y si s s et, H R: h a z ar d r ati o, I A: i nt eri m a n al y si s, m F A S: m o difi e d f ull a n al y si s s et, O S: o v er all s ur vi v al, 
P F S:  pr o gr e s si o n fr e e s ur vi v al.  
T he i nteri m O S a n d P F S a nal ysis will be c o n d ucte d o n t he m F A S  f or ar m C vs. B c o m paris o n a n d 
o n t he F A S f or ar m A vs. B c o m p aris o n , wit h t he pri mar y a n al ysis p o p ulati o n bei n g t he hi g h P D -
L 1 + s u bset of t he m F A S  a n d F A S . T he I D M C will als o be pres e nte d wit h s u bject dis p ositi o n, 
s u bject bac k gr o u n d, b aseli ne disease a n d d e m o gra p hic i nf or mati o n, al o n g wit h safet y i nf or mati o n. 
Details of t he I D M C missi o n, c o m p ositi o n, a n d o perati o ns are pr o vi de d i n t he I D M C c hart er.  
A n i n de pe n d e nt statistical pr o vi der will perf or m t h e  u n bli n de d  i nteri m s afet y a n d efficac y a nal ysis 
t o s u p p ort t he I D M C. After t he pr os pecti vel y det er mi ne d data c ut -off date is reac he d w he n t he 
deter mi ne d n u m ber of O S  e ve nts i n hi g h e x pressi o n P D -L 1 + s u bjects is a p pr o xi matel y o bs er ve d 
f or t he i nteri m a nal ysis, t he i n de pe n de nt statistical pr o vi der will pre pare t he o ut p uts  ( usi n g 
pr o gra ms pre pare d b y t h e bli n de d  t ea m b ase d o n d u m m y treat me nt a n d P D -L 1 + v aria bles ) i n 
a gree m e nt wit h t he I D M C c harter a n d tr a ns mit t he a n al ys es, ta b ulati o ns, a n d listi n gs t o t he I D M C 
f or t he meeti n g. Res ults fr o m t he i nteri m safet y a n d efficac y a nal ysis will be tra ns mitte d fr o m t he 
i n de pe n de nt, u n bli n de d statisticia n t o t he I D M C o nl y. T he i n de pe n de nt statisticia n will be 
a vaila ble at t he ID M C m eeti n g s h o ul d a n y q u esti o ns fr o m t he I D M C me m bers arise re gar di n g t he 
data a n d / or a n al yses.  
A cl ose d testi n g pr oce d ure wit h hierarc hicall y or dere d h y p ot h eses is a p plie d i n t he st u d y . If t he 
o ne -si de d p-v al ue fr o m t he stratifie d l o g -ra n k test of P F S  or O S  i n hi g h e x pressi o n P D-L 1 + 
s u bjects is bel o w t he si g nifica nce le vel at t he i nteri m a nal ysis base d o n a La n -De Mets al p ha 
s pe n di n g f u ncti o n f or O’ Brie n-Fle mi n g b o u n d aries ( see Ta ble 2 ), t he treat me nt differe nce will be 
clai me d as statisticall y si g nifica nt a n d t he ne xt ste p i n  t he hierarc hical testi n g strate g y will be 
teste d (see S ecti o n 1 5. 1. 1 ). If, at t he ti me of t his i nteri m a nal ysis, t he P F S  or O S of a v el u ma b 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 5 /1 0 2  
 
 
assi g ne d s u bjects is s h o w n t o be s u peri or t o t hat of t h ose ra n d o mize d t o t he c h e m ot hera p y gr o u p  
i n hi g h e x pressi o n P D-L 1 +  s u bjects wit h a p -val ue bel o w  t he si g nifica nce le vel at t he i nteri m 
a nal ysis base d o n a La n -De Mets al p h a s pe n di n g f u ncti o n f or O’ Brie n -Fl e mi n g b o u n daries ( see 
Ta ble 2 ), t he I D M C ma y declare s u peri or efficac y i n t he a vel u ma b treat me nt ar m c o m pare d wit h 
t h ose ra n d o mize d t o recei ve c he m ot hera p y. T his i nteri m a nal ysis of P F S  a n d O S will be perf or me d 
i n a ma n n er i de ntic al t o t he fi nal efficac y a n al ysis. Details of hi erarc hical testi n g strate g y are 
pr o vi de d i n Secti o n 1 5. 1. 1 . I n cas e of a p ositi ve i nteri m a nal ysis (i.e. at least o ne reject e d n ull 
h y p ot hesis i n eit her t he c o m paris o n of C vers us B or A vers us B  f or P F S or O S) all a nal yses 
descri be d i n t his S A P will be perf or m e d t o facilitate re p ort writi n g.  
A partial data b ase l oc k will be perf or me d f or t he i n teri m a nal ysis. A d ata re vie w meeti n g will be 
hel d pri or t o t he i nteri m a nal ysis.  
7. 3  
Fi n al A n al ysis   
T his a nal ysis will i ncl u de t he fi nal a nal ysis, or s o calle d pri mar y a n al ysis, of t he P F S a n d O S 
pri mar y e n d p oi nt s, a n d a nal ysis of sec o n dar y e n d p oi nts i ncl u di n g B OR , a n d safet y. Descri pti ve 
statistics will als o be re p orte d i ncl u di n g s u bject dis p ositi o n, de m o gra p hics, me dical hist or y , a n d 
ot her baseli ne c haracteristics, al o n g wit h safet y i nf or mati o n  (a d v erse e ve nts, deat hs, a n d cli nical 
la b orat or y e v al uati o n). 
F or t his tri al t he fi nal efficac y a nal ysis will b e c o n d ucte d after t he pr os pecti vel y d eter mi ne d dat a 
c ut-off d ate w h e n t he n u m ber of O S  e v e nts i n hi g h e x pressi o n P D -L 1 + s u bjects reac h es 
a p pr o xi matel y 1 7 3  i n ar ms B a n d C ( m F A S) base d o n t he e v e nt pr ojecti o n pr o vi de d b y t he 
u n bli n de d tea m  a n d a mi ni m u m f oll o w -u p of 2 0 m o nt hs is o bser ve d . T he O’ Brie n-Fl e mi n g 
i nf or mati o n fracti o n f or t y p e I err or a n d t he efficac y b o u n d aries bas e d o n a La n-De M ets s pe n di n g 
f u ncti o n are prese nte d i n Ta ble 2  f or differe nt n u m ber of P F S a n d O S e ve nts i n hi g h e x pressi o n 
P D -L 1 + s u bjects at t he i nteri m a nal ysis  a n d will be a dj uste d f or fi nal P F S  a n d O S  a nal ysis . N o 
i nfere ntial efficac y a n al ysis will be perf or me d f or h y p ot h eses t hat are rejecte d at t he i nteri m 
a nal ysis. I n t his sit uati o n, a nal ysis ma y be c o n d u cte d t o e n h a nce precisi o n of esti mates after t he 
st u d y is deter mi ne d t o st o p earl y at t he i nteri m a nal ysis. H y p ot hes es t hat ca n n ot be reject e d at 
i nteri m ca n be teste d at t he fi nal a nal ysis f oll o wi n g t he hierarc hical testi n g pr oce d ure at t he 
re mai ni n g si g nifica nce le vel base d o n t h e La n-De Mets al p ha s p e n di n g f u ncti o n f or O’ Brie n -
Fle mi n g b o u n d aries t o c o ntr ol t he o verall T y pe 1 err or rate at 0. 0 2 5 ( o n e -si de d). 
St u d y staff i n v ol ve d wit h t he da y t o d a y ma na ge m e nt of t he tri al, as well as a n y s p o ns or staff, will 
n ot ha ve access t o t he res ults u n bli n de d t o b ot h treat me nt gr o u p a n d e x pressi o n P D -L 1 + stat us  
u nless t he trial is st o p pe d at i nteri m as rec o m me n d e d b y t h e I D M C . 
A partial data b ase l o c k will be perf or me d f or t he fi nal P F S a n d  O S a nal ysis . A data re vi e w m eeti n g 
will be hel d pri or t o t he fi nal P F S a n d O S a nal ysis . 
7. 4  
F oll o w -u p a n al ysis   
S u bject f oll o w -u p f or pr o gressi o n a n d s ur vi val will c o nti n ue u ntil 5 years after t h e last s u bject 
recei v es t he l ast d ose of a vel u ma b. T h e S p o ns or ma y t er mi nate t h e st u d y at a n y ti me o n ce access 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 6 /1 0 2  
 
 
t o i n vesti gati o nal me dici nal pr o d uct (I M P) f or s u bjects still be nefitti n g is pr o visi o ne d via a r oll 
o ver st u d y, e x pa n de d access, mar kete d pr o d uct  or a n ot her mec h a nis m of access as a p pr o priate.  
T heref ore , t he f ull data base l oc k will ta ke place eit her 5 years after t he last s u bject recei ves t he 
last d ose of a vel u ma b or after t he S p o ns or deci des t o ter mi nate t he st u d y , w hic he ver occ urs first.  
F oll o w -u p a n al ysis will i ncl u de s u bject stat us a n d s ur vi val f oll o w-u p i nf or mati o n i n a listi n g . 
De pe n di n g o n t he stat us of t he st u d y , a d diti o nal varia bles, e. g. f or safet y, ma y als o be i ncl u de d.  
8  
C h a n ges t o t he Pl a n ne d A n al yses i n t he Cli nic al Tri al Pr ot oc ol   
T he statistical met h o ds s pecifie d i n t his d oc u me nt are i n acc or da nce wit h pr ot oc ol versi o n 6 . 0 
( date d 0 3 J a n uar y 2 0 1 9 ).  
8. 1  
C O VI D -1 9 I m p act   
N o c ha n ges t o t he pla n ne d a nal ysis of t he efficac y e n d p oi nts will be perf or me d d ue t o t he i m pact 
of C or o na vir us diseas e 2 0 1 9 ( C O VI D -1 9) o ut brea k.  
A d diti o nal o ut p uts (s u m mar y ta ble a n d listi n g) will be ge nerat e d t o des cri be t he i m pact of C O VI D -
1 9 i n ter ms of t he f oll o wi n g:  
•  O n -treat me nt d uri n g t he pa n de mic 
•  O n -st u d y d uri n g t h e pa n de mic 
•  P ote ntiall y affecte d b y C O VI D -1 9  
•  A d verse eve nts  
•  C O VI D -1 9 vacci nati o ns  
•  C O VI D -1 9 vacci nati o n ass ociate d A Es   
•  Pr ot oc ol de viati o ns (i m p orta nt a n d n o n-i m p orta nt) 
•  Misse d v isits (i ncl u di n g n u m ber of misse d visits) 
•  Misse d  or dela ye d  effic ac y e val uati o ns  
•  Dr u g ad mi nistrati o n - misse d d oses  
•  Treat me nt d isc o nti n uati o n 
•  Disc o nti n uati o n of st u d y sssess me nts 
•  St u d y d is c o nti n uati o n 
•  Deat h  
T he start of C O VI D -1 9 pa n de mic will be defi ne d b y c o u ntr y as t he earlier of t he date of t he first 
deat h fr o m C O VI D -1 9 acc or di n g t o t he p u blis he d data b y E ur o pea n Ce ntr e f or Disease Pre ve nti o n 
a n d C o ntr ol o n 2 6t h J u ne 2 0 2 0 ( htt ps:// w w w.ec dc. e ur o pa. e u/e n/ p u blicati o ns -data/ d o w nl oa d -
t o da ys-d ata -ge o gra p hi c -distri b uti o n -c o vi d-1 9 -cases -w orl d wi de ) or 1 1t h M arc h 2 0 2 0 ( w he n t he 
W H O declare d t h e C O VI D -1 9 pa n de mic).  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 7 /1 0 2  
 
 
C O VI D -1 9 relate d A Es  defi ne d b y t he Me d D R A C O VI D -1 9 S M Q f or t he s pecific Me d D R A versi o n 
use d f or fi nal c o di n g.  S u m maries will i ncl u de:   
•  A ta ble wit h T E A Es ass o ciate d t o C O VI D -1 9, w he n ≥ 1 0 patie nts wit h A Es are o bser ve d . 
•  A listi n g c o m prisi n g all C O VI D -1 9 relate d A E t er ms.  
T he W H O -D D sta n d ar di ze d dr u g gr o u pi n g ( S D G) “ Vacci nes f or C O VI D -1 9” is a s u b gr o u p of t he 
o verarc hi n g S D G “ Dr u gs a n d vacci nes f or C O VI D -1 9”. T h e vacci ne -relate d S D G is f urt her 
s u b di vi de d i nt o s u b gr o u p S D Gs i de ntif yi n g t y pe of vacci ne (e. g. D N A vacci nes f or C O VI D -1 9, 
I n acti vate d vacci nes f or C O VI D-1 9, etc.) .  A ta ble wit h o v erall n u m ber of patie nts wit h 
vacci nati o ns recei ve d b y S D G s u b gr o u ps a n d p r o d uct na me ( preferre d ter m) will be pr o d uce d if  ≥ 
1 0 patie nt s wit h vacci nati o ns are o bser ve d. A listi n g will be create d re gar dless of t he n u m ber of 
s u bjects vacci n ate d. 
A fre q u e nc y ta ble will be pr o d uce d f or t he f ull a nal ysis set t o prese nt t he n u m ber of s u bjects wit h  
a n y pr ot o c ol de viati o ns relate d t o C O VI D -1 9 (c ate g orize d b y fre q u e nc y of s u bjects wit h a pr ot oc ol 
de viati o n o verall as well as b y cat e g or y a n d t y p e of pr ot oc ol de viati o n).  I m p orta nt a n d n o n -
i m p orta nt pr ot oc ols de viati o ns will be c o m bi ne d f or t his s u m mar y. I n a d diti o n, a listi n g of  
pr ot oc ol de viati o n s attri b ute d t o C O VI D-1 9 will als o be pr o d uce d.  
8. 2  
Dis p ositi o n of S u bjects a n d Disc o nti n u ati o ns   
A n alysis sets: Scree ni n g A n alysis Set / F A S / m F A S by P D -L 1 ex pressi o n st at us  / S afety C o h ort 
A n alysis Set  
T he f oll o wi n g will be s u m marize d o verall a n d per treat me nt gr o u p i n t he scree ni n g a n al ysis set. 
T he s u m mar y will als o be prese nte d f or all F A S s u bjects a n d m F A S s u bjects, b y e x pressi o n P D -
L 1 + stat us (a n y, m o derate -a n d-hi g h, hi g h), sta rti n g fr o m “ N u m ber a n d perce nta ge of ra n d o mize d 
s u bjects”. T he p erce nta ges bel o w will be calc ulat e d base d o n t he n u m ber of s u bjects i n t he F A S 
a n d m F A S b y e x pressi o n P D -L 1 + stat us, res pecti vel y:  
•  T otal n u m ber of s u bjects scree n e d o verall  
•  N u m ber of s u bjects  w h o disc o nti n ue d fr o m t he trial pri or t o ra n d o mizati o n o verall a n d 
gr o u pe d b y t he mai n r eas o n (i.e. scree n fail ures)  
•  N u m ber a n d p erce nta ge of ra n d o mize d s u bjects i n t he f oll o wi n g p o p ulati o ns:  
•  F A S  
•  m F A S  
•  H R Q o L -A S  
•  m H R Q o L -A S  
•  Safet y -A S  
•  P K a nal ysis set  
•  N u m ber a n d p erce nta ge of s u bjects ra n d o mize d b ut n ot treate d  
•  N u m ber a n d p erce nta ge of s u bjects w h o recei ve d at least o ne d ose of treat me nt  
•  N u m ber a n d p erce nta ge of ra n d o mize d s u bjects still o n treat me nt  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 8 /1 0 2  
 
 
•  N u m ber a n d p erce nta ge of ra n d o mize d s u bjects w h o c o m plete d t reat me nt 
N ote : treat me nt c o m plet e d if deat h, P D or 6-c ycles of c he m ot hera p y f or at least o ne 
c he m ot hera p y c o m plete d  
•  N u m ber a n d perce nta ge of ra n d o mize d s u bjects w h o disc o nti n ue d treat me nt a n d reas o ns 
f or treat me nt disc o nti n uati o n 
•  N u m ber a n d perce nt a ge of r a n d o mize d s u bjects 
w h o disc o nti n ue d o ne dr u g i n 
c he m ot hera p y ar m b ut are still o n treat me nt  
•  N u m ber a n d perce nta ge of s u bjects w h o disc o nti n ue d or c o m plete d  t he treat me nt b ut are 
still i n f oll o w-u p  i ncl u di n g n u m ber of s u bjects still i n f oll o w-u p f or P F S a n d  t h ose still i n 
f oll o w-u p f or O S  
•  N u m ber a n d p erce nta ge of s u bjects w h o re-i nitiat e d a vel u ma b treat me nt, a n d n u m ber of 
c o m pleti o ns ( deat h or P D) a n d disc o nti n uati o ns after re -i nitiati o n 
•  N u m ber a n d p erce nta ge of s u bjects w h o s witc h e d t o a vel u ma b after pr o gre ssi o n i n t he 
c he m ot hera p y ar m, a n d n u m ber of c o m pleti o ns ( deat h or P D) a n d disc o nti n uati o ns a n d 
disc o nti n uati o n reas o ns after s witc h  
•  N u m ber a n d p erce nta ge of ra n d o mize d s u bjects w h o disc o nti n ue d trial  
•  N u m ber a n d p erce nta ge of ra n d o mize d s u bjects p er reas o n f or tri al disc o nti n uati o n 
T he res ults of t he ra n d o mizati o n al g orit h m (acc or di n g t o I W R S) will be s u m marize d as f oll o ws 
f or all ra n d o mize d s u bjects: 
•  N u m ber a n d perce nta ge of ra n d o mize d s u bjects o verall, b y re gi o n ( E ur o pea n Ec o n o mic 
Area ( E E A), re q uir e d b y E u dra C T), N ort h A merica, Lati n A merica, Asi a, A ustralasia, 
Africa a n d Mi d dle East), b y c o u ntr y wit hi n re gi o n  
•  N u m ber a n d p erce nta ge of ra n d o mize d s u bjects b y ce nter  
•  N u m ber a n d p erce nta ge of ra n d o mize d s u bjects b y ra n d o mizati o n strata (I W R S)  
•  N u m ber a n d p erce nta ge of ra n d o mize d s u bjects b y ra n d o mizati o n strata (e C R F)  
•  Cr oss ta b ulati o n: strat u m b y I W R S vs. strat u m b y e C R F ( hist ol o g y o nl y)  
•  Cr oss ta b ulati o n: s u bjects ra n d o mize d (a vel u ma b/c he m ot hera p y/a vel u ma b wee kl y) vs. 
s u bjects treate d (a vel u ma b/c he m ot hera p y/a vel u ma b wee kl y/ n o t treate d)  
•  Reas o ns if ra n d o mize d is differe nt fr o m treate d  
9  
A n al ysis Sets   
Scree ni n g A n al ysis Set  
T he scree ni n g a nal ysis set  will  i ncl u de all s u bjects w h o si g ne d t h e i nf or me d c o nse nt.  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 9 /1 0 2  
 
 
F ull A n al ysis Set   
T he f ull a nal ysis set ( F A S) will i ncl u de all s u bjects w h o were ra n d o mize d t o st u d y treat me nt. 
A nal ys es perf or me d o n t he F A S will ta ke i nt o acc o u nt s u bjects’ all ocati o n t o treat me nt gr o u ps as 
ra n d o mize d. F or s u bjects w h o are ra n d o mize d m or e t ha n o n ce wit h differe nt s u bject i de ntifier, t he 
first ra n d o mizati o n will be use d i n t he a nal ysis set. 
M o difie d F ull A n al ysis Set  
T he m o difie d F A S ( m F A S) is defi ne d as t he F A S restricte d t o s u bjects w h o were ra n d o ml y 
assi g ne d t o treat me nt acc or di n g t o C T P versi o n 4. 0 or later, after Ar m C wa s acti vate d i n t he 
treat me nt all ocati o n.  
T he  3 6 s u bjects w h o w ere ra n d o mize d after i m ple me nta ti o n of pr ot oc ol v ersi o n 4. 0, b ut acc or di n g 
t o pr ot oc ol versi o n 3. 0, will be i ncl u de d i n t he F A S b ut n ot i n t he m F A S. 
H R Q o L A n al ysis Set  
T he H R Q o L a n al ysis set ( H R Q o L-A S) is a s u bset of t he F A S a n d will i ncl u de all F A S s u bjects 
w h o meet b ot h of t he f oll o w i n g criteria: 
•  Ha ve at least o ne bas eli ne H R Q o L q uesti o n naire c o m plete d  
•  Ha ve at least o ne p ost -baseli ne H R Q o L q uesti o n naire c o m plete d  
M o difie d H R Q o L A n al ysis Set  
T he m o difie d H R Q o L a nal ysis set ( m H R Q o L A S) is a s u bset of t he m F A S a n d will i ncl u de  all 
m F A S s u bjects w h o meet b ot h of t he f oll o wi n g criteria:  
•  Ha ve at least o ne bas eli ne H R Q o L q uesti o n naire c o m plete d  
•  Ha ve at least o ne p ost -baseli ne H R Q o L q uesti o n naire c o m plete d  
S afet y A n al ysis Set    
T he Safet y a nal ysis set ( Safet y-A S) will i ncl u de all ra n d o mize d s u bjects w h o were a d mi nistere d 
at least o n e d os e of t he st u d y m e dicati o n, i.e. a v el u ma b or c he m ot hera p y. A nal ys es p erf or m e d o n 
t he Safet y a nal ysis set will ta ke i nt o acc o u nt s u bj ects’ all ocati o n t o tr eat m e nt gr o u ps as tr eate d : 
su bjects will be classifie d a cc or di n g t o t he treat me nt assi g ne d at ra n d o mizati o n u nless t he i nc orrect 
treat me nt(s) w as/ were recei ve d t hr o u g h o ut t he d osi n g peri o d i n w hic h case patie nts will be 
classifie d acc or di n g t o t h e first st u d y tr eat me nt r ecei ve d. 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 0 /1 0 2  
 
 
M o difie d S afet y  A n al ysis Set  
T he m o difie d Safet y -A S  ( mSafet y -A S ) is defi n e d as t he Safet y -A S  restrict e d t o s u bjects w h o were 
ra n d o ml y assi g n e d t o treat me nt acc or di n g t o C T P versi o n 4. 0 or lat er, after Ar m C wa s acti vate d 
i n t he treat me nt all ocati o n.  
S afet y C o h ort A n al ysis Set  
T he Saf et y C o h ort a nal ysis set will i ncl u de all s u bjects e nr olle d ( n ot ra n d o mize d) i n t he safet y 
c o h ort w h o h a ve recei ve d at least o n e d ose of a v el u ma b. F or t hese s u bj ects, data listi n gs will be 
pr o vi de d , a n d a “ Safet y C o h ort” c ol u m n will be i ncl u de d o n selecte d safet y ta bles. 
P K A n al ysis Set  
P K A nal ysis set is a s u bset of t he safet y a nal ysis set a n d will i ncl u de all s u bjects i n t he avel u ma b 
treat me nt ar ms w h o ha ve at least o ne meas ura ble p ost -d ose dr u g c o nce ntrati o n.   
P D -L 1 E x pressi o n P ositi vit y  Criteri a  
T he i ncl usi o n criteria f or p ositi ve P D-L 1 is d eter mi ne d b y a Da k o P D -L 1 i m m u n o hist oc he mistr y  
(I H C) p h ar m D x c o m pa ni o n dia g n ostic test, v ali dat e d f or t he p ur p ose of t his trial. T he P D-L 1 I H C 
assa y a n d t he sc ori n g al g orit h m t o deter mi ne l o w, m o derate, a n d hi g h P D-L 1 e x pressi o n  le vel will 
be defi ne d a n d vali date d pri or t o c o n d ucti n g a n y statistical a nal ys es. Details are s pecifie d bel o w:  
•  Hi g h e x pressi o n P D -L 1 +:  T u m or cells dee me d p ositi ve f or P D -L 1 e x pressi o n ( P D -L 1 +) at 
a n y stai ni n g i nte nsit y ( 1 +, 2 + or 3 +) i n ≥8 0 %  a n d ≤1 0 0 % of t u m or cells   
•  M o derate e x pressi o n P D -L 1 +: T u m or cells dee m e d p ositi ve f or P D -L 1 e x pressi o n ( P D -
L 1 +) at a n y stai ni n g i nte nsit y ( 1 +, 2 + or 3 +) i n ≥5 0 % a n d < 8 0 % of t u m or cells  
•  L o w e x pressi o n P D -L 1 +: T u m or cells dee me d p ositi ve f or P D -L 1 e x pressi o n ( P D -L 1 +) at 
a n y stai ni n g i nte nsit y ( 1 +, 2 + or 3 +) i n ≥1 % a n d < 5 0 % of t u m or cells  
F or p ur p ose of a nal yses, t he f oll o wi n g cate g orizati o n will be c o nsi dere d  (cite d as P D-L 1 stat us i n 
t he f oll o wi n g): 
•  A n y e x pressi o n P D -L 1 + t u m or  cells at a n y stai ni n g i nte nsit y (i.e. l o w, m o derate a n d hi g h) 
•  M o derate a n d hi g h e x pressi o n P D -L 1 + t u m or  cells at a n y stai ni n g i nte nsit y  (i.e. m o derat e 
a n d hi g h)  
•  Hi g h e x pressi o n P D -L 1 + t u m or  cells at a n y stai ni n g i nte nsit y (i.e. hi g h o nl y) 
Fr o m pr ot oc ol v ersi o n 4 , cate g orizati o n will be ca pt ure d b y t he testi n g la b  via t he I W R S. P D -L 1 +  
e x pressi o n classificati o n f or s u bjects e nr olle d pri or t o versi o n 4  will be deri ve d  fr o m t he res ults of 
t he Da k o P D-L 1 I H C p h ar m D x c o m pa ni o n dia g n ostic test.  T he st u d y t ea m is bli n de d t o P D -L 1 +  
e x pressi o n.  
All a nal ysis sets t o be c o nsi dere d are prese nte d i n Ta ble 3 . 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 1 /1 0 2  
 
 
T a ble 3  
A n al ysis Sets  b y P D -L 1 st at us   
 
Scree ni n g 
A n al ysis 
Set  
F ull 
A n al ysis 
Set ( F A S)  
M o difie d 
A n al ysis Set 
( m F A S) 
H R Q o L 
A n al ysis Set 
( H R Q o L-A S)  
M o difie d 
H R Q o L 
A n al ysis Set 
( m H R Q o L-A S)  
S afet y 
A n al ysis Set 
( S afet y-A S)  
P K 
A n al ysis 
Set  
A n y 
e x pressi o n 
P D -L 1 +  
Scree ni n g 
A nal ysis Set  
F A S  
m F A S  
H R Q o L -A S  
m H R Q o L -A S  
Safet y -A S  
P K 
A nal ysis 
Set  
M o derate 
a n d hi g h 
e x pressi o n 
P D -L 1 +  
 
F A S, m o d 
a n d hi g h 
P D -L 1 +  
m F A S, m o d 
a n d hi g h P D -
L 1 +  
H R Q o L -A S, 
m o d a n d hi g h 
P D -L 1 +  
m H R Q o L -A S, 
m o d a n d hi g h 
P D -L 1 +  
 
 
Hi g h 
e x pressi o n 
P D -L 1 +  
 
F A S, hi g h 
P D -L 1 +  
m F A S, hi g h 
P D -L 1 +  
H R Q o L -A S, 
hi g h P D -L 1 +  
m H R Q o L -A S, 
hi g h P D -L 1 +  
 
 
Ta ble 4  s u m marizes t he use of t he a n al ysis sets i n t he differe nt a nal yses.  
T a ble 4  
St atistic al A n al ysis b y A n al ysis Set   
A n al yses  
F A S  
m F A S  
H R Q o L -
A S  
m H R Q o L -
A S  
S afet y -A S  
m S afet y -
A S  
P K A n al ysis 
Set  
Baseli ne C haracteristics  
✓ 
✓ 
 
 
✓ 
✓ 
 
P ast a n d C o nc o mita nt 
T hera pies  
✓ 
✓ 
 
 
 
 
 
I m p orta nt Pr ot oc ol 
De viati o ns  
✓ 
✓ 
 
 
 
 
 
C o m plia nce a n d 
E x p os ure  
 
 
 
 
✓ 
✓ 
 
Efficac y: Pri mar y  
✓1 
✓2 
 
 
 
 
 
Efficac y: Sec o n dar y - 
B O R  
✓1 
✓2 
 
 
 
 
 
Efficac y: Sec o n dar y - 
H R Q o L  
 
 
✓1 
✓2 
 
 
 
Safet y  
 
 
 
 
✓ 
✓3  
 
 
F or eac h a nal ysis set e xce pt Safet y -A S, a n y e x pressi o n P D -L 1 +, m o derate a n d hi g h  e x pressi o n P D -L 1 +, a n d 
hi g h e x pressi o n P D -L 1 + will be prese nte d se paratel y.  
1 F A S a n d H R Q o L A nal ysis Set will be use d f or ar m A vs. ar m B c o m paris o n  
2 m F A S a n d m o difie d H R Q o L A nal ysis Set will be use d f or ar m C vs. ar m B c o m paris o n  
3 Selecte d Safet y a nal y ses o nl y 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 2 /1 0 2  
 
 
S u b gr o u p A n al ysis Sets  
S u b gr o u p a n al yses will b e perf or me d o n pri mar y a n d sec o n d ar y efficac y e n d p oi nts base d o n t he 
s u b gr o u ps as defi ne d b el o w.  
F or i ncl u di n g bas eli ne varia bles i nt o C o x's pr o p orti o nal hazar ds 
m o d el f or O S a n d P F S 
m ulti variate a nal ysis, a n d l o gistic re gressi o n m o del f or B O R m ulti variate a nal ysis, t he f oll o wi n g 
para meterizati o n is t o be use d. F or varia bl es wit h m ore t ha n t w o cate g ories, a n i n dicat or varia ble 
will be defi ne d f or eac h cate g or y e x ce pt f or t he first cate g or y, w hi c h al wa ys defi nes t he refere n ce. 
T he fi nal para meterizati o n will be u p date d a n d fi x e d at t he Data R e vie w M eeti n g , at t he latest , a n d 
d oc u me nte d i n a n a m e n d me nt t o t his S A P if differe nt fr o m t he pre vi o us  d efi niti o n.  
T he  P D -L 1 + stat us (a n y, m o derate a n d hi g h, hi g h e x pressi o n) is part of t he hierarc hical testi n g 
pr oce d ure descri be d bel o w i n S ecti o n 1 5 . T he pr o g n ostic val u e of P D-L 1 +  stat us is n ot fir ml y 
esta blis he d a n d will be a nal yze d here. It s h o ul d als o be e x pl ore d if hi g h e x pressi o n P D -L 1 + 
s u bjects ha ve a greater tr eat me nt effect, i.e., if t his is a pre dicti ve fact or. P D -L 1 + l e vel s u b gr o u ps 
(l o w, m o derate, hi g h e x pressi o n) are o nl y rele va nt t o t he a nal yses perf or me d o n t he F A S a n d 
m F A S.  
 
. T he p ur p ose of s u b gr o u ps a ge, ge n der, re gi o n, race, a n d et h nicit y are t o c hec k i nter nal 
c o nsiste nc y wit hi n t he t ar gete d p o p ulati o n. S u b gr o u ps hist ol o g y, E C O G P S a n d s m o ki n g ha bits 
are k n o w n pr o g n ostic  fact ors f or l u n g ca ncer p atie nts. I n cas e of a l o w n u m ber of s u bjects wit hi n 
a cate g or y ( < 2 5 s u bjects  wit h hi g h P D -L 1 + e x pressi o n  fr o m all t hr ee treat m e nt gr o u ps c o m bi ne d), 
t he cate g ori es ma y be p o ole d  w he n mea ni n gf ul . T he s u b gr o u p a n al ysis will n ot be perf or m e d o n 
a n y s u b gr o u p cat e g or y  “ Missi n g”.  
T he f oll o wi n g s u b gr o u ps will be defi ne d:  
•  E x pressi o n P D -L 1 +  le v el 
•  L o w ( Refere nce)  
•  M o derate  
•  Hi g h  
•  A ge gr o u p 1  
•  A ge < 6 5 years  (Refere nce ) 
•  A ge ≥6 5 years  
•  A ge Gr o u p 2  
•  A ge < 7 5 years ( Ref ere n ce) 
•  A ge ≥ 7 5 years  
Gl o bal Versi o n I D: C CI
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 3 /1 0 2  
 
 
•   Ge n der  
•  Male ( Ref ere n ce) 
•  Fe male  
•  Race  
•  Ca ucasia n/ W hite ( Ref ere nce) 
•  Asia n  
•  Blac k/ Africa n A merica n  
•  Ot her or u n k n o w n (e x cl u di n g “ missi n g”)  
•  Et h nicit y  
•  His pa nic/ Lati n o ( Refere n ce) 
•  N o n -His pa nic/ Lati n o  
•  Et h nicit y  
•  J a pa nese li vi n g i n J a pa n ( Refere nce) 
•  All ot her s u bjects  
•  P o ole d Re gi o n  
•  U S  a n d Wester n E ur o pe ( Ref ere nce)  
•  Easter n E ur o p e  
•  Asia  
•  Rest of t he W orl d  ( A ustr alasia, Lati n A m erica, Africa a n d/ or Mi d dle East will be i ncl u de d 
as a d diti o nal s u b gr o u ps if i ncl u di n g > 1 0 % of t he o veral l ra n d o mize d/treat e d p o p ulati o n) 
•  E C O G P S at baseli ne  
•  E C O G P S 0 ( Ref ere n ce) 
•  E C O G P S 1  
•  N S C L C hist ol o g y  as c oll ecte d o n t he “ Disea s e Hist or y” e C R F pa ge 
•  S q ua m o us cell ( Refere nce) 
•  N o n -s q ua m o us cell  
•  S m o ki n g stat us  
•  Ne ver s m o k er ( Refere nce) 
•  E ver s m o ker  
•  Li ver metastasis at baseli ne as c ollecte d i n t he “ Site” varia ble o n t he tar get a n d/ or n o n-tar get 
lesi o ns e C R F pa ges  w h ere t he “ T y pe” is n ot N O D E  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 4 /1 0 2  
 
 
•  A bse nt ( Ref ere nce) 
•  Prese nt  
•  B o ne metast asis at baseli ne as c ollect e d i n t he “ Site” varia bl e o n t he tar get a n d/ or n o n -tar get 
lesi o ns e C R F pa ges 
•  A bse nt ( Ref ere nce) 
•  Prese nt  
•  Visceral m etastasis at b aseli ne as c ollecte d i n t h e “ Site” varia ble o n t he tar get a n d/ or n o n -t ar get 
lesi o ns e C R F pa ges as a n y fr o m t he f oll o wi n g list  w here t he “ T y pe” is n ot N O D E : 
“Oes o p ha g us, St o mac h, S mall i ntesti nes, Pa ncreas, Li ver, S plee n, Ki d ne y, Bla d der, A dre nal, 
O me nt u m, C ol o n ”  
•  A bse nt ( Ref ere nce) 
•  Prese nt  
•  Ple ural eff usi o n  at bas eli ne, c ollecte d as “ Ple ura” i n t he “ Site” varia ble o n t he  n o n -tar get 
lesi o ns e C R F pa ges 
•  A bse nt ( Ref ere nce) 
•  Prese nt  
•  Brai n m etastasis at bas eli ne as c ollecte d o n t he brai n e val uati o n pa ge or i n t he “ Site” varia ble 
o n t he Pri or a nti -ca n cer ra di o -t hera p y/s ur ger y e C R F pa ges  
•  A bse nt ( Ref ere nce) 
•  Prese nt  
•  Pri or Ra di ot hera p y f or T h ora x as c ollecte d  i n t he “ Site” varia ble o n t he Pri or a nti -ca n cer ra di o -
t hera p y e C R F as f oll o ws: Es o p ha g us, Lar y n x, L u n g, Ple ura, M e diasti nal N o des, A xillar y 
N o des, S u pracla vic ular N o des, Para -a ortic n o des, Breast, T h yr oi d, Pericar di u m, s pi nal c or d ; or, 
i n t he “ Site = ot her” v aria ble as f oll o ws (i de ntifi e d b y me di cal re vie w): l u n g, m e diasti n u m, 
me diasti nal , hil u m , c hest, l y m p h n o de stati o n 7, s u bcari nal l y m p h n o de: 
•  A bse nt ( Ref ere nce) 
•  Prese nt  
•  T u m or M utati o nal B ur de n ( T M B) wit h t u m or o nl y bi oi nf or matics pi peli ne –  t he t otal n u m ber 
of N o n -s y n o n y m o us s o matic varia nts per me ga base .  F o ur s u b gr o u ps will be f or me d usi n g 
q ua ntiles:  
•  ≤ 2 5 % q ua ntile  ( Refere n ce) 
•  > 2 5 % q ua ntile - ≤ 5 0 % q ua ntile  
•  > 5 0 % q ua ntile - ≤ 7 5 % q ua ntile  
•  > 7 5 % q ua ntile  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 5 /1 0 2  
 
 
A n al yses i n J a p a nese s u bjects  
I n or der t o satisf y re qu ir e me nts of t he J a pa nese P har mace uticals a n d Me di cal De vi ces A ge nc y , a 
s u bset of data s u m maries will be pr o d uce d f or J a pa nese s u bjects.  T hes e will i ncl u de s u m maries 
of:  
•  S u bject d is p ositi o n 
•  S u bjects ra n d o mize d vs treate d  
•  A nal ysis sets  
•  De m o gra p hic c haracteristics  
•  Disease hist or y  
•  P D -L 1 e x pressi o n stat us  
•  S u bse q ue nt a nti -ca n cer dr u g tr eat me nts  
•  S u bse q ue nt i m m u ne c hec k p oi nt i n hi bit ors  
•  A vel u ma b a n d c h e m ot hera p y treat me nt e x p os ure  
•  A d verse e ve nts ( o verall, relate d, gra de ≥ 3, relate d gra de ≥ 3, seri o us)  
•  O verall s ur vi v al, pr o gressi o n -free s ur vi val, c o nfir me d best o verall res p o ns e,  d urati o n of 
res p o nse, 
  
1 0  
Ge ner al S pecific ati o ns f or St atistic al A n al yses   
U nless ot her wise i n dicate d all a nal yses will be pres e nte d se paratel y f or t he t hree treat me nt gr o u ps. 
Baseli ne c haracteristics s u m mar y a n d t he efficac y a nal ysis will be perf or m e d o n t he F A S a n d t he 
m F A S  se paratel y f or a n y e x pressi o n P D -L 1 +, m o derate a n d hi g h e x pressi o n P D -L 1 + a n d hi g h 
e x pressi o n P D -L 1 + . A nal yses p erf or me d o n t he F A S a n d m F A S will ta ke i nt o acc o u nt s u bjects’ 
all ocati o n t o treat me nt gr o u ps as ra n d o mize d. A nal yses p erf or me d o n t he safet y p o p ulati o n will 
c o nsi der s u bjects as tr eat e d.   
Deri ve d va ri a bles bel o w f or t he safet y c o h ort will be base d o n t he date of first d ose of st u d y dr u g 
i nstea d of ra n d o mizati o n, w he ne ver a p plica bl e. 
Gl o bal Versi o n I D: C CI
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 6 /1 0 2  
 
 
D at a h a n dli n g after c ut -off d ate:  
Data after t he data c ut-off date ma y n ot u n der g o t he clea ni n g pr ocess  a n d will n ot be  use d f or 
s u m mar y statistics, statistical a nal yses, or i m p utati o ns .  
P o oli n g of ce nters:  
I n or der t o pr o vi de o v erall esti mates of treat me nt effects, data will be p o ole d acr oss ce nt ers.  T h e 
“ce nter” fact or will n ot be c o nsi dere d i n statistical m o dels or f o r s u b gr o u p a nal yses d ue t o t he hi g h 
n u m ber of p artici pati n g ce nters i n relati o n t o t he a ntici pate d s mall n u m ber of s u bjects ra n d o mize d 
at eac h ce nter.  
U nsc he d ule d visits:  
Data c ollect e d at u nsc he d ule d visits will be i ncl u de d a n d a nal yz e d f or b ot h safet y a n d effi cac y 
a nal ys es i n t he sa me fas hi o n as t he data c ollect e d at sc he d ule d visits  e x ce pt w here ot her wise n ote d 
i n t he secti o ns t hat f oll o w. Descri pti ve statistics ( mea n, sta n dar d de vi ati o n, me dia n, mi ni m u m, 
ma xi m u m, q uartiles) b y n o mi nal ti me p oi nt f or s afet y e n d p oi nts s uc h as la b orat or y meas ure me nts, 
E C Gs a n d vital si g ns will i ncl u de o nl y d ata fr o m s c he d ule d visits  per pr ot o c ol .  
Si g nific a nce le vel:  
T he o verall si g nifica nce le vel is 2. 5 % o ne -si de d. T he c o nfir mat or y statistical test f or t he pri mar y 
a n d sec o n dar y effic ac y e n d p oi nt a nal ysis is descri be d i n Secti o n 1 5. 1  al o n g wit h pr oce d ures f or 
c o ntr olli n g t he o v erall t y pe I err or rate . All ot her stat istical a nal ys es perf or me d o n t he sec o n d ar y 
a n d ot her e n d p oi nts defi ne d i n t his S A P are t o b e re gar de d as  
 T he  statistical tests 
perf or me d o n t h e pri mar y a n d s ec o n dar y efficac y e n d p oi nts i n c o m p ari n g treat me nt ar ms will be 
o ne -si de d, a n d t he statistical tests t o c o m pare tr eat me nt ar ms o n ot her  
 a n d safet y 
a nal ys es will be t w o -si de d.  
C o nfi de nce i nter vals will be t w o -si de d wit h a c o nfi de nce le vel of 9 5 %, if n ot ot her wise s pecifie d.  
Prese nt ati o n of c o nti n u o us a n d q u alit ati ve v ari a bles:  
C o nti n u o us varia bles will be s u m marize d usi n g d escri pti ve statistics i.e., n u m ber of n o n -missi n g 
val ues a n d n u m ber of missi n g val ues, mea n, me dia n, sta n dar d de viati o n, mi ni m u m, ma xi m u m a n d 
first a n d t hir d q uartile ( Q 1 a n d Q 3).  
Q ualitati ve varia bles will b e s u m marize d b y c o u nts a n d perce nta ges. U nless ot her wise state d t he 
calc ulati o n of pr o p orti o ns will i ncl u de t he missi n g cate g or y. T heref ore c o u nts of missi n g 
o bser vati o ns will be i ncl u de d i n t he de n o mi nat or a n d prese nt e d as a s e parate cate g or y.  
I n cas e t he a nal ysis refers o nl y t o certai n visits , perce nta ges will be b ase d o n t he n u m ber of s u bjects 
still prese nt i n t he trial at t hat visit, u nless ot her wise s pecifie d. 
N o s u m mar y statistics or b o x pl ots will be prese nte d if less t ha n 5 s u bjects are a v aila ble i n at l east 
o ne treat me nt gr o u p.  
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 7 /1 0 2  
 
 
Defi niti o n of b aseli ne:  
F or efficac y a n al ys es  (i n cl u di n g H R Q o L) : 
T he last meas ure me nt pri or t o ra n d o mizati o n will ser ve as t he baseli ne meas ure m e nt. If s uc h a 
val ue is missi n g, t h e last meas ure me nt pri or t o t he first st u d y dr u g a d mi nistrati o n will be use d as 
t he baseli ne meas ure me nt f or t he efficac y a n al ysis e x ce pt f or a nal yses of t u m or assess me nt data 
w here t he b aseli ne assess me nt w o ul d be c o nsi dere d missi n g .  
If a n assess me nt is pla n ne d t o be perf or me d pri or t o t he ra n d o mizati o n/first d ose of st u d y treat me nt 
i n t he pr ot oc ol a n d t he assess me nt is perf or me d o n t he sa me da y as t he ra n d o mizati o n/first d ose 
of st u d y treat me nt, it will be ass u me d t h at it was p erf or me d pri or t o ra n d o mizati o n/st u d y tr eat me nt 
a d mi nistrati o n, if assess m e nt ti me p oi nt is n ot c ollecte d or is missi n g. If assess me nt ti me p oi nts 
are c ollect e d, t he o bser ve d ti me p oi nt will be use d t o deter mi ne pre -ra n d o mizati o n/ pre-d ose o n 
st u d y d a y 1 f or bas eli ne calc ulati o n. U nsc he d ul e d assess me nts will be use d i n t he deter m i nati o n 
of baseli ne. H o we ver, if ti me is missi n g, a n u nsc he d ule d ass ess me nt o n st u d y da y 1 will be 
c o nsi dere d t o ha v e bee n o btai ne d after st u d y tr eat me nt a d mi nistrati o n.  
F or safet y a nal ys es:  
T he last meas ure me nt pri or t o t he first st u d y dr u g a d mi nistrati o n  will be use d as t he bas eli ne 
meas ure me nt.  
If a n assess me nt is pla n ne d t o be perf or me d pri or t o t he first d ose of st u d y tr eat me nt i n t he pr ot oc ol 
a n d t he assess me nt is perf or me d o n t he sa me d a y as t he first a d mi nis trati o n of st u d y treat me nt, it 
will be as s u me d t hat it was perf or m e d pri or t o st u d y treat me nt a d mi nistrati o n, if assess me nt ti me 
p oi nt is n ot c ollecte d or is missi n g. If assess me nt ti me p oi nts are c ollecte d, t he o bser ve d ti me p oi nt 
will be use d t o deter mi ne pre -d ose o n st u d y da y 1 f or baseli ne ca lc ulati o n.  
U nsc he d ule d assess me nts will be use d i n t he d eter mi nati o n of bas eli ne. H o we ver, if ti me is 
missi n g, a n u nsc h e d ule d assess me nt o n st u d y da y 1 will be c o nsi dere d t o ha ve bee n o btai ne d after 
st u d y treat me nt a d mi nistrati o n.  
S u bjects w h o start trea t me nt a n d disc o nti n ue fr o m t he st u d y o n t h e sa me da y ma y h a ve t w o 
differe nt sets of data c oll ecte d o n st u d y da y 1 ( o ne d uri n g st u d y a n d o ne i n t he e n d of treat me nt 
visit ). Data re p ort e d at t h e e n d of tr eat me nt visit are n ot eli gi ble f or bas eli ne selecti o n.  
If a sc h e d ule d pre-d os e meas ur e me nt act u all y occ urre d p ost -d ose, t h e n t he c orres p o n di n g 
meas ure me nt will be tr eate d a n d a nal yze d si milar t o a n u nsc he d ule d p ost -d ose mea s ure m e nt. 
Baseli ne f or H R a n d Q T/ Q Tc assess me nts will be deri ve d fr o m t he visit w here b ot h H R a n d Q T 
are n ot missi n g. U ns c he d ule d assess me nts will n ot be i ncl u de d i n t he calc ulati o n of t he a vera ge. 
Q Tc  ass ess me nts  will o nl y b e deri ve d if n ot c o nsiste ntl y c ollecte d f or all s u bjects i n t he e C R F. I n 
s uc h cases Q Tc ass ess me nts will be deri ve d base d o n H R a n d Q T.  
E ve n if b ot h ce ntr al a n d l ocal la bs are c ollecte d i n t he st u d y, t he b aseli ne will be deri ve d base d 
o nl y o n t he ce ntral la b c ollecte d data.  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 8 /1 0 2  
 
 
Defi niti o n of d ur ati o n:  
D urati o n will be calc ulate d b y t h e differe nce of start a n d st o p date + 1, if n ot ot her wise s pecifie d. 
F or e x a m ple, s ur vi val ti me ( da ys) = date of d eat h –  date of ra n d o mizati o n + 1.  
T he ti me si nce a n e ve nt ( e. g. ti me si nce first dia g n osis) will  be calc ulate d as  refere nce date mi n us 
date of e v e nt.  
Defi niti o n of st u d y d a y/tre at me nt d a y:  
St u d y da y / Treat me nt d a y are defi ne d relati ve t o t he date of ra n d o mizati o n / start of treat me nt. 
St u d y d a y 1 defi nes t he d a y of ra n d o mizati o n, t he da y b ef ore is d efi ne d as St u d y da y – 1 ( n o St u d y 
da y 0 is defi ne d). Treat me nt da y will be calc ulate d acc or di n gl y, treat me nt da y 1 is defi ne d as t he 
date of first a d mi nistrati o n of treat me nt ( a vel u ma b  or c he m ot hera p y). 
Defi niti o n of o n -tre at me nt peri o d: 
O n -treat me nt p eri o d is defi ne d as t he ti me fr o m t h e first st u d y dr u g a d mi nistrati o n t o t he last dr u g 
a d mi nistrati o n date + 3 0 da ys or t he earliest date of s u bse q ue nt a nti -ca ncer dr u g t hera p y mi n us 1 
da y, w hic he v er occ urs first, u nless ot her wise state d.  
F or s u bjects ra n d o mize d t o t he c he m ot hera p y ar m w h o s witc h t o a v el u ma b after pr o gressi o n, 
a vel u ma b is als o re gar de d as s u bse q ue nt a nti -ca n cer dr u g t h era p y i n t he a b o ve defi niti o n of o n-
treat me nt peri o d. 
F or s u bj ects s witc hi n g t o a vel u ma b, a sec o n d o n -treatme nt p eri o d is d efi ne d si milarl y as a b o ve as 
t he ti me fr o m t he first a v el u ma b a d mi nistrati o n t o t he last a vel u ma b a d mi nistrati o n date + 3 0 da ys 
or earliest dat e of s u bse q ue nt a nti -ca ncer dr u g t hera p y after t he s witc h t o a vel u ma b mi n us 1 da y, 
w hic he ver occ u rs first, u nless ot her wise state d. 
S u m m ar y st atistics o ver ti me:  
F or descri pti ve statistics o ver ti me b y n o mi nal visit or ti me p oi nt f or H R Q o L data a n d safet y 
e n d p oi nts (la b orat or y, E C G a n d vital si g ns) , o nl y t h ose visits/ti me p oi nts t hat ha ve at l east 5 
su bjects i n b ot h treat me nt ar ms will be i ncl u de d i n t he s u m mar y ta bl es a n d fi g ures. T he e x ce pti o n 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 9 /1 0 2  
 
 
is Disc o nti n uati o n a n d E n d-of -Treat me nt visit w hic h will be i n cl u de d i n t he s u m mar y statistics 
des pite t he n u m ber of s u bjects w h o c o m plete d s u c h visit.  
St a n d ar d deri v ati o ns a n d re p orti n g c o n ve nti o ns:  
T he f oll o wi n g c o n versi o n fact ors will be use d t o c o n vert da ys i nt o wee ks, m o nt hs or years:  
1 wee k = 7 d a ys; 1 m o nt h = 3 0. 4 3 7 5 da ys, 1 year = 3 6 5. 2 5 da ys.  
De m o gra p hics a n d p h ysical meas ur e me nts:  
•  A ge [ years]:  
•   ( date of gi ve n i nf or me d c o nse nt - date of birt h + 1) / 3 6 5. 2 5  
•  I n case of missi n g da y o nl y: A ge [ years]: ( year/ m o nt h of gi ve n i nf or me d c o nse nt –  
year/ m o nt h of birt h) / 1 2  
•  I n case o nl y year of birt h is gi ve n: A ge [ years]: ( year of gi ve n i nf or me d c o nse nt - 
year of birt h)  
T he i nte ger part of t he calc ulate d a ge will be use d f or re p orti n g p ur p ose.  
•  Site c o des will be use d f or t he deter mi nati o n of t h e s u bject’s ge o gra p hic re gi o n.  
•  B MI ( k g/ m 2) = wei g ht ( k g)/[ hei g ht ( m)]2.  
•  B S A ( m²) = ([ hei g ht ( c m) x wei g ht ( k g)] /  3 6 0 0) 0. 5 
S m o ki n g hist or y c o m p ut ati o n:  
•  N ote: ‘c he wi n g t o ba cc o’ is n ot ta ke n i nt o acc o u nt f or a nal ysis of s m o ki n g hist or y  
•  Ci garette e q ui vale nts are calc ulate d as f oll o ws: o ne ci gar is re gar de d e q ui vale nt t o 5 
ci garettes a n d 1 pi pe is re gar de d e q ui v ale nt t o 3 ci garettes  
•  D urati o n of s m o ki n g [ years]:  
(e n d date of s m o ki n g –  st art date of s m o ki n g + 1) / 3 6 5. 2 5 
•  Pac k -years:  
-  calc ulate ci garette e q ui vale nts per da y usi n g t he c o n versi o n fact ors gi ve n a b o ve  
-  c o n vert t o pac ks p er da y w here 2 0 ci garettes are re gar de d as 1  pac k  
-  pac k -years = p ac ks p er da y × d urati o n of s m o ki n g [ years] 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 0 /1 0 2  
 
 
Disease c h aracteristics c o m p utati o n:  
•  Ti me si nce i nitial ca ncer dia g n osis ( m o nt hs) =  
( date of ra n d o mizati o n –  date of i nitial ca ncer dia g n osis) / 3 0. 4 3 7 5  
•  Ti me si nce first dia g n osis of d oc u me nt e d, l ocall y a d va nce d, i n o p era ble or m etastatic diseas e 
( m o nt hs) =  
( date of ra n d o mizati o n –  date of d oc u me nt e d, l ocall y a d va n ce d, i n o pera ble or metastatic 
disease) / 3 0. 4 3 7 5  
Pri or -a nti ca ncer t hera p y c o m p utati o n  ( dr u g, ra di ot hera p y, s ur ger y): 
•  Ti me si nce las t a nti-ca n cer dr u g t hera p y ( m o nt hs) =  
( date of ra n d o mizati o n –  date of last a nti -ca ncer t h era p y pri or ra n d o mizati o n) / 3 0. 4 3 7 5  
P D -L 1 E x pressi o n Le v el c o m p utati o n:  
•  Ti me fr o m sa m pli n g d ate t o date of ra n d o mizati o n ( m o nt hs) =  
( date of ra n d o mizati o n – date of tiss ue sa m pli n g)/ 3 0. 4 3 7 5 
F or re p orti n g c o n ve nti o ns, mea n a n d me dia n s h o ul d ge nerall y be dis pla ye d t o o ne m ore deci mal 
place t ha n t he ra w dat a a n d sta n dar d de vi ati o n s h o ul d be dis pla ye d t o t w o m ore deci mal places 
t ha n t he ra w data. Perce nta ges will be re p ort e d t o o ne deci mal pl ace. T he r o u n di n g will be 
perf or me d t o cl osest i nte ger / first deci mal usi n g t he c o m m o n mi d -p oi nt bet wee n t he t w o 
c o nsec uti ve v al ues. E. g. 5. 1 t o 5. 4 will be r o u n de d t o a n i nte ger of 5, a n d 5. 5 t o 5. 9 will be r o u n de d 
t o a n i nte ger of 6. 
D at a c ollecte d after s witc hi n g t o a vel u m a b a n d re-i niti ate d tre at me nt: 
S witc h refers t o s u bjects w h o cr oss o ver fr o m c h e m ot hera p y t o a vel u ma b after diseas e pr o gressi o n 
c o nfir me d b y I R C ( o pti o n all o we d i n pr ot oc ol versi o n 3. 0 b ut n o l o n ger i n pr ot oc ol versi o n 4. 0). 
Re -i nitiati o n refers t o s u bjects wit h a c o nfir me d C R w h o e x per ie nce rela pses after st o p pi n g 
treat me nt wit h a vel u ma b a n d w h o re -start a vel u ma b treat me nt. 
Data c ollecte d aft er s wit c hi n g t o a v el u ma b a n d re-i nitiati o n of treat me nt will n ot be i ncl u de d i n 
t he mai n a nal ys es f or s afet y a n d efficac y e x ce pt f or o verall s ur vi val , s u m mar y of d eat h a n d 
dis p ositi o n  as well as f or P F S se nsiti vit y a nal yses as s pecifie d b el o w . Se parate ta bles a n d listi n gs 
will be creat e d t o s pecificall y des cri be d ata c ollect e d after s witc h. Data listi n gs will be creat e d f or 
all t he data c ollecte d af ter re-i nitiati o n of st u d y treat me nt wit h a fla g v aria bl e t o i n dicate s uc h d ata 
is c ollecte d after t he re-i nitiati o n of st u d y tr eat me nt.  
D at a c ollecte d i n s af et y c o h ort:  
Data c ollecte d i n t he s afet y c o h ort will be i ncl u de d i n all listi n gs, i ncl u di n g t h ose  create d f or 
ra n d o mize d s u bjects. T he data f or t h e safet y c o h ort will be prese nte d as a s e parat e treat me nt ar m 
i n t hese listi n gs as well as i n selecte d safet y ta bles.  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 1 /1 0 2  
 
 
H a n dli n g of missi n g d at a:  
U nless ot her wise s pecifi e d i n t his S A P, all data will be e val u ate d as o bser ve d, a n d n o i m p utati o n 
met h o d f or missi n g val ues will be use d.  
I n all s u bject data listi n gs, i m p ute d val ues will be prese nte d. I n all listi n gs, i m p ute d i nf or mati o n 
will be fla g ge d.  
Missi n g statistics, e. g. w he n t he y ca n n ot be cal c ulate d, s h o u l d be pres e nte d as “ n d ”. F or e x a m ple, 
if n = 1, t h e me as ure of varia bilit y (sta n d ar d d e viati o n) ca n n ot be c o m p ute d a n d s h o ul d be pres e nte d 
as “ n d”.  
H a n dli n g of i nc o m plete d ates:  
I n c o m plete d ates f or dise ase hist or y  (i nitial dia g n osis date, date of d oc u me nte d, l ocall y a d v a nce d, 
i n o pera ble or m etastatic disease dia g n osis) will be i m p ute d as f oll o ws: 
•  If t he da y is missi n g, it will be i m p ute d t o t he 1 5t h da y of t he m o nt h.  
•  If b ot h d a y a n d m o nt h are missi n g a n d t h e year is pri or t o t he year of t he first st u d y treat me nt, 
t he m o nt h a n d da y will be i m p ute d as J ul y 1st. 
•  If b ot h da y a n d m o nt h are missi n g a n d t he year is sa me as t he year of t he first st u d y treat me nt, 
t he m o nt h a n d da y will be i m p ute d as J a n uar y 1st.  
•  If t he date is c o m plet el y missi n g, n o i m p utati o n will be perf or me d.  
F or calc ulati o n of d urati o ns, i nc o m plete d ates f or  nic oti ne c o ns u m pti o n  (start/e n d dates) will be 
i m p ute d as f oll o ws: 
•  As da y is n ot c ollecte d, it will be i m p ute d t o t he 1 5 t h da y of t he m o nt h.  
•  If m o nt h is missi n g a n d t he year is pri or t o t he ye ar of t he first st u d y tr eat me nt, t he m o nt h a n d 
da y will be i m p ute d as J ul y 1 st. 
•  If m o nt h is missi n g a n d t he year is sa me as t he year of t he first st u d y treat me nt, t he m o nt h a n d 
da y will be i m p ute d as J a n ua r y 1st.  
•  If start date is n o n-missi n g b ut e n d date is missi n g (c urre nt s m o ker), e n d date will be i m p ute d 
b y c ut -off dat e.  
•  If t he date of first st u d y treat me nt is missi n g, ra n d o mizati o n date will be use d i nstea d. 
I n c o m plete A E -rel ate d d ates  will be i m p ute d as f oll o ws:  
•  If t he A E o nset date is missi n g c o m pletel y, t he n t he o nset date will be re place d b y t h e start of 
st u d y treat me nt. 
•  If o nl y t h e da y p art of t he A E o nset date is missi n g, b ut t he m o nt h a n d year are e q ual t o t he start 
of st u d y treat me nt, t he n t he A E o nset d ate will b e re place d b y t h e start of st u d y treat me nt. F or 
e x a m ple, if t he A E o nset date is --/J A N/ 2 0 1 5, a n d st u d y treat me nt start date is 1 5/J A N/ 2 0 1 5, 
t he n t he i m p ute d A E o nset date will be 1 5/J A N/2 0 1 5.  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 2 /1 0 2  
 
 
•  If b ot h t he d a y a n d m o nt h of t he A E o nset d ate are missi n g b ut t h e o nset year is e q ual t o t h e 
start of st u d y treat me nt, t he n t he o nset d ate will be re place d b y t he start of st u d y treat me nt. F or 
e x a m ple, if A E o nset date is --/---/ 2 0 1 4, a n d st u d y treat me nt start date is 1 9/ N O V/ 2 0 1 4, t he n 
t he i m p ute d A E o nset dat e will be 1 9/ N O V/ 2 0 1 4. 
•  I n all ot her cases t he missi n g o nset da y or missi n g o nset m o nt h will be re place d b y 1. F or 
e x a m ple:  
o   if A E o nset date is --/ F E B/ 2 0 1 5 a n d st u d y tr eat me nt start date is 0 3/ M A R/ 2 0 1 5, 
t he n t he i m p ute d A E o nset date will be 0 1/ F E B/ 2 0 1 5.  
o  if A E o nset date is --/---/ 2 0 1 5 a n d st u d y tr eat me nt start date is 1 2/ D E C/ 2 0 1 4, t he n 
t he i m p ute d A E o nset dat e will be 0 1/J A N/ 2 0 1 5.  
•  I n c o m plete st o p d ate will be re place d b y t h e last da y of t he m o nt h (if d a y is missi n g o nl y), if 
n ot res ulti n g i n a date lat er t ha n t he d ate of s u bject's d eat h. I n t he latter cas e t he d ate of d eat h 
will be use d t o i m p ute t he i nc o m plete st o p date.  
•  I n all ot her cases t he i nc o m plete st o p date will n ot be i m p ute d.   
F urt her i nf or mati o n after c ut -off (li ke fatal o utc o me) mi g ht b e ta ke n fr o m Safet y data base a n d 
i ncl u de d se paratel y i nt o CS R.  
I n c o m plete pri or/c o nc o mit a nt me dic ati o n d ates  will be i m p ute d as f oll o ws:  
•  If t he me dicati o n start date is missi n g c o m pletel y, t he n t he me dicati o n date will be re plac e d b y 
t he start of st u d y tr eat me nt. 
•  If t he d a y of me dicati o n start date is missi n g, b ut t he m o nt h a n d year are e q ual t o t he start of 
st u d y tr eat me nt, t he n t he me dicati o n start date will be re place d b y t he start of st u d y tr eat me nt. 
F or e x a m ple, if t he me dic ati o n start date is --/J A N/ 2 0 1 5, a n d st u d y treat me nt start date is 
1 5/J A N/ 2 0 1 5, t he n t he i m p ute d me dicati o n start date will be 1 5/J A N /2 0 1 5.  
•  If b ot h t he da y a n d m o nt h of me dicati o n start date are missi n g b ut t he start year is e q u al t o t he 
start of st u d y treat me nt, t he n t he me dicati o n date will be re place d b y t he start of st u d y treat me nt. 
F or e x a m ple, if t he me dicati o n start date is --/---/ 2 0 1 4, a n d st u d y tr eat me nt start date is 
1 9/ N O V/ 2 0 1 4 , t he n t he i m p ute d me dicati o n start date will be 1 9/ N O V/ 2 0 1 4. 
•  I n all ot her cases t he missi n g me dicati o n  start d a y or missi n g me dicati o n start m o nt h will be 
re place d b y  1. F or e x a m ple:  
o   if me dicati o n start  dat e is --/ F E B/ 2 0 1 5 a n d st u d y treat me nt start date is 
0 3/ M A R/ 2 0 1 5, t he n t he i m p ute d me dicati o n start date will be 0 1/ F E B / 2 0 1 5.  
o  if me dicati o n start d ate is --/---/ 2 0 1 5 a n d st u d y treat me nt start date is 1 2/ D E C/ 2 0 1 4, 
t he n t he i m p ute d me dicati o n start date will be 0 1/J A N/ 2 0 1 5.  
•  I n c o m plete st o p d ate will be re place d b y t h e last da y of t he m o nt h (if d a y is missi n g o nl y), if 
n ot res ulti n g i n a date lat er t ha n t he d ate of s u bject's d eat h. I n t he latter cas e t he d ate of d eat h 
will be use d t o i m p ute t he i nc o m plete st o p date.  
•  I n all other cases t he i nc o m plete me dicati o n st o p date will n ot be i m p ute d.  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 3 /1 0 2  
 
 
I n c o m plete s u bse q ue nt a nti-c a ncer t h er a p y st art d ates  will be i m p ute d as f oll o ws:  
•  If o nl y d a y is missi n g, it will be i m p ute d as t he last da y of t he m o nt h u nless t he e n d date 
of s u bse q ue nt a nti -ca n cer t hera p y is bef ore t hat date . I n t hat case, t he i n c o m plete a nti-
ca ncer t hera p y start date  will be i m p ute d as t he e n d date of t he a nti -ca ncer t hera p y. 
•  If b ot h da y a n d m o nt h are missi n g, n o i m p utati o n will be perf or me d.  
I n c o m plete e x p os ure d ates  will be i m p ute d as f oll o ws:  
•  If t he st u d y me dicati o n start date is missi n g, it is ass u me d t hat t he first d ose of st u d y 
treat me nt me dicati o n is gi ve n at t he ra n d o mizati o n date. T he ra n d o mizati o n date will 
re place i nc o m plete dat es of t he first d ose of st u d y treat me nt.  
•  I n cas e t he last dat e of st u d y dr u g is i nc o m plete t he date of last a d mi nistrati o n of st u d y 
dr u g will be ta ke n fr o m t he treat me nt ter mi nati o n e C R F pa ges.  
D ate of l ast d ose of st u d y dr u g  if u n k n o w n or partiall y u n k n o w n will be i m p ute d as f oll o ws: 
•  If t he last date of st u d y dr u g is c o m pletel y missi n g a n d t here is n o E n d of Treat me nt e C R F 
pa ge a n d n o d eat h d ate t he s u bject s h o ul d be c o nsi dere d t o be o n g oi n g a n d use t he last 
d osi n g date o n or  pri or t o t he c ut -off d ate f or t h e a nal ysis as t he last d osi n g date  
•  If t h e last date of st u d y dr u g is c o m pletel y or partiall y missi n g a n d t here is eit her a n E n d 
of Treat me nt e C R F pa ge or a deat h date a vaila bl e ( wit hi n t he c ut -off date) t he n i m p ute d 
last dose date:  
= 3 1 D E C Y Y Y Y, if o nl y Year is a v aila ble a n d Year < Year of mi n ( E O T d ate, deat h d ate)  
= Last da y of t he m o nt h, if b ot h Year a n d M o nt h are a vaila bl e a n d Year = Year of    
mi n ( E O T date, deat h dat e) a n d M o nt h < t he m o nt h of mi n ( E O T date, deat h da te)  
= mi n ( E O T date, d eat h d ate), f or all ot her cases  
T he  last ali ve date will b e deri v e d f or patie nts n ot k n o w n t o ha ve die d at t he a nal ysis c ut -off usi n g 
t he latest c o m plete date a m o n g t he f oll o wi n g: 
•  All patie nt assess me nt d ates ( bl o o d dra ws (la b orat or y, P K), vital si g ns, perf or ma n ce stat us, 
E C G, t u m or assess me nts , q ualit y of life assess me nt) 
•  Start a n d e n d dates of a nti -ca ncer t hera pies a d mi nistere d aft er st u d y treat me nt disc o nti n uati o n  
•  A E start a n d e n d d ates  
•  Date last k n o w n t o be ali ve c ollecte d o n t h e e C R F f or m “ S u bject Stat us / S ur vi val F oll o w -u p”  
•  St u d y dr u g start a n d e n d dates  
•  Ra n d o mizati o n date  
•  Date of disc o nti n uati o n o n dis p ositi o n e C R F pa ges ( d o n ot use if reas o n f or disc o nti n uati o n is 
l ost t o f oll o w-u p).  
 Assess me nt dates aft er t h e c ut-off d ate will n ot be a p plie d t o deri ve t h e last ali ve date.    
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 4 /1 0 2  
 
 
Missi n g or partial de at h d ates  will be i m p ute d base d o n t he last ali ve date: 
•  If t h e date is missi n g it will be i m p ute d as da y after date of last c o ntact fr o m t he eC R F “S u bject 
Stat us / S ur vi val F oll o w -U p ” pa ge  
•  If t he d a y or m o nt h is missi n g, deat h will be i m p ute d t o t he ma xi m u m of t he f ull ( n o n-i m p ute d) 
da y after t he date of last c o ntact  a n d t he f oll o wi n g:  
o  Missi n g da y: 1
st da y of t he m o nt h a n d year of deat h  
o  Missi n g da y a n d m o nt h: J a n uar y 1st of t he year of deat h  
F or t u m or assess me nts, if t here are m ulti ple sca n dates ass ociate d wit h a n e val uati o n, i.e., 
ra di ol o gic al assess me nts occ ur o v er a s eries of da ys rat her t ha n t he sa me d a y, t h e c h oice of d ate 
of assess me nt c o ul d i m p act t he dat e of pr o gressi o n a n d/ or date of res p o nse. If t here are m ulti ple 
sca n dates ass ociat e d wit h a n e val uati o n, t he earliest of t he sca n dates ass ociate d wit h t he 
e val uati o n will be use d as t he date of ass ess me nt.  
H a n dli n g of m ulti ple H R Q o L a n d/ or L a b or at or y rec or ds per n o mi n al visit  
•  T he rec or d t o be i ncl u d e d i n s u m mar y statistics will be t he o ne w hic h is t he nearest t o t he 
sc he d ule d visit.  
•  I n case t here are rec or ds wit h e q ual dista nce bet wee n assess me nt date a n d sc he d ule d visit (i.e. 
o ne bef ore, o ne after), t he o ne a ft er n o mi nal visit will be i ncl u de d i n s u m mar y statistics f or 
H R Q o L a n d t he o ne pri or t o t he n o mi nal visit da y will be use d f or la b orat or y assess me nts . 
•  O ver t he c o urs e of t h e st u d y, t here h a ve b ee n cas es o bser ve d w here t w o or m ore res ults f or a 
gi ve n a nal y te s hare visit na me, c ollecti o n date, a n d c ollecti o n ti me. I n s u c h cases, a n a d diti o nal 
rec or d f or t h e gi ve n para meter, visit, date, a n d ti me is o ut p ut wit h D T Y P E = ‘ A V E R A G E’ a n d 
A V A L = t he a vera ge of t he res ults fr o m t he d u plicate rec or ds. W he n a d u plicat e rec or d c o ul d 
be c h ose n f or t he Baseli ne rec or d, or f or i ncl usi o n i n b y -visit s u m maries, t he D T Y P E = 
‘ A V E R A G E’ rec or d is use d. 
•  All a vaila ble assess me nts will be ke pt i n A Da M dataset ( A D Q S  a n d A D L B( H E M A/ C H E M) ) 
as all i n di vi d ual assess me nts ma y b e i ncl u de d i n s o me of t he a nal ys es (e. g. T U D D a n al ysis). 
All statistical a nal yses will be perf or m e d usi n g S A S ® Versi o n 9. 4  or hi g her , or R ( w w w.r-
pr oject. or g), versi o n 3. 2. 5 or hi g h er . 
L a b or at or y v al ues o utsi de of li mits of q u a ntit ati o n   
F or la b orat or y assess me nts i n dicati n g t hat t he sa m ple teste d bel o w t he l o wer li mit of q ua ntitati o n 
( L L O Q) f or t he a n al yt e i n q uesti o n, half t he l o wer li mit of q ua ntitati o n ( ½ * L L O Q) will be use d as 
t he a nal ysis val ue. F or la b orat or y ass ess me nts testi n g a b o v e t he u p per li mit of q ua ntitati o n 
( U L O Q), t h e a nal ysis val ue will be i m p ute d as U L O Q + 1 *(t he l e vel of precisi o n of U L O Q). F or 
e x a m ple, if  a val ue “ > 7. 0”  is re p orte d, t he le vel of precisi o n is 0. 1 a n d t he a nal ysis val ue will be 
7. 1. T he i m p ute d a nal ysis val ues will be use d i n all a nal ys es (e. g. s u m mar y statistics) a n d will be 
use d f or deter mi nati o n of t o xicit y gra di n g.  Listi n gs will prese nt t he sta n dar dize d u nit val ues as 
pr o vi de d i n t he ra w d ata, i n dicati n g t he assess me nt val ue was n ot q ua ntifia ble.  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 5 /1 0 2  
 
 
1 1  
Tri al S u bjects   
T he s u bsecti o ns i n t his secti o n i ncl u de s pecifi cati o ns f or re p orti n g s u bject dis p ositi o n a n d 
treat me nt/trial disc o nti n uati o ns. A d diti o nall y pr oce d ures f or re p orti n g pr ot oc ol de viati o ns are 
pr o vi d e d. 
1 1. 1  
Pr ot oc ol De vi ati o ns   
A n alysis sets: F A S / m F A S  by P D -L 1  ex pressi o n  st at us / S afety C o h ort A n alysis Set 
All i m p orta nt pr ot oc ol de viati o ns (I P Ds) acc or di n g t o I C H E 3 will be re p orte d. T hese i ncl u de : 
•  
S u bjects t hat are d ose d o n t he st u d y d es pite n ot satisf yi n g t he i ncl usi o n  a n d e x cl usi o n  
criteria;  
•  
S u bjects t hat de vel o p wit h dra wal criteria w hilst o n t he st u d y b ut are n ot wit h dra w n;  
•  
S u bjects t hat recei v e t he wr o n g treat me nt or a n i n c orrect d ose;  
•  
S u bjects t hat recei v e a n e x cl u de d c o nc o mita nt me dicati o n ; 
•  
De viati o n fr o m G o o d Cli nical Practice ( G C P).  
I P Ds will be deter mi ne d f or all s u bjects b y eit her me dical re vi e w pr ocesses or pr o gra m mi n g base d 
o n t he i ncl usi o n/e x cl usi o n criteria or ot h er criteria prese nte d i n t he pr ot o c ol.  
I n a d diti o n, a s u bset of I P Ds are i d e ntifie d as cli nicall y i m p orta nt pr ot oc ol de viati o ns ( CI P D) a n d 
are i ncl u de d  i n A p p e n di x II. 
All i m p orta nt pr ot oc ol de viati o ns will be d oc u me nte d i n C DI S C datas ets w het her i de ntifie d 
t hr o u g h site m o nit ori n g, me dical re view or pr o gra m mi n g.  T he c o m plete list of I P Ds a n d CI P Ds 
are m ai ntai ne d b y t h e m e dical te a m a n d will be fi nalize d pri or t o data bas e l oc k. T h ese pr ot oc ol 
de viati o ns will be prese nte d i n a data listi n g.   
All I P Ds a n d CI P Ds i de ntifie d b y me dical re vie w pr ocess a n d / or pr o gra m mi n g will be prese nte d 
i n t he s u m mar y ta bl es b y treatme nt ar m a n d i n data listi n gs.   
1 2  
De m o gr a p hics a n d Ot her B aseli ne C h ar acteristics   
A n alysis sets: F A S  / m F A S , all by P D-L 1  ex pressi o n  st at us, S afety -A S  (i ncl u di n g S afety C o h ort 
c ol u m n) , m o difie d S afety-A S  
1 2. 1  
De m o gr a p hics   
De m o gra p hic c h aracteristics will be s u m marize d b y treat me nt gr o u p usi n g t he f oll o wi n g 
i nf or mati o n fr o m t he ‘Scree ni n g/ Baseli ne Visit ’ eC R F pa ges.  
•  De m o gra p hic c haracteristics  
-  Ge n der : Mal e, Fe male  
-  Race: 
W hite, Bla c k or Africa n A meri ca n, Asi a n, A merica n I n dia n or Alas ka 
Nati ve, Nati ve H a waiia n or ot her Pacific Isla n der, Ot her, U n k n o w n  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 6 /1 0 2  
 
 
-  Et h nic ori gi n: His pa nic/ Lati n o ( Yes/ N o), J a pa nes e ( Yes/ N o)  
-  A ge ( years): s u m mar y st atistics  
-  A ge cat e g ories : < 6 5 years, ≥6 5 years  
▪ 6 5 -< 7 5 , 7 5-< 8 5 , ≥8 5 
-  P o ole d Re gi o n:  
▪ N ort h A meric a  a n d Wester n E ur o pe   
▪ Easter n E ur o p e  
▪ Asia  
▪ Rest of t he W orl d  
-  Ge o gra p hic R e gi o n:  
▪ N ort h A meric a  
▪ Lati n A merica  
▪ Wester n E ur o pe  
▪ Easter n E u r o pe 
▪ A ustral asia 
▪ Asia  
▪ Africa  
▪ Mi d dle East  
-  E E A: Yes or N o  
-  Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) Perf or ma nce Stat us: 0 or 1  
-  Hei g ht ( c m)  
-  Wei g ht ( k g)  
-  B o d y Mass I n d e x ( B MI) ( k g/ m 2) 
-  B o d y S urface Area ( B S A) ( m²)  
Site c o des will be use d f or t he deter mi nati o n of  t h e s u bject’s ge o gra p hic re gi o n. 
T he listi n g of de m o gra p hics a n d b aseli ne c haract eristics will i ncl u de t h e f oll o wi n g i nf or m ati o n: 
s u bject i de ntifier, treat me nt gr o u p, a ge, ge n der , race, hei g ht (c m), wei g ht ( k g), B MI ( k g/ m2), B S A 
( m²), a n d E C O G perf or m a nce stat us. 
1 2. 2  
Me dic al Hist or y   
Me dical hist or y will be c o de d usi n g t he m ost c urre nt a vaila ble v ersi o n of Me dical Dicti o nar y f or 
Re g ulat or y Acti vities ( M e d D R A) a n d will be s u m marize d fr o m t he “Me dical Hist or y ” e C R F pa ge. 
Me dical hist or y will be s u m marize d as t he n u m bers a n d perce nta ges of s u bjects b y Me d D R A 
preferre d t er m ( P T) as e ve nt cate g or y a n d 
Me d D R A pri mar y s yst e m or ga n class ( S O C) as 
s u m mar y cate g or y. Eac h s u bject will be c o u nte d o nl y o nce wit hi n eac h P T or S O C.  
Me dical hist or y will be dis pla ye d i n ter ms of fre q ue nc y ta bles: or dere d b y pri mar y S O C a n d P T 
i n al p ha betical or d er. 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 7 /1 0 2  
 
 
1 2. 3  
Ot her B aseli ne C h ar acteristics   
1 2. 3. 1  
Dise ase C h ar acteristics   
I nf or mati o n o n dise ase c haracteristics c ollecte d o n t he “ Disease Hist or y” e C R F p a ge will be 
s u m marize d i n t otal a n d b y treat me nt ar m. S u m mar y statistic s will be pres e nte d f or: 
•  Site of pri mar y t u m or  ( U p per l o be, l eft l u n g / U p per l o be, ri g ht l u n g / Mi d dle l o be, ri g ht 
l u n g / L o wer l o be, left l u n g / L o wer l o be, ri g ht l u n g / O verl a p pi n g lesi o n of l u n g / L u n g, 
N O S)  
•  Ti me si nce i nitial ca ncer dia g n os is ( m o nt hs) 
•  Ti me si nce first dia g n osis of d oc u me nt e d, l ocall y a d va nce d, i n o p era ble or m etastatic diseas e 
( m o nt hs) 
•  T u m or hist o pat h ol o gic / c yt ol o gic t y pe  
-  S q ua m o us cell  
-  N o n -s q ua m o us cell  
-  A de n ocarci n o ma  
-  Br o nc h o al ve olar  
-  Lar ge cell  
-  Ot her  
•  T N M classificati o n at i nitial dia g n osis  
•  Sta ge at i nitial dia g n osis per t he 7t h I A S L C a n d AJ C C classificati o ns  
•  T N M classificati o n at st u d y e ntr y  
•  Sta ge at st u d y e ntr y per t he 7t h I A S L C a n d AJ C C classificati o ns  
•  S m o ki n g hist or y  
-  Ne ver s m o ker vs e v er s m o ker (i ncl u di n g f urt her brea k d o w n: re g u lar user / occasi o nal 
user / f or mer user) as c ollecte d i n t he e C R F  
-  S m o ki n g e x p os ure ( pac k -years): 0, < 2 0, 2 0 -< 4 0, ≥4 0 a n d s u m mar y st atistics  
-  Years si nc e q uitti n g: ne ver s m o ker, c urre nt s m o ker, < 5, 5 -< 1 0, ≥1 0 a n d s u m mar y 
statistics 
•  Li ver metastasis at bas el i ne 
-  Prese nt (at least o n e tar get or n o n -tar get lesi o n wit h site = “li ver”) 
-  A bse nt ( n o tar get or n o n -tar get lesi o ns wit h site = “li ver”) 
•  B o ne metast asis at baseli ne  
-  Prese nt (at least o n e tar get or n o n -tar get lesi o n wit h site = “ B o n e lesi o n”) 
-  A bse nt ( n o tar get or n o n-tar get lesi o ns wit h site = “ B o ne l esi o n”) 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 8 /1 0 2  
 
 
•  Visceral met astasis at baseli ne  (see Secti o n 8. 2  f or defi niti o n) 
-  Prese nt  
-  A bse nt  
Baseli ne c haracteristics wit h res pect t o p h ysic al e x a mi nati o ns, E C G a n d he mat ol o g y/ bi oc he mistr y 
will be part of Secti o n 1 6  ( Safet y E val uati o n). 
Listi n g of diseas e hist or y will be pr o vi de d wit h all rele va nt data (as c ollect e d o n t he e C R F pa ge  
f or Diseas e Hist or y) a n d deri ve d varia bles use d i n t he a b o ve ta ble. 
1 2. 3. 2  
Pri or A nti -C a ncer T her a pies   
T he n u m be r a n d perce nta ge of s u bjects i n eac h of t he f oll o wi n g a nti -ca ncer t hera p y cate g ories will 
be ta b ulate d:  
•  S u bjects wit h at least o ne t y pe of pri or a nti -ca ncer treat me nt  
•  S u bjects wit h at least o ne pri or a nti -ca n cer dr u g t h era p y  
•  S u bjects wit h at least o ne pri o r a nti-ca n cer ra di ot h era p y  
•  S u bjects wit h at least o ne pri or a nti -ca n cer s ur ger y  
Pri or a nti -ca ncer dr u g t h era p y will be s u m marize d as f oll o ws:  
•  N u m ber of s u bjects wit h at least o ne pri or a nti -ca n cer dr u g t h era p y  
•  N u m ber of s u bjects wit h at le ast o ne pri or a nti -ca ncer dr u g t hera p y f or l ocall y a d v a nce d 
disease  
•  T y pe of pri or a nti -ca ncer t hera p y: C yt ot o xic t hera p y / E n d ocri ne t hera p y / M o n ocl o nal 
a nti b o dies t hera p y / S mall m olec ules / I m m u n ot hera p y / Ot her  
•  I nte nt of T hera p y: Ne o-A dj u va nt / A dj u va nt / L o ca ll y a d va n ce d 
•  Best res p o nse: C o m plete Res p o nse ( C R) / Partial Res p o nse ( P R) / Sta ble Disease ( S D) / 
Pr o gressi ve Diseas e ( P D) / N ot assessa ble / U n k n o w n / N ot a p plica ble. Best res p o nse is 
deri ve d fr o m t he l ast treat me nt re gi me n  
•  T he pri or a nti -ca ncer dr u gs wi ll als o be e xte nsi vel y d etaile d wit h t he n u m b er a n d perce nt a ge 
of s u bjects b y t he dr u g class a n d preferre d ter m i n a ta ble. A s u bject will be c o u nte d o nl y 
o nce wit hi n a gi ve n dr u g class a n d wit hi n a gi v e n dr u g na me, e ve n if h e/s he recei ve d t he 
sa me me dicati o n at differe nt ti mes. T he s u m mar y will be s orte d o n decreasi n g fre q ue nc y of 
dr u g class a n d decreasi n g fre q ue n c y of dr u g na m e i n a gi ve n dr u g class . I n case of e q u al 
fre q ue n c y re gar di n g dr u g class (res p ecti vel y dr u g na me), al p ha betical or d er will be use d. 
T he listi n gs of pri or a nti -ca ncer treat me nts a n d pr oce d ures will als o be pr o vi de d as f oll o ws. T hese 
will i ncl u de t he s u bject i de ntificati o n n u m ber, a n d all t he rel e va nt c ollecte d dat a -fiel ds o n t he 
c orres p o n di n g e C R F pa ges.  
•  Listi n g of pri or a nti -ca n cer dru g t hera pies  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 9 /1 0 2  
 
 
•  Listi n g of pri or a nti -ca n cer ra di ot hera p y  
•  Listi n g of pri or a nti -ca n cer s ur geries  
1 2. 3. 3  
P D -L 1 E x pressi o n St at us a n d B aseli ne 
  
P D -L 1 e x pressi o n le vel will be s u m marize d f or c ut-off val ues of 1 %, 5 0 %, a n d 8 0 % per t he 
pat h ol o g y re p ort f or m ( P R F). T u m or ass ociat e d i m m u ne cell a n d t u m or i nterface stat us 
(“ P ositi ve”, “ N e gati ve”, “ N ot pres e nt”) will als o be s u m marize d per t he  P at h ol o g y Re p ort F or m  
(P R F ).  
T he perce nt of  t u m or cells at eac h P D-L 1 stai ni n g i nte nsit y ( 0, 1 +, 2 +, a n d 3 +) is als o c ollecte d o n 
t he P R F. T he res ults base d o n t he t otal perce nt a ge of t u m or cells at eac h P D-L 1 stai ni n g i nte nsit y 
will be s u m mariz e d base d o n t he cate g ori es bel o w:   
•  Ne gati ve: ≥ 0 % t o 1 %   
•  L o w : ≥ 1 % t o < 5 0 % at a n y P D -L 1 i nte nsit y  
•  M o derate : ≥ 5 0 % t o < 8 0 % at a n y P D-L 1 i nte nsit y  
•  Hi g h  ≥ 8 0 %  at a n y P D -L 1 i nte nsit y  
•  N o n -e val ua bl e  
T he dates of sa m ple c ollecti o n f or P D -L 1 e x pressi o n a nal ysis will be s u m marize d usi n g t he 
f oll o wi n g varia bles: 
•  Ti m e fr o m sa m pli n g date t o date of ra n d o mizati o n ( m o nt hs), defi ne d as (ra n d o mizati o n date –  
t he date of tiss ue sa m pli n g) / 3 0. 4 3 7 5 
•  N u m ber of s u bjects f or w h o m t he sa m ple was c oll ecte d pri or t o a n y pri or a nti -ca ncer t hera p y 
1 3  
Pre vi o us or C o nc o mit a nt Me dic ati o ns/ Pr oce d ures   
A n alysis sets: F A S  / m F A S, all by P D-L 1 ex pressi o n st at us 
1 3. 1  
Pri or a n d C o nc o mit a nt Me dic ati o ns/ Pr oce d ures   
C o nc o mit a nt me dic ati o ns  are me dicati o ns, ot her t ha n st u d y m e dicati o ns, w hic h starte d pri or t o 
first d ose date of st u d y treat me nt a n d c o nti n ue d o n o n-treat me nt peri o d as well as t h ose starte d 
d uri n g o n -treat me nt peri o d.  
Pri o r me dic ati o ns  are me dicati o ns, ot her t ha n st u d y me dicati o ns a n d pre -me dicati o ns f or st u d y 
dr u g, w hic h are starte d b ef ore first a d mi nistrati o n of st u d y tr eat me nt.  
Pri or a n d c o nc o mita nt me dicati o ns will be s u m m arize d fr o m t he “ C o nc o mita nt 
Me dicati o ns 
Details” e C R F pa ge. Pre -me dicati o ns f or st u d y dr u g will als o be s u m marize d se paratel y.  
I n cases w here t he date v al ues d o n ot all o w u ne q ui v ocal all ocati o n of a me dicati o n t o c o nc o mita nt 
(as o p p ose d t o pri or ) m e dicatio n , t he me dicati o n will be c o nsi dere d as c o n c o mita nt me dicati o n. 
Gl o bal Versi o n I D: C CI
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 0 /1 0 2  
 
 
S u m mar y of pri or a n d c o nc o mita nt me dicati o ns will i ncl u de t he n u m ber a n d perce nt a ge of s u bjects 
b y A n at o mical T hera pe utic C he mical ( A T C) Classificati o n le vel 2 a n d P T . A s u bject will be 
c o u nte d o nl y o n ce wit hi n a gi ve n dr u g class a n d wit hi n a gi ve n dr u g n a me, e ve n if h e/s he recei ve d 
t he sa me me dicati o n at differe nt ti mes. If a n y pri or or c o nc o mita nt me dicati o n is classifie d i nt o 
m ulti ple A T C classes, t he me dicati o n will be s u m marize d se paratel y u n der eac h of t hese A T C 
classes. T he s u m mar y ta bles will be s orte d o n decreasi n g fre q u e nc y of dr u g class a n d decreasi n g 
fre q ue n c y of dr u g na me i n a gi ve n dr u g class. I n case of e q ual fre q ue nc y re gar di n g dr u g class 
(res pecti vel y dr u g na me), al p ha betical or der will be use d. I n case a n y s pecific me dicati o n d oes n ot 
ha ve A T C classificati o n le vel 2 c o de d ter m, it will be s u m marize d u n der “ U na v aila ble A T C 
classificati o n” cate g or y.  
A listi n g of c o nc o mita nt me dicati o ns will be create d wit h t he rele va nt i nf or mati o n c ollecte d o n t he 
“ C o nc o mita nt Me dicati o ns Details” e C R F pa ge.  
All c o nc urre nt pr oce d ures, w hic h were u n derta ke n a n y ti me d uri n g t he o n -treat me nt peri o d, will 
be s u m marize d acc or di n g t o t he e C R F pa ge “ C o nc o mita nt Pr oce d ures Details”. N u m ber a n d 
perce nt a ge  of s u bjects wit h c o nc urre nt pr oce d ures will be ta b ulate d o verall a n d b y reas o n f or 
pr oce d ure as c ollecte d i n t he e C R F pa ge “ C o nc o mita nt Pr oce d ures D etails”.  
A listi n g of c o n c urre nt pr oce d ures will b e create d wit h t he rele va nt i nf or m ati o n c ollecte d o n t he 
“ C o nc o mita nt Pr oce d ures Details” e C R F pa ge.  
1 3. 2  
S u bse q ue nt A nti -C a ncer T her a pies/ Pr oce d ures   
A nti -ca ncer tr eat me nt aft er disc o nti n uati o n will b e pr o vi de d i n a d ata listi n g wit h data r etrie v e d 
fr o m e C R F pa ges o n a nti -ca n cer dr u g treat me nts, ra di ot hera pi es a n d s ur geri es aft er 
disc o nti n uati o n . T he earliest date of start of ne w a nti -ca ncer dr u g  t hera p y will be use d f or t he 
defi niti o n of t he o n -treat me nt peri o d a n d t he earliest date of start of ne w a nti-ca ncer t hera p y will 
be use d f or ce ns ori n g f or effic ac y a n al ys es.  
N u m ber a n d perce nta ge of s u bjects wit h a n y a nti -ca ncer tr eat me nt after disc o nti n uati o n or P D 
(i ncl u di n g s u bjects fr o m c he m ot hera p y ar m w h o recei ve d a vel u ma b after c o nfir mati o n o f P D) will 
be ta b ulate d o verall a n d b y t y pe of t hera p y b as e d o n t he data c ollecte d fr o m t he anti -ca ncer 
treat me nt aft er disc o nti n uati o n  or P D  e C R F pa ge s: A vel u ma b / C yt ot o xic t hera p y / E n d o cri ne 
t hera p y / M o n o cl o nal a nti b o dies t hera p y / S mall m olec ules / Im m u n ot hera p y / Ot her.  I n a d diti o n, 
t he n u m ber a n d p erce nta ge of s u bjects w h o recei ve d s u bse q ue nt i m m u ne t hera p y as c hec k p oi nt 
i n hi bit ors ( C PI) (a vel u ma b, 
ni v ol u ma b, 
pe m br oliz u ma b, la m br oliz u ma b, atez oliz u ma b, 
d ur val u ma b , tre meli m u m a b or i pili m u ma b) will be  ta b ulate d b y tr eat me nt ar ms. T he fi n al list of 
s u bse q ue nt i m m u ne t hera pies will be pr o vi de d u p o n me dical re vi e w of all s u bse q ue nt a nti -ca ncer 
t hera pies. 
S u m mar y statistics will be create d f or best res p o ns e acr oss all p ost st u d y tr eat me nts base d o n t he 
data c ollecte d fr o m t he “ A nti -Ca ncer Treat me nt after Disc o nti n uati o n Details” e C R F pa ge. F or 
s u bjects w h o recei ve d m ore t ha n o ne a nti-ca ncer dr u g t hera p y after treat me nt disc o nti n uati o n, t he 
best o verall res p o ns e a m o n g all a nti -ca nc er dr u g t hera pies will be s u m mari ze d.  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 1 /1 0 2  
 
 
S u m mar y of s u bs e q ue nt a nti -ca ncer treat me nt will i ncl u de t he n u m ber a n d perce nt a ge of s u bjects 
b y A T C Classificati o n le vel 2 a n d P T . T he sa m e a p pr oac h as pri or a n d c o nc o mita nt me dicati o ns 
will be a p plie d i n prese nti n g  t he s u m mar y ta bl e of s u bse q ue nt a nti-ca n cer treat me nt.  
1 4  
Tre at me nt C o m pli a nce a n d E x p os ure   
A n alysis sets: S afety A n alysis Set  / S afety C o h ort A n alysis Set 
All d osi n g calc ulati o ns 
a n d s u m maries 
will be base d o n av el u ma b a n d c h e m ot hera p y 
ad mi nistrati o n e C R Fs pa ges.  
S u bjects ra n d o mize d t o ar m A will recei ve a n I V i nf usi o n of a vel u ma b at a d ose of 1 0  m g/ k g o ver 
t he d urati o n of 1 h o ur (-1 0/ + 2 0 mi n utes) o nce e v er y 2 wee ks ( o ne c ycl e).  
S u bjects ra n d o mize d t o ar m B (c he m ot hera p y plati n u m -base d d o u blet ) ar m will recei ve I V 
i nf usi o n acc or di n g t o t he la bel i nstr ucti o ns a n d per l ocal a d mi nistrati o n g ui deli nes o ver t h e 
d urati o n of 1 h o ur  o nce e ver y 3  wee ks ( o ne c ycl e) , f or a m a xi m u m of 6 c ycles. T he c h oice of t he 
c he m ot hera p y a d mi nistere d de pe n ds o n hist ol o g y:  
- 
S u bjects wit h N S C L C of s q ua m o us hist ol o g y will recei v e eit her:  
o  ge m cita bi ne i n c o m bi nati o n wit h cis plati n  ( u p t o 6 c ycles); or 
o  ge m cita bi ne i n c o m bi nati o n wit h car b o plati n  ( u p t o 6 c ycles); or  
o  paclita x el i n c o m bi nati o n wit h car b o plati n  ( u p t o 6 c ycles).   
- 
S u bjects wit h N S C L C of n o n -s q ua m o us hist ol o g y will recei ve eit her:  
o  pe metre x e d i n c o m bi nati o n wit h cis plati n ( u p t o 6 c ycles); or 
o  pe metre x e d i n c o m bi nati o n wit h car b o plati n ( u p t o 6 c ycles); or 
o  pe metre x e d i n c o m bi nati o n wit h cis plati n ( u p t o 4 c ycles), f oll o we d b y p e m etre x e d 
mai nte na nce ; or 
o  pe metre x e d i n c o m bi nati o n wit h car b o plati n ( u p t o 4 c ycl es), f oll o we d b y 
pe metre x e d mai nte na nce . 
S u bjects ra n d o mize d t o ar m C will recei ve a n I V inf usi o n of a vel u ma b  at a d ose of 1 0 m g/ k g o ver 
t he d urati o n of 1 h o ur (-1 0/ + 2 0 mi n utes) e ver y wee k f or 1 2 c o ns ec uti ve wee ks, f oll o w e d b y 
a vel u ma b at a d os e of 1 0 m g/ k g o nce e ver y 2 wee ks .  
A nal ysis of e x p os ure will be bas e d o n t he calc ulate d act u al d ose l e vels (t otal d ose / wei g ht f or 
a vel u ma b, t otal d ose / deri ve d B S A f or c he m ot hera p y). 
Ar m A ( a v el u m a b):  
F or s u bjects ra n d o mize d t o a vel u ma b  i n ar m A, t he d ose le vel is calc ulate d as act ual d os e 
a d mi nistere d/ wei g ht ( m g/ k g). T he last a vaila ble wei g ht of t he s u bject o n or pri or t o t he d a y of 
d osi n g will be use d.  
T he d urati o n of a v el u ma b treat me nt (i n wee ks) d uri n g t he tri al is defi ne d as: 
d ur ati o n = ( d at e  of  l ast d os e  of  a v el u m a b  −d at e  of  first d os e  of  a v el u m a b  + 1 4
7
)  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 2 /1 0 2  
 
 
T he c u m ulati ve d ose ( m g/ k g) of a v el u ma b  per s u b ject i n a ti me peri o d is t he s u m of t he act ual 
d ose le vels t hat t he s u bject recei v e d wit hi n t hat peri o d (i.e. t otal d ose a d mi nistere d ( m g) / wei g ht 
( k g)). 
Eac h c ycl e is defi ne d b y a 2 -wee k peri o d. T he d ose i nte nsit y a n d t he rel ati ve d ose i nte nsit y  of 
a vel uma b  will be calc ulate d f or eac h s u bject acr oss all c ycl es.  
T he d ose i nte nsit y ( m g/ k g/c ycl e) of a vel u ma b p er c ycle is defi n e d as : 
d os e  i nt e nsit y = ( c u m ul ati v e d os e  of  a v el u m a b  (m g / k g ) 
(d ur ati o n  of  a v el u m a b  (i n w e e ks ))/ 2 )  
T he relati ve d os e i nte nsit y of a v el u ma b  is defi ne d as t he act ual d ose i nte nsit y di vi de d b y t h e 
pla n ne d d ose as s p ecifie d i n t he pr ot oc ol per c ycle  a n d e x presse d i n % : 
r el ati v e d os e  i nt e nsit y = 1 0 0  x ( d os e  i nt e nsit y (m g / k g / c ycl e) 
1 0  (m g / k g )
)  
Ar m B (c he m ot her a p y ): 
F or c h e m ot hera p y ar m, t he n u m ber a n d perce nta ge of s u bjects per plati n u m -base d d o u blet will be 
ta b ulate d as well as t h e n u m ber a n d perce nt a ge of s u bjects wit h pe metre x e d mai nte na nce . 
T he d urati o n of c h e m ot hera p y tr eat me nt (i n wee ks) d uri n g t h e trial is defi n e d as: 
d ur ati o n = ( 𝑑𝑎𝑡𝑒 𝑜𝑓 last  𝑑𝑜𝑠𝑒 𝑜𝑓 c h e m ot h er a p y −d at e  of  first d os e  of  c h e m ot h er a p y
7
)  
w here last c he m ot hera p y = ma xi m u m of ( date of last d ose of c he m ot hera p y pr o d uct 1 + C o m p da ys, 
date of last d ose of c he m ot hera p y pr o d uct 2 + C o m p Da ys) w here C o m p Da ys = 2 1 f or Car b o pl ati n, 
Cis plati n, Pe metre x e d a n d Paclita x el; 1 4 f or Ge mcita bi ne . 
T he s u bjects w h o recei ve d pe metre x e d will be c o nsi dere d as ha vi n g recei ve d a mai nte na nce 
t hera p y if t he plati n u m-b ase d c h e m ot hera p y (cis plati n or car b o plati n) has b ee n d efi nitel y st o p pe d 
a n d if at l east o ne d ose of pe metre x e d has bee n recei v e d after t he date of last plati n u m -base d 
c he m ot hera p y d os e . 
T he d urati o n of m ai nte n a nce t hera p y (i n wee ks) f or s u bjects wit h p e metre x e d mai nte na nce is 
defi ne d as:  
d ur ati o n = ( d at e  of  l ast d os e  p e m etr e x e d  m ai nt e n a nc e + 2 1 −d at e  of  first d os e  p e m etr e x e d  m ai nt e n a nc e
7
)  
w here t he d ate of first d ose of mai nte na nce t hera p y is t he date of first d ose of pe metre x e d after t he 
date of last d ose of ass ociate d plati n u m -base d c h e m ot hera p y (cis plati n or car b o plati n).  
Eac h c ycle is defi ne d b y a 3 -wee k peri o d.  F or a nal ysis p ur p ose, a c ycle will be assi g ne d  f or eac h 
a d mi nistrati o n of at least o ne c he m ot hera p y pr o d uct . A c o m plete c ycle will be assi g ne d if t he 
plati n u m -base d d o u blet h a s bee n a d mi nistere d  as pla n ne d . 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 3 /1 0 2  
 
 
Ar m C ( w ee kl y a vel u m a b):  
F or s u bjects ra n d o mize d t o a vel u ma b  i n ar m C, t he d ose le vel is calc ulate d as act ual d ose 
a d mi nistere d/ wei g ht ( m g/ k g). T he last a vaila ble wei g ht of t he s u bject o n or pri or t o t he d a y of 
d osi n g will be use d.  
T he d urati o n of a v el u ma b treat me nt (i n wee ks) d uri n g t he tri al is defi ne d as: 
d ur ati o n  (p eri o d  1 ) = ( d at e  of  l ast d os e  i n p eri o d  1  −d at e  of  first d os e  of  a v el u m a b  + 7
7
)  
w here t he last d ose i n peri o d 1 is t he last d ose of a vel u ma b bef ore ( or e q ual t o) wee k 1 2  
d ur ati o n  (p eri o d  2 ) = ( d at e  of  l ast d os e  of  a v el u m a b  −d at e  of  first d os e  i n p eri o d  2  + 1 4
7
)  
w here t he first d ose i n peri o d 2 is t he start date of t he first 2 -wee k a d mi nistrati o n i nter val after wee k 1 2  
t ot al d ur ati o n = ( d at e  of  l ast d os e  of  a v el u m a b  −d at e  of  first d os e  of  a v el u m a b  + A
7
)  
w here A is 7 if treat me nt is disc o nti n ue d bef ore wee k 1 3 , or 1 4 if treat me nt is disc o nti n ue d after wee k 1 3  
T he c u m ulati ve d ose ( m g/ k g) of a v el u ma b  per s u bject i n a ti me peri o d is t he s u m of t he act ual 
d ose le vels t hat t he s u bject recei v e d wit hi n t hat peri o d (i.e. t otal d ose a d mi nistere d ( m g) / wei g ht 
( k g)). 
Eac h c ycl e is defi ne d b y a 2 -wee k peri o d . T he d ose i nte nsit y a n d t he rel ati ve d ose i nte nsit y of 
a vel u ma b  will be calc ulate d f or eac h s u bject acr oss all c ycl es.  
T he d ose i nte nsit y ( m g/ k g/c ycl e) of a vel u ma b p er c ycle is defi n e d as:  
d os e  i nt e nsit y (p eri o d  1 ) = ( c u m ul ati v e  d os e  of  a v el u m a b  i n p eri o d  1  (m g / k g ) 
d ur ati o n  of  a v el u m a b  i n p eri o d  1  (i n w e e ks )/ 2
)  
d os e  i nt e nsit y (p eri o d  2 ) = ( c u m ul ati v e  d os e  of  a v el u m a b  i n p eri o d  2  (m g / k g ) 
d ur ati o n  of  a v el u m a b  i n p eri o d  2  (i n w e e ks )/ 2
)  
t ot al d os e  i nt e nsit y = (
t ot al c u m ul ati v e d os e  of  a v el u m a b  (m g / k g ) 
(d ur ati o n  i n p eri o d  1 +  d ur ati o n  i n p eri o d  2  (i n w e e ks ))/ 2 )  
T he relati ve d o s e i nte nsit y of a v el u ma b is defi ne d as t he act ual d ose i nte nsit y di vi de d b y t h e 
pla n ne d d ose as s p ecifie d i n t he pr ot oc ol per c ycle a n d e x presse d i n %:  
r el ati v e d os e  i nt e nsit y (p eri o d  1 ) = 1 0 0  x ( d os e  i nt e nsit y of  p eri o d  1  (m g / k g / c ycl e) 
2 0  (m g / k g )
)  
r el ati v e d os e  i nt e nsit y (p eri o d  2 ) = 1 0 0  x ( d os e  i nt e nsit y of  p eri o d  2  (m g / k g / c ycl e) 
1 0  (m g / k g )
)  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 4 /1 0 2  
 
 
t ot al r el ati v e d os e  i nt e nsit y = 1 0 0  x ( t ot al d os e  i nt e nsit y (m g / k g / c ycl e) 
1 0  (m g / k g )
)  
T he f oll o wi n g s u m mar y ta bles will be pr o vi de d:  
F or a v el u ma b ar m s: 
•  D urati o n of t hera p y ( wee ks)   
•  T otal n u m ber of i nf usi o ns recei v e d  
•  C u m ulati ve d ose of t hera p y ( m g/ k g)  
•  D ose i nte nsit y ( m g/ k g/ c ycle) 
•  Relati ve d ose i nte nsit y of t hera p y ( %)  
F or c h e m ot hera p y ar m : 
•  Fre q u e nc y c o u nt of differe nt plati n u m -base d d o u blet use d   
•  D urati o n of t hera p y ( wee ks)  
•  N u m ber of c ycles  a n d c o m plete c ycles  
•  N u m ber a n d p erce nta ge of s u bjects wit h pe metre x e d mai nte na nce  
•  N u m ber of mai nte n a nce c ycles f or s u bj ects wit h pe metre x e d mai nte na nce  
•  D urati o n of mai nte na n ce t hera p y f or s u bj ects wit h pe metre xe d mai nte na nce ( wee ks)  
 
D ose Re d ucti o n f or c he m ot her a p y ar m 
D ose re d ucti o ns are i de ntifie d o n t he a d mi nistrati o n e C R F pa ge b y t he i n vesti gat or. N u m ber  a n d 
perce nt a ge  of s u bjects wit h at least o ne d ose re d ucti o n as rec or de d i n e C R F as well as a brea k d o w n 
of d ose re d u cti o ns ( 1 / 2 / 3 / ≥4) will be s u m marize d f or t he c he m ot hera p y ar m.  
D ose Del a y  
Dela ys will be deri ve d base d o n i nf usi o n date f or t he t hree treat me nt gr ou ps a n d will be gr o u pe d 
i nt o t he f oll o wi n g cate g ories base d o n t he de viati o n of t he act ual t o t he pla n ne d treat me nt 
a d mi nistrati o n da y (relati ve t o t he pre vi o us treat me nt a d mi nistrati o n date):  
•  N o dela y (i ncl u di n g 1 -2 da ys d ela ys)  
•  3 -6 da ys dela y  
•  7 or m ore da ys d ela y  
F or e x a m ple, if o ne s u bj ect recei v es a v el u ma b o n da y 1, t he n t h e ne xt a v el u ma b a d mi nistrati o n 
date will be o n da y 1 5; h o we ver, if t he s u bject recei ves a vel u ma b at da y 1 6 or 1 7, t his is c o nsi dere d 
as ‘ n o dela y’.  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 5 /1 0 2  
 
 
N u m ber a n d perce nt a ge of s u bjects  wit h at least o ne dela ye d i nf usi o n as well as a brea k d o w n of 
d ose dela ys ( 1 / 2 / ≥3) a n d ma xi m u m le n gt h of d ela y, i.e. t he w orst c ase of dela y if s u bjects ha v e 
m ulti ple d ose dela ys will be s u m mariz e d.  
F or ar m C ( wee kl y a v el u ma b), res ults will be prese nt e d o n t he o v erall treat me nt peri o d a n d als o 
se parat el y o n t h e first 1 2 wee ks of treat me nt (i.e. wee kl y a d mi nistrati o n peri o d of a vel u ma b). 
A vel u m a b i nf usi o n r ate re d ucti o ns  
I nf usi o n rate re d u cti o ns as rec or de d o n t he e C R F will be use d f or a nal ysis. N u m ber a n d perce nta ge 
of s u bjects wit h at least o ne i nf usi o n rate re d ucti o n as well as a brea k d o w n of i nf usi o n rat e 
re d ucti o ns ( 1 / 2 / ≥3) will be s u m marize d f or t he a vel u ma b treat me nt gr o u ps. 
A listi n g of st u d y dr u g a d mi nistrati o n will be creat e d wit h t he i nf or mati o n c ollecte d o n t he 
avel u ma b / c he m ot hera p y a d mi nistrati o n details e C R F pa ge.  
1 5  
E n d p oi nt E v al u ati o n   
T he pri mar y e n d p oi nt s of t he trial are t he pr o gressi o n free s ur vi v al ( P F S) ti me a n d o verall s ur vi val 
( O S) ti me. T he trial will be c o nsi dere d t o ha ve m et its o bjecti ve if eit her or b ot h of t he pri mar y 
e n d p oi nts are p ositi ve . 
P F S is defi ne d as t he ti me (i n m o nt hs) fr o m ra n d o miza ti o n t o t he date of t he  first d oc u me ntati o n 
of P D  as a dj u dicat e d b y t he I R C , or d eat h  d u e t o a n y ca use i n t he a bse n ce of d o c u me nte d P D, 
w hic he ver occ urs first.  O S ti me is defi ne d as t h e ti me (i n m o nt hs) fr o m ra n d o mizati o n t o t he date 
of deat h,  re gar dless of t he act ual ca use of t he s u bject’s deat h. 
T he sec o n dar y efficac y e n d p oi nts  i ncl u de best o verall res p o nse ( B O R)  acc or di n g t o R E CI S T  1. 1 
a n d as a dj u dicate d b y t he I R C . Ra di ol o gi cal assess me nts will be use d i ncl u di n g a dj u dicate d 
re vie ws. 
A hiera rc hical testi n g str ate g y will be a p plie d t o test s u peri orit y of eit her a vel u ma b re gi me n vs 
S O C c he m ot hera p y f or t he pri mar y e n d p oi nts P F S a n d O S. T he F A S will be use d f or t he 
co m paris o ns of Ar m A a n d Ar m B a n d m F A S will be use d f or t he c o m paris o n of Ar m C a n d Ar m 
B:  
Hierarc h y Ste p 1: P F S a n d O S i n t he hi g h e x pressi o n P D -L 1 + p o p ulati o n  
Hierarc h y Ste p 2: P F S a n d O S i n t he m o derate a n d hi g h e x pressi o n P D -L 1 + p o p ulati o n 
(i ncl u di n g hi g h e x pressi o n P D-L 1 + p o p ulati o n)   
Hierarc h y Ste p 3: O S i n t he a n y e x pressi o n P D -L 1 + p o p ulati o n  
A cl ose d testi n g pr oce d ure will be use d wit h wei g hte d B o nferr o ni tests acc or di n g t o H o m mel, 
Bretz, Ma urer 2 0 0 7 (1 ) t o acc o u nt f or m ulti plicit y. F or t he cl os ure test, it h ol ds: a n i ntersecti o n 
h y p ot hesis H i ca n o nl y b e reje cte d if all i ntersecti o n h y p ot hes es i m pl yi n g H I ca n als o be  rej ecte d 
b y t heir l ocal t ests. F urt her d etails are pr o vi de d i n Secti o n  1 5. 1. 1  
 
 
 
Gl o bal Versi o n I D: C CI
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 6 /1 0 2  
 
 
1 5. 1  
Pri m ar y E n d p oi nt A n al yses   
T he pri mar y statistical c o m paris o ns of Ar m A vs . Ar m B will be perf or m e d wit h t he F A S. T he 
pri mar y statistical c o m p aris o n of Ar m C vs . Ar m B will be perf or me d wit h t he m F A S t o e ns ure  a 
ra n d o mize d c o m paris o n of treat me nt ar ms t hat is n ot i m pacte d b y t h e ti me of ran d o mizati o n.  
1 5. 1. 1  
Hier arc hic al testi n g   
T he f oll o wi n g pr oce d ure is use d:  
•  All h y p ot heses c o m pari n g Ar m C vs Ar m B get t hree ti mes t he wei g ht of t he h y p ot h eses 
c o m pari n g Ar m A vs Ar m B, ie, wei g ht  ¾ a n d ¼.  C orres p o n di n g h y p ot heses f or P F S a n d O S 
get differe nt wei g hts, ie, 2/ 3 f or P F S a n d 1/ 3 f or O S.  
•  E x ce pti o n:  
as  
l o n g  
as  
a n  
h y p o t h esis  
wit h  
P D-L 1  
hi g h  
e x pressi o n  
( H 0 _ 1 A, H 0 _ 2 A, H 0 _ 1 C, H 0 _ 2 C) is i ncl u de d i n a n i ntersecti o n h y p ot hesis t he c orres p o n di n g 
h y p ot hes es f or P D -L 1 m o derate a n d hi g h e x pressi o n ( H 0 _ 3 A, H 0 _ 4 A, H 0 _ 3 C, H 0 _ 4 C) a n d all 
h y p ot hes es f or a n y P D -L 1 + ( H 0 _ 6 A, H 0 _ 6 C ) get wei g ht  0, as l o n g as b ot h h y p ot hes es ( P F S 
a n d O S) wit h P D -L 1 m o derate e x pressi o n ( H 0 _ 3 A, H 0 _ 4 A a n d H 0 _ 3 C, H 0 _ 4 C) is i ncl u de d i n 
a n i ntersecti o n h y p ot hesis t he c orres p o n di n g O S h y p ot hes es f or a n y P D -L 1 + ( H 0 _ 6 A a n d 
H 0 _ 6 C) get wei g ht 0.  
•  F or h y p ot h eses wit h i nteri m a n al yses t he c orres p o n di n g si g nifica nce le vels at i nteri m a n d fi nal 
a nal ysis are defi ne d bas e d o n -s pe n di n g a p pr oac hes usi n g l ocal si g nifica n ce le vels acc or di n g 
t o 1 a n d 2. 
•  S u m of t he wei g hts f or eac h i ntersecti o n h y p ot h esis is 1.  
T he statistical h y p ot h eses  are d escri be d b el o w. T he si g nifica nce le vels n ote d are t h e mi ni m u m 
si g nifica n ce le v els t hat ca n t o be use d f or t he c orres p o n di n g h y p ot hesis. De pe n di n g o n t he alrea d y 
rejecte d h y p ot hesis acc or di n g t o cl ose d testi n g pr oce d ure a b o ve t he l ocal si g nifica nce lev el mi g ht 
i ncreas e. 
Hierarc h y Ste p 1: C o m paris o ns f or hi g h e x pressi o n P D -L 1 + p o p ulati o n  
P F S f or hi g h e x pressi o n P D -L 1 + i n t he F A S: Ar m A vers us B c o m paris o n at α  =  0. 0 0 4 1 7 or 
a b o ve acc or di n g t o cl ose d testi n g pr oce d ure  
H 0 _ 1 A: 1 A(t) = 1 h1 B(t),  1 h ≥ 1, vers us H 1 _ 1 A: 1 B(t) = h1 C(t),  1 h < 1,  
O S f or hi g h e x pressi o n P D -L 1 + i n t he F A S: Ar m A vers us B c o m paris o n at α  =  0. 0 0 2 0 8 or 
a b o ve acc or di n g t o cl ose d testi n g pr oce d ure  
H 0 _ 2 A: 2 A(t) = 2 h2 B(t),  2 h ≥ 1, vers us H 1 _ 2 A: 2 A(t) = 2 h2 B(t),  2 h < 1 , 
P F S f or hi g h e x pressi o n P D -L 1 + i n t he m F A S: Ar m C vers us B c o m paris o n at α  =  0. 0 1 2 5 
or a b o ve acc or di n g t o cl ose d testi n g pr oce d ure  
H 0 _ 1 C: 1 C(t) = 1 h1 B(t),  1 h ≥ 1, vers us H 1 _ 1 C: 1 B(t) = 1 h1 B(t),  1 h < 1,  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 7 /1 0 2  
 
 
O S f or hi g h e x pressi o n P D -L 1 + i n t he m F A S: Ar m C vers us B c o m paris o n at α  =  0. 0 0 6 2 5 
or a b o ve acc or di n g t o cl ose d testi n g pr oce d ure  
H 0 _ 2 C: 2 C(t) = 2 h2 B(t),  2 h ≥ 1, vers us H 1 _ 2 C: 2 C(t) = 2 h2 B(t),  2 h < 1,  
If l ocal si g nifica nt res ults are o btai ne d i n Hierarc h y Ste p 1, i nf ere ntial t esti n g will pr ocee d t o 
c orres p o n di n g h y p ot hes es i n Hierarc h y Ste p 2.  
Hierarc h y Ste p 2: C o m paris o ns f or m o derat e a n d hi g h e x pressi o n P D -L 1 + p o p ulati o n  
P F S f or m o derate a n d hi g h e x pressi o n P D -L 1 + i n t he F A S: Ar m A vers us B c o m p aris o n at 
α  =  0. 0 0 4 1 7 or a b o ve acc or di n g t o cl ose d t esti n g pr oce d ure  
H 0 _ 3 A: 3 A(t) = 3 m3 B(t),  3 m ≥ 1, vers us H 1 _ 3 A: 3 A(t) = 3 m3 B(t),  3 m < 1,  
O S f or m o derate a n d hi g h e x pressi o n P D -L 1 + i n t he F A S: Ar m A vers us B c o m paris o n at 
α  =  0. 0 0 2 0 8 or a b o ve acc or di n g t o cl ose d t esti n g pr oce d ure  
H 0 _ 4 A: 4 A(t) = 4 m4 B(t),  4 m ≥ 1, vers us H 1 _ 4 A: 2 A(t) = 4 m4 B(t),  4 m < 1,  
P F S f or m o d erate a n d hi g h e x pressi o n P D -L 1 + i n t he m F A S: Ar m C vers us B c o m paris o n 
at α  =  0. 0 0 1 2 5 or a b o ve acc or di n g t o cl ose d testi n g pr o ce d ure  
H 0 _ 3 C: 3 C(t) = 3 m3 B(t),  3 m ≥ 1, vers us H 1 _ 3 C: 3 C(t) = 3 m3 B(t),  3 m < 1,  
O S f or m o d erate a n d hi g h e x pressi o n P D -L 1 + i n t he m F A S: Ar m C vs B c o m paris o n at 
α  =  0. 0 0 6 2 5 or a b o ve acc or di n g t o cl ose d t esti n g pr oce d ure  
H 0 _ 4 C: 4 C(t) = 4 m4 B(t),  4 m ≥ 1, vers us H 1 _ 4 C: 4 C(t) = 4 m4 B(t),  4 m < 1,  
If l oc al si g nifica nt res ults are o btai ne d f or Hierarc h y 2, i nfere ntial testi n g will pr ocee d t o 
c orres p o n di n g h y p ot hes es i n Hierarc h y 3.  
Hierarc h y Ste p 3: C o m paris o ns f or a n y e x pressi o n P D -L 1 + p o p ulati o n:  
O S f or a n y e x pressi o n P D -L 1 + i n t he F A S: Ar m A vers us B c o m paris o n at α = 0. 0 0 2 0 8 or 
a b o ve acc or di n g t o cl ose d testi n g pr oce d ure  
H 0 _ 6 A: 6 A(t) = 6ll6 B(t), 6l ≥ 1, vers us H 1 _ 6 A: 6 A(t) = 6l6 B(t),  6l < 1,  
O S f or a n y e x pressi o n P D -L 1 + i n t he m F A S: Ar m C vs B c o m p aris o n at  α = 0. 0 0 6 2 5 or 
a b o ve acc or di n g t o cl ose d testi n g pr oce d ure  
H 0 _ 6 C: 6 C(t) = 6ll6 B(t), 6l ≥ 1, vers us H 1 _ 6 C: 6 C(t) = 6l6 B(t),  6l < 1,  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 8 /1 0 2  
 
 
 
Fi g ure 1  I nfere nti al Testi n g Pr o ce d ure  
I nteri m a nal yses are pl a n ne d f or P F S a n d O S base d o n re q uire d O S e ve nts  a n d mi ni m u m f oll o w -u p 
ti me of 1 0 m o nt hs f or t h e hi g h e x pressi o n P D-L 1 + p o p ulati o n.  I nt eri m  a n d fi nal  a n al ysis f or P F S  
a n d O S  will be c o n d ucte d at t he sa me ti me.  Al p ha will be s pe nt acc or di n g t o La n -De M ets wit h 
O’ Brie n -Fle mi n g -li ke b o u n daries wit h t he l ocal si g nifica n ce le vel at t he first hierarc h y ste p.  
F urt her details are  gi ve n i n Secti o n  7. 2 . 
1 5. 1. 2  
Pr o gressi o n Free S ur vi v al   
A n alysis sets: F A S  / m F A S, by P D-L 1  ex pressi o n  st at us 
P F S is  defi ne d as t he ti me fr o m date of ra n d o mizati o n u ntil date of t he first d oc u me ntati o n of P D  
per R E CI S T 1. 1  or d eat h d ue t o a n y ca us e i n t he a bse nce of d oc u me nt e d P D, w hic he ver o cc urs 
first. T he P F S will be defi ne d acc or di n g t o R E CI S T 1. 1 a n d as a dj u dicate d b y a n I R C. Details o n 
deter mi nati o n of t he first disease pr o gressi o n date will be s pecifie d i n t he I R C c harter.   
P F S ti me (i n m o nt hs) is defi ne d as:  
 ( Date of P D or deat h - d ate of ra n d o mizati o n + 1)  / 3 0. 4 3 7 5 ( m o nt hs) 
F or t he pri mar y a nal ysis , P F S data will be ce ns ore d o n t he date of t h e last a d e q uate t u m or 
assess me nt f or s u bjects w h o d o n ot ha ve a n e ve nt ( P D or deat h), f or s u bjects w h o start ne w 
a ntica ncer treat me nt pri or t o a n e ve nt, or f or s u bjects wit h a n e ve nt after t w o or  m ore missi n g 
t u m or assess me nts. S u bjects w h o d o n ot ha ve a bas eli ne t u m or assess me nt or w h o d o n ot ha ve a n y 
p ost -baseli ne t u m or assess me nts will be ce ns ore d o n t he date of ra n d o mizati o n u nless deat h 
occ urre d o n or b ef ore t h e ti me of t he s ec o n d pl a n ne d t u m or assess me nt, i n w hic h case t he d eat h 
will be c o nsi dere d a n e ve nt.  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 9 /1 0 2  
 
 
If a t u m or ass ess me nt was perf or me d o n t h e sa me da y as start of n e w a nti-ca ncer t h era p y, it will 
be ass u me d t hat t he t u m or assess me nt was perf or me d pri or t o t he start of t he ne w a nti -ca n cer 
t hera p y, t heref ore t he t u m or assess me nt will be i ncl u de d i n t he deri vati o n of t he P F S ti me. 
A n a de q uat e t u m or assess me nt is defi ne d as a t u m or assess me nt wit h res ult t hat is n ot “ N E” or 
“ N A”.  
S o me s u bjects ma y start ne w a ntica ncer t hera p y pri or t o d oc u me nte d diseas e pr o gressi o n. F or s uc h 
s u bjects, t he pr ot oc ol re q uires t u m or assess me nts t o be c o nti n ue d per sc he d ule of assess me nts 
t hr o u g h d oc u m e nte d dise ase pr o gressi o n or deat h t o e na ble c o n d uct of a s u p p orti ve a nal ysis f or 
P F S t hat will i g n ore (t hat is, n ot ce ns or s u bjects at) start of ne w a ntica n cer treat me nt.  
T he ce ns ori n g a n d e v e nt date o pti o ns t o be c o nsi d ere d f or t h e P F S a nal ysis are prese nt e d i n T a ble 
5 . 
T a ble 5  
O utc o me a n d e ve nt d ates f or P F S a n d d ur ati o n of res p o nse a n al yses   
Sce n ari o  
D ate of e ve nt/ce ns ori n g  
O utc o me  
N o baseli ne assess me nt  
Date of   ra n d o mizati o n 
Ce ns ore d a 
P D or deat h:  
 After at 
m ost o ne 
missi n g or i n a de q uate p ost -
baseli ne t u m or assess me nt, O R  
≤ 1 2 wee ks after ra n d o miz ati o n  
Date of P D or deat h  
E ve nt  
 
P D or deat h after 2 or m ore missi n g c or i n a de q uate 
p ost -baseli ne t u m or assess me nts  
Date of last a de q uate t u m or assess me nt b 
d oc u me nti n g n o P D bef ore ne w a nti -
ca ncer t h era p y is gi ve n or miss e d t u m or 
assess me nts  
Ce ns ore d  
 
N o P D a n d n o deat h  
Date of last a de q uate t u m or assess me nt b 
d oc u me nti n g n o P D bef ore ne w a nti -
ca ncer t h era p y is gi ve n or miss e d t u m or 
assess me nts  
Ce ns ore d  
 
Treat me nt  
disc o nti n uati o n  
d ue  t o  ‘ Disease 
pr o gressi o n’ wit h o ut d oc u me nte d pr o gressi o n  
N ot a p plica ble  
I nf or mati o n is i g n ore d. 
O utc o me is deri ve d base d 
o n  
d oc u me nte d 
pr o gressi o n o nl y.  
Ne w a nti -ca ncer t h era p y gi ve n  
Date of last a de q uate t u m or assess me nt b 
d oc u me nti n g n o P D bef ore ne w a nti -
ca ncer t h era p y is gi ve n or miss e d t u m or 
assess me nts  
Ce ns ore d  
 
a H o we ver if t h e patie nt dies ≤1 2 we e ks aft er ra n d o mizati o n t h e deat h  is a n e ve nt wit h date of deat h date 
b If t h ere are n o a de q uate p ost-baseli ne assess me nts pri or t o t h e P D or deat h, t h e n t h e ti me wit h o ut a de q uate assess me nt s h o ul d 
be meas ure d fr o m t h e date of ra n d o mizati o n; if t h e criteria were met t h e ce ns ori n g will be o n t h e date of ra n d o mizati o n  
c Deri vati o n of 2 or m ore missi n g t u m or assess me nts acc or di n g t o t he f oll o wi n g r ules:  
Last E val u a ble Sca n Pri or t o E ve nt ( P D or Deat h) , 
da ys si nce tre at me nt start  
Ce ns or if D urati o n Bet wee n Last Sca n a n d E ve nt  
[ Da y 1, Da y 3 2 2] 
> 8 4 da ys ( 1 2 wee ks)  
[ Da y 3 2 3, Da y 3 6 5] 
> 1 2 6 da ys ( 1 8 wee ks)  
> Da y 3 6 5  
> 1 6 8 da ys ( 2 4 wee ks)  
 
T he pri mar y efficac y a nal ysis will c o m pare t h e P F S ti me bet w ee n ar m A a n d ar m B  ( F A S), a n d 
bet wee n ar m C a n d ar m B  ( m F A S), a n d will be p erf or me d usi n g a o ne-si de d stratifie d l o g ra n k 
test base d o n t he si g nifica nce le vel at t he i nteri m a n d t he fi nal a nal ysis as s pecifie d i n Ta ble 2 , 
Sect i o n 7. 2  a n d usi n g t he hi erarc hical a p pr oac h defi ne d i n S ecti o n 1 5. 1. 1 . T he stratificati o n fac t ors 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 0 /1 0 2  
 
 
are t h os e use d f or ra n d o mizati o n as ca pt ure d via t he I W R S ( N S C L C hist ol o g y: s q ua m o us v ers us 
n o n -s q ua m o us cell, a n d P D-L 1 t u m or e x pressi o n: l o w e x pressi o n vers us m o derate e x pressi o n 
vers us hi g h e x pressi o n). Missi n g P D -L 1 e x pressi o n classificati o n f or s u bjects e nr olle d pri or t o 
A me n d me nt 3 will be i m p ute d fr o m t he res ults of t he Da k o P D -L 1 i m m u n o hist oc he mistr y (I H C) 
p har m D x c o m pa ni o n dia g n ostic test.  
T he f oll o wi n g n ull h y p ot hes es will be teste d (see S ecti o n 1 5. 1. 1  f or m ore d etails): 
H 0: A (t) = B (t),  ≥ 1, vers us H 1: A (t) =B (t),  < 1,  
H 0: C (t) = B (t),  ≥ 1, vers us H 1: C (t) =B (t),  < 1,  
w here (t) re pres e nts t he hazar d at ti me t a n d  t he u n k n o w n c o nsta nt of pr o p orti o nalit y of h azar ds 
i n treat me nt gr o u ps A (a vel u ma b), B ( c he m ot hera p y) a n d C ( wee kl y a vel u ma b) .  
T he treat me nt effect will be esti mate d usi n g a C o x’s Pr o p orti o nal Hazar d m o del stratifie d b y t he 
ra n d o mizati o n strata t o calc ulate t h e hazar d rati o a n d its t w o -si de d CI i n li ne wit h t he l ocal 
si g nifica n ce le vel. I n a d diti o n 9 5 % CIs will be pr o vi de d. Eac h strat u m will defi ne a se parate 
baseli ne hazar d f u ncti o n ( usi n g t h e ' S T R A T A' st ate me nt i n S A S P R O C P H R E G), i.e. f or t h e i -t h 
strat u m t he hazar d f u ncti o n is e x presse d as: h(i;t) = h(i, 0;t) e x p( x ), w here h(i, 0;t) defi n es t he 
baseli ne hazar d f u ncti o n f or t he i -t h strat u m a n d x defi nes t he treat me nt gr o u p ( 0 =c he m ot hera p y, 
1 =  a vel u ma b ) a n d  is t he u n k n o w n re gressi o n para meter. 
I n or der t o acc o u nt f or t h e gr o u p se q u e ntial desi g n as a p plie d i n t his st u d y, t he re p eate d CI m et h o d 
acc or di n g t o  J e n nis o n a n d T ur n b ull (2 ), will be us e d t o c o nstr uct t he t w o-si de d CI f or t he i nteri m 
a n d t he fi nal a nal ysis. T he al p ha val ue as s pecifie d i n Ta ble 2 , Secti o n 7. 2  will be a p plie d t o 
calc ulate t he t w o -si de d CI f or t he i nteri m a n al ysis a n d t he fi nal a n al ysis, res pecti vel y. 
Ties will be h a n dle d b y re placi n g t h e pr o p orti o nal hazar ds m o d el b y t he discrete l o gistic m o del 
(Ties = Discrete o pti o n i n S A S P R O C P H R E G).  
Ka pla n -Mei er esti mates ( pr o d uct -li mit esti mates) will be prese nte d b y treat me nt gr o u p t o get h er 
wit h a s u m mar y of ass ociate d statistics i ncl u di n g t he me dia n s ur vi val ti me wit h t w o -si de d 9 5 % 
CIs. I n p artic ular, t h e P F S rate at 6, 9, 1 2 a n d 15  m o nt hs will be esti mate d wit h c orres p o n di n g t w o -
si de d 9 5 % CIs. T he CIs f or t he me di a n will be calc ul ate d acc or di n g t o Br o o k me yer a n d 
Cr o wle y  (3 ) a n d t he CIs f or t he s ur vi val f u ncti o n esti mates at t he ti me p oi nts defi ne d a b o ve will 
be deri ve d usi n g t he l o g -l o g tra nsf or mati o n acc or di n g t o Kal bfl eisc h a n d Pre ntice 
(4 ) 
(c o nft y pe =l o gl o g defa ult o pti o n i n S A S P R O C LI F E T E S T). T he esti mate of t he sta n dar d err or 
will be c o m p ute d usi n g Gree n w o o d’s f or m ula.  Ka pla n -Mei er pl ots will be dis pla ye d b y P D -L 1 
stat us a n d b y N S C L C hist ol o g y. 
T he pr o p orti o nal hazar ds ass u m pti o n f or t he pri mar y a n al ysis will be vis uall y c hec ke d b y  pl otti n g 
l o g(-l o g[s ur vi val]) vers us l o g(ti me) b y tr eat me nt ar m.  
F or i m p uti n g missi n g parts of dates of deat h , t he r ules defi ne d i n t he Secti o n 1 0  will be use d.  I n 
all ot her cas es missi n g or i nc o m plete dates will n ot be i m p ute d . Pr o gressi o n dates are e x pecte d t o 
be re p ort e d as c o m plete dates.  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 1 /1 0 2  
 
 
Fre q u e nc y ( n u m ber a n d perce nt a ge) of s u bjects wit h eac h e ve nt t y p e ( P D or deat h) a n d ce ns ori n g 
reas o ns will be prese nte d b y treat me nt ar m. Ce ns ori n g reas o ns are as f oll o ws:  
•  A d mi nistrati ve ce ns ori n g: O n g oi n g i n t he st u d y wit h o ut a n e ve nt  
•  N o n -a d mi nistrati ve ce ns ori n g:  
o  N o  baseli ne ass ess me nt  
o  N o a de q uat e p ost -baseli n e assess me nt   
o  Start of ne w a nti -ca ncer t hera p y 
o  E ve nt after 2 or m ore missi n g or i na d e q uate p ost -baseli ne assess me nts  
o  Wit h dra wal of c o nse nt  
o  L ost t o f oll o w -u p  
L ost t o f oll o w -u p will i ncl u de t he f oll o wi n g s u bjects:  
•  L ost t o f oll o w -u p stat us is c ollecte d o n t he e C R F treat me nt ter mi nati o n pa ge pri or t o t he 
a nal ysis c ut -off  
T w o or m ore misse d or i na de q uate p ost -b aseli ne t u m or assess me nts i m me diatel y prece di n g  
a nal ysis c ut -off dat e  (s ee criteri a i n T a ble 5 ). T he P F S  ti me or ce ns ori n g ti me a n d t h e reas o ns f or 
ce ns ori n g will als o be prese nte d i n a s u bject listi n g.  
1 5. 1. 3  
O ver all S ur vi v al   
A n alysis sets: F A S / m F A S, by P D -L 1  ex pressi o n  st at us 
O S ti me is defi ne d as t he ti me fr o m ra n d o mizati o n t o t he  date  of d eat h,  re gar dless of t h e act ual ca us e 
of t he s u bject’s deat h.  F or s u bjects w h o are still ali ve at t he ti me of data a n al ysis or w h o are l ost 
t o f oll o w u p, O S ti me will be ce ns ore d at the last rec or de d date t h at t he s u bject is k n o w n t o be 
ali ve as s pecifi e d i n S ecti o n 1 0  as of t he data c ut -off date f or t he a n al ysis.   
O verall s ur vi val ti me (i n m o nt hs) is defi ne d as: 
 
( Date of d eat h –  dat e of ra n d o mizati o n + 1) / 3 0. 4 3 7 5  
T he a nal ysis of O S will be a nal o g o us t o t hat f or P F S  ti me as descri be d in S ecti o n 1 5. 1. 2 . T he 
n o mi nal p -val ue as s pecifie d i n  Ta ble 2  will be a p plie d t o calc ulate t he t w o -si de d CI f or t he i nteri m 
a nal ysis a n d t he fi nal a n al ysis, res pecti vel y.  
C o x’s Pr o p orti o nal Hazar d m o del stratifie d b y t h e ra n d o mizati o n strata will be us e d t o calc ulate 
t he hazar d rati o a n d its t w o-si de d CI. K a pla n -M eier esti mates will be prese nt e d b y tr eat me nt gr o u p 
t o get her wit h a s u m mar y of ass ociate d statistics i n cl u di n g t he me di a n s ur vi val ti me wit h t w o-si de d 
CIs. I n p artic ular, t he O S  rate at 1 2, 1 8,  2 4 a n d 3 0 m o nt hs will be esti mate d wit h c orres p o n di n g 
t w o-si de d 9 5 % CI. 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 2 /1 0 2  
 
 
Fre q u e nc y ( n u m ber a n d perce nt a ge) of s u bjects wit h a n e ve nt ( deat h) a n d ce ns ori n g reas o ns will 
be prese nt e d b y treat me nt ar m. Ce ns ori n g reas o ns are as f oll o ws:  
•  Ali ve  
•  Wit h dra wal of c o nse nt  
•  L ost t o f oll o w -u p  
L ost t o f oll o w -u p will i ncl u de t he f oll o wi n g s u bjects:  
•  L ost t o f oll o w -u p stat us is c ollecte d o n t he e C R F treat me nt ter mi nati o n pa ge pri or t o t he 
a nal ysis c ut -off;  
•  S u bjects wit h t he last ali ve date > 1 4 wee ks pri or t o t he a nal ysis  c ut-off d ate ( d urati o n of 
1 4 wee ks is base d o n t h e assess me nt sc he d ule of e ver y 3 m o nt hs f or s ur vi v al f oll o w -u p 
i nter val + 1 wee k wi n d o w). 
T he O S ti me or ce ns ori n g ti me a n d t he reas o ns f or ce ns ori n g will als o be prese nt e d i n a s u bject 
listi n g. 
1 5. 1. 4  
Se nsiti vit y A n al yses of Pri m ar y E n d p oi nt s  
A n alysis sets:  F A S / m F A S, by P D -L 1  ex pressi o n  st at us 
T he f oll o wi n g se nsiti vit y a nal yses will be p erf or me d t o e x pl ore t he r o b ust ness of t he pri mar y 
a nal ysis.  T h ese a nal ys es are re gar de d as p urel y 
 T he u na dj uste d 9 5 %  CI will be 
calc ulate d f or all se nsiti vit y a n al ys es of t he pri mar y e n d p oi nt s. T he se nsiti vit y a nal yses will 
i ncl u de t he f oll o wi n g: 
•  P F S base d o n I R C assess me nt a n d c o u nti n g all P D a n d deat hs as e ve nts wit h o ut c o nsi deri n g 
t he ce ns ori n g r ule f or P D or deat h as d escri be d i n Ta ble 5 ; 
•  P F S base d o n I R C assess me nt a n d i nitiati o n of s u bse q ue nt  a nti-ca n cer t hera pies will n ot be use d 
as a ce ns ori n g reas o n f or P F S;  
•  P F S a n d O S base d o n treate d s u bjects o nl y (safet y a nal ysis s et)  
•  A n u nstratifie d a nal ysis will be perf or me d t o c o m pare t he P F S a n d O S ti me a n d t o esti mate t he 
treat me nt effect; 
•  T he pri ma r y a n al ysis will be re peate d usi n g str ata acc or di n g t o e C R F i nstea d of IW R S data  (f or 
hist ol o g y o nl y) ; 
•  P F S acc or di n g t o i n vesti gat or ass ess me nt will be a nal yze d. F or t his se nsiti vit y a nal ysis, t he date 
of t u m or assess me nt will be deri ve d fr o m t he “ Ass ess me nt of Diseas e Base d o n I m a gi n g” e C R F 
pa ge . T he earliest t u m or assess me nt date c orres p o n di n g t o t he res pecti ve visit t hat is c ollecte d 
o n t his pa ge will be use d f or date of dis ease pr o gressi o n a n d date of res p o nse ; 
•  A s u m mar y of c o nc or da nce of dis ease pr o gressi o n stat us bet wee n I R C a n d i n vesti gat or 
assess me nt will be pr o vi de d i ncl u di n g stat us of “ N o E ve nt”, “ Pr o gressi ve disease” a n d “ Deat h 
Gl o bal Versi o n I D: C CI
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 3 /1 0 2  
 
 
as e ve nt” as w ell as t he n u m ber of cas es w here P D was assesse d at differe nt ti m e p oi nts b y I R C 
a n d i n vesti gat or (s hift ta bles per treat me nt ar m); 
•   If t he act ual n u m b er of O S  e ve nts i n hi g h e x pressi o n P D -L 1 + patie nts is 1 0 % m ore t h a n t he 
pla n ne d n u m ber of O S  e ve nts at t he i nteri m a n al ysis, i.e. if t here are > 1 4 3  O S  e ve nts i n hi g h 
e x pressi o n P D -L 1 + patie nts  f or ar ms B a n d C base d o n t he pr os pecti vel y deter mi ne d c ut-off 
date at t he i nteri m a nal ysis or  > 1 9 1  e ve nts at t he fi nal a nal ysis,  a n d t he i ncreas e is n ot d ue t o 
t he re q uire me nt f or at least 1 0 or  2 0 m o nt hs of f oll o w -u p,  t he a nal ysis will be re peate d usi n g 
t he first c ut-off d ate at w hic h e x actl y 1 3 0 or 1 7 3 O S e ve nts , res pecti vel y, in hi g h e x pressi o n 
P D -L 1 + patie nts were o bser ve d i n t he st u d y ;  
•  T he pri mar y O S a nal ysis will be re peate d b y ce ns ori n g t h ose F A S  a n d m F A S  s u bjects w h o 
recei ve d s u bse q ue nt  i m m u ne t hera p y s uc h as C PI  (a v el u ma b, ni v ol u ma b, pe m br oliz u ma b, 
la m br oliz u ma b, atez oliz u ma b, d ur val u ma b, tre meli m u ma b or i pili m u ma b) after disc o nti n ui n g 
t he st u d y tr eat me nt wit h t he date of t he first d ose of s u bse q ue nt a nti -ca ncer t hera p y mi n us 1 
da y . T h e fi nal list of s u bse q ue nt i m m u ne t hera p y will be pr o vi de d u p o n me dical re vie w of all 
s u bse q ue nt a nti-ca n cer t hera pies.  
•  T he i nteracti o n ter m f or treat me nt * P D -L 1 stat us(l o w/ m o d erate/ hi g h) will be assesse d f or b ot h 
O S a n d P F S via C o x re gressi o n m o dels. T he C o x re gressi o n m o del will be fitte d wit h t he P F S 
or O S ti me as t he de p e n de nt varia bl e; P D -L 1 e x pressi o n stat us , treat me nt, a n d t he tr eat me nt-
b y -P D -L 1 e x pressi o n stat us  i nteracti o n as e x pla nat or y varia bles. A p -val u e f or t he i nteracti o n 
test ( Li keli h o o d Rati o test) will be pr o vi de d. 
Met h o ds f or e v al u ati n g t he v ali dit y of m o del ass u m pti o ns  
T he pr o p orti o nal hazar ds ass u m pti o n will be c hec ke d vis uall y f or t he pri mar y a nal ysis b y pl o tti n g 
l o g(-l o g( P F S or O S, res p ecti vel y )) v ers us l o g(ti me) wit hi n eac h ra n d o mizati o n strat u m.  
Sc h oe nfel d resi d u als i ncl u di n g a L O E S S c ur ve will be pl otte d t o i n vesti gate gra p hicall y vi olati o ns 
of t he pr o p orti o nal hazar ds ass u m pti o n. Sc h oe nfel d resi d uals will be c o m p ute d i n S A S usi n g t he 
P H R E G pr oce d ure a n d usi n g t he O U T P U T state me nt a n d  t he ke y w or d R E S S C H. 
Wit h 
pr o p orti o nal hazar ds t he L O E S S c ur ve s h o ul d be parallel t o t he x -a xis.  
If t hes e s h o w lar ge de part ures fr o m pr o p orti o nal hazar ds t he n P F S a n d O S w ill als o be a nal yze d 
base d o n restri cte d mea n s ur vi val ti me ( R M S T) differe nces ( Z ha n g, 2 0 1 3).   
Restricte d Me a n S ur vi v al Ti me ( R M S T)  
T he R M S T met h o d ol o g y is a p plica ble i n de pe n de ntl y of t he pr o p orti o nal haz ar ds ( P H) ass u m pti o n 
a n d ca n b e use d, at a mi ni m u m,  as a se nsiti vit y a nal ysis t o e x pl ore t he r o b ust ness of t he pri mar y 
a nal ysis res ults. I n partic ular, as it pert ai ns t o t he c ut -off p oi nt (τ) t o e val u ate t he R M S T, it is n ot e d 
t hat t he c ut-off p oi nt s h o ul d n ot e x cee d t he mi ni m u m of t he lar gest o bser ve d ti me  f or b ot h 
treat me nt ar ms s o t hat t he R M S T of all treat me nt ar ms bei n g e v al uate d ca n b e a de q u atel y esti mate d 
a n d c o m paris o n bet w ee n treat me nts is feasi ble; τ s h o ul d be cli nicall y m ea ni n gf ul a n d cl oser t o t he 
e n d of t he st u d y f oll o w -u p s o t hat t h e maj orit y o f s ur vi val o ut c o mes will be c o v ere d b y t h e ti me 
i nter val. T he R M S T u p t o ti me τ ca n t he n be i nter prete d as t he e x pecte d s ur vi val ti me restri cte d t o 
t he c o m m o n f oll o w-u p ti me τ a m o n g all patie nts. T he selecti o n of τ s h o ul d e ns ure t hat t he R M S T 
e val uati o n wi ll n ot g o b e y o n d t h e ma xi m u m ti me p oi nt w here t h e e val uati o n ca n be perf or me d 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 4 /1 0 2  
 
 
w hile als o ta ki n g i nt o acc o u nt a lar ge peri o d of ti me t hat is e x pecte d t o pr o vi de a mea ni n gf ul 
assess me nt of treat me nt effect. T o a v oi d ar bitrar y sel ecti o n of t he c o m m o n c ut -off τ f or b ot h 
treat me nt ar ms, t hree sets of a nal yses will be perf or me d: 
•  τ1 = mi ni m u m of (lar gest o bser ve d s ur vi val ti me f or a vel u ma b ar m s, lar gest o bser ve d s ur vi val 
ti me f or c he m ot hera p y ar m).   
•  τ2 = mi ni m u m of (lar gest s ur vi val e ve nt ti me f or a vel u ma b ar m s, lar gest s ur vi val e ve nt ti me f or 
c he m ot hera p y ar m).  
•  τ3 = mi d p oi nt bet wee n τ 1 a n d τ 2. 
I n t his se cti o n, ‘s ur vi val’ is mea nt t o de n ote P F S or O S , res pecti vel y. 
T he treat me nt effect b et w ee n t he avel u ma b ar m s a n d t he c he m ot hera p y ar m will be assesse d b ase d 
o n t h e differe n ce i n R M S T. T he ass ociate d 9 5 % CI f or t he differe nce i n mea ns a n d 1 -si de d p-val ue 
will be ge nerate d. R M S T as a f u ncti o n of τ a n d t he ass ociate d treat me nt effect bet wee n t he t hree 
treat me nt ar ms will be pl otte d a gai nst ti me τ. 
M ulti varia ble C o x re gressi o n a nal ysis will be carrie d o ut t o assess a n d a dj ust t he treat me nt effect 
f or rele v a nt baseli ne fact ors of p ote ntial pr o g n osti c i m pact. T his a nal ysis will be base d o n t he P F S  
acc or di n g t o t h e I R C ass ess me nt a n d O S   as d efi n e d i n t he pri mar y a nal ysis ( Secti o n s 1 5. 1. 2  a n d 
1 5. 1. 3 ) usi n g t he ce ns ori n g r ul es descri be d i n  Ta ble 5 . A ste p wise sel ecti o n pr oce d ure will ser ve 
t o i de ntif y e x pla nat or y v aria bles of p ote ntial pr o g n ostic v al ues a d diti o nal t o t he ra n d o mizati o n 
strata w hic h will be i ncl u de d i n all m o dels d uri n g t he selecti o n pr oce d ure. T he C o x's Pr o p orti o nal 
Hazar d m o del is defi ne d as: h(t) = h( 0;t) e x p( X b), w here h( 0;t) d efi nes t he b aseli ne hazar d f u ncti o n 
a n d X defi nes t he vect or of e x pla nat or y varia bles a n d b t he u n k n o w n vect or of re gressi o n 
para meters. Varia b les are e ntere d i nt o a n d re m o ve d fr o m t he m o del i n s uc h a wa y t h at eac h 
f or war d selecti o n ste p ca n be f oll o we d b y o n e or m ore bac k war d eli mi nati o n ste ps. T he ste p wise 
selecti o n pr ocess ter mi nates if n o f urt her varia ble ca n be a d de d t o t he m o del or if t he v aria ble j ust 
e ntere d i nt o t he m o d el is t he o nl y varia ble re m o ve d i n t he s u bs e q ue nt b ac k war d eli mi nati o n. T he 
le vel of si g nifica n ce f or a n e x pla nat or y v aria ble t o e nter t he m o del is set t o 0. 1 5 ( p-val ue of Sc ore 
test) a n d t he si g nifica nce le vel f or re m o vi n g it is set t o 0.4 0 ( p -val ue of Wal d test). T his a nal ysis 
will be perf or me d usi n g t he ste p wise selecti o n met h o d i n S A S ( Pr oc P H R E G). O nce t his pr oce d ure 
st o ps, t he fact or 'treat me nt gr o u p' will be a d d e d t o t he last selecte d m o del i n or der t o e val uate t he 
effect of treat me nt o n P F S or O S ti me w he n a dj uste d f or t he selecte d e x pla nat or y v aria bles. T h e 
hazar d rati os of all selecte d e x pla nat or y vari a bles a n d of treat me nt effects will be re p orte d 
i ncl u di n g 2-si de d 9 5 % c o nfi de nce i nter vals. N o i nteracti o ns will be c o nsi dere d. P ost -baseli ne 
fact ors will n ot be c o nsi d ere d f or t he m o del. 
1 5. 1. 5  
S u b gr o u p A n al ysis of Pri m ar y E n d p oi nt s  
A n alysis sets: F A S / m F A S, by P D -L 1  ex pressi o n  st at us  
T he s u b gr o u p a nal yses will be perf or me d o n t he pri mar y e n d p oi nts f or all s u b gr o u p le vels defi ne d 
i n Secti o n 8. 2  “ S u b gr o u p A nal ysis Sets” . All t he s u b gr o u p a n al yses are e x pl orat or y a n d will be 
Gl o bal Versi o n I D: C CI
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 5 /1 0 2  
 
 
perf or me d as u nstratifie d ; n o a dj ust me nt f or m ulti plicit y will be perf or me d . T he P F S a n d O S ti me 
bet wee n t h e t w o a v el u ma b gr o u ps a n d t he c h e m ot hera p y gr o u p will be c o m pare d usi n g a t w o -
side d u nstratifie d l o g ra n k test per s u b gr o u p le vel; a n d t he u nstratifi e d H R a n d its c orres p o n di n g 
9 5 % CI will be c o m p ute d per s u b gr o u p le vel.   
I n t he case of a l o w n u m ber of s u bj ects wit hi n a cate g or y ( < 2 5 s u bjects wit h hi g h P D -L 1 + 
e x pressi o n fr o m all t hree treat me nt gr o u ps c o m bi ne d), t he cate g ories will be p o ole d w he n 
mea ni n gf ul . 
T o assess t he heter o ge neit y of treat me nt effects acr oss t he s u b gr o u p le vels, t w o C o x re gressi o n 
m o del will be fitte d wit h t he P F S or O S  ti me as t h e de p e n de nt v aria ble; s u b gr o u p, treat me nt, a n d  
wit h a n d wit h o ut t he treat me nt -b y -s u b gr o u p i nteracti o n as e x planat or y v ari a bles.  
•  M o del 1: treat me nt + s u b gr o u p  
•  M o del 2: treat me nt + s u b gr o u p + treat me nt *s u b gr o u p -varia ble  
A p -val ue f or t he i nteracti o n test ( Li keli h o o d Rati o test) will be pr o vi de d t o get her wit h t he H R a n d 
c orres p o n di n g 9 5 % CI of t he i nteracti o n m o del para meter.  
T he H R a n d its c orres p o n di n g 9 5 % CI of all s u b gr o u ps will als o be prese nt e d i n a f orest pl ot.  
T hi s a nal ysis will be d o n e o n  t he F A S  a n d m F A S , res pecti vel y. 
1 5. 1. 6  
Ti me of F oll o w -U p   
A n alysis sets: F A S / m F A S, by P D -L 1  ex pressi o n  st at us 
A Ka pla n -M eier pl ot f or P F S a n d O S  f oll o w-u p d urati o n will als o be ge nerat e d t o assess t he 
f oll o w-u p ti me i n t he treat me nt ar ms re versi n g t he P F S  a n d O S ce ns ori n g i n dicat or . 
Ka pla n -Mei er esti mates ( pr o d uct -li mit esti mates) will be prese nte d b y treat me nt ar m t o get her wit h 
t he me dia n ti me of f oll o w-u p f or P F S a n d O S . I n partic ular, t he f oll o w-u p rate f or O S at 1 2, 1 8, 
2 4, a n d 3 0  m o nt hs a n d t he f oll o w -u p rate f or P F S at 6, 9, 1 2, a n d 1 5 m o nt hs will be esti mate d wit h 
c orres p o n di n g t w o -si d e d 9 5 % CIs.  
1 5. 2  
Sec o n d ar y E n d p oi nt A n al yses   
Sec o n dar y efficac y a nal yses will be perf or me d o n t he F A S  a n d t he m F A S , b y e x pressi o n P D -L 1 + 
stat us. Sec o n dar y a nal ysis of s u bject-re p orte d o utc o mes / q ualit y of life will be perf or me d o n t he 
H R Q o L a nal ysis set  a n d m o difie d H R Q o L a nal ysis set .   
1 5. 2. 1  
C o nfir me d Best O ver all Res p o nse   
A n alysis sets: F A S / m F A S, by P D -L 1  ex pressi o n  st at us 
T he c o nfir me d B O R is d efi ne d as t he b e st res p o nse o btai ne d a m o n g all t u m or assess me nt visits 
after t he date of ra n d o miz ati o n u ntil d oc u me nte d disease pr o gressi o n , ta ki n g re q uir e me nts f or 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 6 /1 0 2  
 
 
c o nfir mati o n i nt o acc o u nt as detaile d b el o w.  T h e t u m or res p o nse at eac h assess me nt visit will be 
deter mi ne d  acc or di n g t o R E CI S T 1. 1 (A p pe n di x I) b y a n I R C. Ra di ol o gical assess me nts will be 
use d i ncl u di n g a dj u dicat e d re vie ws . Details of det er mi nati o n of t u m or res p o nse date are pr o vi de d 
i n I ma gi n g Re vie w c harter d oc u me nt.  
O nl y t u m or asse ss me nts perf or me d b ef ore t he start of a n y f urt h er a nti -ca ncer treat me nt will be 
c o nsi dere d i n t he ass ess me nt of c o nfir me d B O R. Cli nical deteri orati o n will n ot be c o nsi dere d as 
d oc u me nte d disease pr o gressi o n.  If a t u m or assess me nt was perf or me d o n t he sa me da y as start of 
ne w a nti -ca ncer t hera p y, it will be ass u me d t hat t h e t u m or assess me nt was perf or me d pri or t o t he 
start of t he ne w a nti-ca ncer t hera p y, t heref ore t he t u m or assess me nt will be i ncl u de d i n t he 
assess me nt of B O R.  
T he f oll o wi n g re q uir e me nt is ta ke n i nt o acc o u nt f or deter mi nati o n of c o nfir me d B O R : 
•  P R or C R nee ds t o be c o nfir me d at a s u bse q ue nt t u m or ass ess me nt, prefera bl y at t he 
re g ularl y sc h e d ule d 6-w ee k assess me nt i nter val, b ut n o s o o ner t ha n 4 wee ks after t he i nitial 
d oc u me ntati o n of C R or P R  a n d bef ore pr o gressi o n;  
•  P R or C R ca n be c o nfir me d at a n ass ess me nt lat er t ha n t he n e xt assess me nt after t he i nitial 
d oc u me ntati o n of P R or C R, res pecti vel y a n d bef ore pr o gressi o n;  
•  T he mi ni m u m d urati o n f or a B O R of S D is defi n e d as at least 6 wee ks aft er r a n d o mizati o n  
a n d bef ore pr o gressi o n;  
•  P D = pr o gressi o n ≤ 1 2 wee ks after date  of ra n d o mizati o n (a n d n ot q ualif yi n g f or C R, P R or 
S D) , i.e. t u m or assess me nt of P D t hat is > 1 2 wee ks after date of ra n d o mizati o n a n d t here is 
n o t u m or assess me nt i n bet wee n will h a v e a B O R of N E.  
Ta ble 6  s u m marizes t he deri vati o n r ules descri be d b y Eise n ha uer et al. f or t he c o nfir me d B O R 
w he n c o nfir mati o n fr o m s u bse q ue nt ass ess me nt is nee de d. F or s u bjects w h o ha ve n o n -tar get 
lesi o ns o nl y at b aseli ne, t he ti me-p oi nt t u m or assess me nt of “ N o n -C R/ n o n -P D” will be e v al uate d 
wit h t he sa me criteria as S D ( mi ni m u m criteria f or S D d urati o n) i n d eri vi n g t he o verall c o nfir me d 
B O R.  
T a ble 6   
Best O ver all Res p o nse W he n C o nfir m ati o n of C R/ P R Is Re q uire d   
O ver all res p o nse 
1 st ti me p oi nt 
O ver all res p o nse 
s u bse q ue nt ti me p oi nt  Best o ver all res p o nse ( B O R)  
C R  
C R  
C R  
C R  
P R  
S D, P D or P R a 
C R  
S D  
S D pr o vi de d mi ni m u m criteri a f or S D d urati o n met; ot her wise, P D  
C R  
P D  
S D pr o vi de d mi ni m u m criteri a f or S D d urati o n met; ot her wise, P D  
C R  
N E  
S D pr o vi de d mi ni m u m criteri a f or S D d urati o n met, ot her wise N E  
P R  
C R  
P R  
P R  
P R  
P R  
P R  
S D  
S D  
P R  
P D  
S D pr o vi de d mi ni m u m criteri a f or S D d urati o n met, ot her wise, P D  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 7 /1 0 2  
 
 
O ver all res p o nse 
1 st ti me p oi nt 
O ver all res p o nse 
s u bse q ue nt ti me p oi nt  Best o ver all res p o nse ( B O R)  
P R  
N E  
S D pr o vi de d mi ni m u m criteri a f or S D d urati o n met, ot her wise N E  
N E  
N E  
N E  
C R = c o m plete res p o nse, P R = partial res p o nse, S D = sta ble disease, P D = pr o gressi ve diseas e, N E = n o n -e val u a ble. 
a If a C R is tr ul y met at first ti me p oi nt, t he n a n y disease see n at a s u bse q ue nt ti me p oi nt, e ve n disease meeti n g P R criteria 
relati ve t o baseli ne, ma kes t h e disease P D at t hat p oi nt (si nce disease m ust h a ve re a p peare d after C R). Best res p o nse w o ul d 
de pe n d  o n w het h er mi ni m u m d urati o n f or S D was met. H o we ver, s o meti mes ‘ C R’ ma y be clai me d w he n s u bse q ue nt sca ns 
s u g gest s mall lesi o ns were li kel y still prese nt a n d i n fact t h e patie nt ha d P R, n ot C R at t h e first ti me p oi nt. U n der t h ese 
circ u mst a nces, t h e ori gi n a l C R s h o ul d be c ha n ge d t o P R a n d t he best res p o nse is P R.   
T he c o nfir me d o bje cti ve res p o nse rate ( O R R) is defi ne d as t he pr o p orti o n of s u bjects h a vi n g 
reac h e d a c o nfir me d B O R of P R or C R acc or di n g t o R E CI S T 1. 1 a n d as pr o vi de d b y t he I R C i n 
t he a nal ysis p o p ulati o n. S u bjects wit h a B O R of n o n -C R/ n o n -P D ( p ossi ble o nl y f or s u bjects 
wit h o ut meas ura ble disease at baseli ne) are n ot c o nsi dere d as ha vi n g ac hie ve d o bjecti ve res p o nse. 
T heref ore t h ese s u bjects will o nl y b e c o u nt e d i n t he de n o mi nat or of t h e rat e, b ut  n ot i n t he 
n u merat or.  
T he c o nfir me d O R R b y treat me nt gr o u p will be calc ulate d al o n g wit h t he t w o -si de d 9 5 % CI usi n g 
t he Cl o p per-Pears o n met h o d (e x act CI f or a bi n o mial pr o p orti o n as c o m p ute d b y defa ult b y t he 
F R E Q pr oce d ure usi n g t he E X A C T o pti o n).  
T he a ss ociati o n of treat me nt ar m a n d o bjecti ve res p o nse will be teste d b y t he Ge neral Ass ociati o n 
Statistic of t he C oc hra n -Ma ntel -Hae nszel test ( C M H) (5 ) wit h t he ra n d o mizati o n strata ta ke n i nt o 
acc o u nt . T h e n ull h y p ot hesis of n o ass oci ati o n i n a n y of t he ra n d o mizati o n strata is teste d a gai nst 
t he alter nati ve, w hic h s p ecifies t h at t here is a n ass ociati o n bet wee n treat me nt effect a n d t u m or 
res p o nse at least i n o ne ra n d o mizati o n strat u m.  
T he stratifie d o d ds rati o i n ter ms of o bjecti ve res p o nse  will als o be esti mate d al o n g wit h its 9 5 % 
CI t o c o m pare t he treat me nt effect. T h e o d ds rati o is defi ne d as t h e o d ds of o bjecti ve res p o ns e wit h 
a vel u ma b di vi de d b y t he o d ds of o bjecti ve res p o nse wit h c he m ot hera p y. T he Bresl o w -Da y test 
will be use d t o c h ec k t he h o m o ge n eit y of t h e o d ds rati o acr oss t he ra n d o mizati o n strata. It tests t h e 
n ull h y p ot hesis t hat o d ds rati os i n all strata are e q ual a gai nst t he alter nati ve h y p ot hesis t hat at least 
i n o ne strat u m t he o d ds rati o is differe nt (6 ). 
I n case t he n ull h y p ot hesis of h o m o ge neit y of o d ds rati os acr oss strata is n ot rejecte d at t he al p ha 
le vel of 5 % t w o-si de d, t he c o m m o n o d ds rati o will be deter mi ne d usi n g  t he Ma ntel-Hae nszel 
esti mate ( b y t h e F R E Q pr oce d ure usi n g C M H o pti o n i n S A S); if t he n ull h y p ot hesis of 
h o m o ge n eit y of o d ds rati o acr oss all strata is reject e d, t he o d ds rati o per str at u m will be calc ulate d 
wit h t he c orres p o n di n g e x act CI  (7 ). 
I n a d diti o n, t he n u m ber a n d perce nta ge of s u bjects wit h B O R of C R, P R, S D, P D, n o n-C R/ n o n -
P D, a n d N E will be ta b ulate d. S u bjects wit h B O R of N E will be s u m marize d b y reas o n f or ha v i n g 
N E stat us. T he f oll o wi n g reas o ns will be use d:  
•  N o baseli ne ass ess me nt  (i n de pe n de nt re vi e w c o m mittee i de ntifies neit her a n y t ar get  n or a n y 
n o n -tar get lesi o ns) 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 8 /1 0 2  
 
 
•  N o p ost -baseli ne ass ess me nts  d ue t o deat h wit hi n 6 wee ks after ra n d o mizati o n  
•  N o p ost -baseli ne ass ess me nts d ue t o ot her reas o ns  
•  All p ost -baseli ne assess me nts ha ve o verall res p o nse N E  
•  Ne w a ntica ncer t hera p y starte d bef ore first p ost -b aseli ne assess me nt  
•  S D of i ns ufficie nt d urati o n ( < 6 wee ks after ra n d o mizati o n wit h o ut f urt her e val u a bl e t u m or 
assess me nt)  
•  P D t o o late (i.e. t u m or assess me nt of P D was > 1 2 wee ks after dat e of ra n d o mizati o n a n d t here 
was n o t u m or assess me nt i n bet wee n ) 
S pecial a n d rare cases w here B O R is N E d ue t o b ot h earl y S D a n d late P D will be classifie d as 
‘ S D of i ns uff icie nt d ur ati o n’. 
1 5. 2. 2  
He alt h -Rel ate d Q u alit y of Life   
A n alysis sets: H R Q o L A n alysis Set / m o difie d H R Q o L A n alysis Set, by P D -L 1  ex pressi o n  st at us 
Healt h -Relate d Q ualit y of Life ( H R Q o L) will be assesse d b y t he E ur o Q O L 5 -di me nsi o ns 
q uesti o n naire ( E Q -5 D)  a n d t he E ur o pea n Or ga ni zati o n f or Researc h a n d Treat me nt of Ca n cer 
( E O R T C) Q ualit y of Lif e Q uesti o n nair e -C ore 3 0 ite ms ( Q L Q -C 3 0) s u p ple me nte d b y t he Q ualit y 
of Life Q uesti o n naire -L u n g ca ncer 1 3 -ite m m o d ule ( Q L Q -L C 1 3).  
 
 
T he E Q -5 D q u esti o n nair e is a ge n eric meas ure of healt h stat us t hat pr o vi d es a des cri pti ve pr ofile 
a n d a si m pl e i n de x val ue. It i ncl u des 5 ite ms assessi n g m o bilit y, s elf -care, us ual acti vities, pai n / 
disc o mf ort, a n xiet y / de pressi o n o n a 5 -le vel res p o nse scal e ( E Q-5 D -5 L): n o pr o ble ms, sli g ht 
pr o ble ms, m o derate pr o ble ms, se vere pr o ble ms a n d e xtre me pr o ble ms. It al s o i ncl u des a vis ual 
a nal o g ue scal e ra n gi n g fr o m 0 t o 1 0 0 f or self -rate d healt h stat us.  A hi g her sc ore i n dicates a b etter 
healt h stat us.   
T he E Q -5 D -5 L sc ori n g s yste m will als o be c o n verte d i nt o a si n gle i n de x val ue. T he i n de x val ue is 
c o u ntr y s pecifi c a n d is a maj or feat ure of t he E Q -5 D i nstr u me nt, facilitati n g t he cal c ulati o n of 
q ualit y -a dj uste d life years ( Q A L Ys) t hat are use d t o i nf or m ec o n o mic e val uati o ns of healt h care 
i nter ve nti o ns. T he U K c o u ntr y s pecific val ue set will be use d i n deri vi n g t he i n dex val ue w hic h 
ra n ges fr o m -0. 5 9 4 ( w orst healt h state) t o 1. 0 0 0 ( b est healt h state).  
T he E O R T C Q L Q -C 3 0 is a q uesti o n nair e d e vel o pe d t o assess t he ge neral as pects of h ealt h -relate d 
q ualit y of life of ca ncer p atie nts. It c o m prises 3 0 it e ms gr o u pe d i nt o 1 5  m u lti-ite m a n d si n gle-ite m 
scales (Ta ble 7 ). T h e 
Q L Q -L C 1 3 
m o d ule c o m prises 1 3 l u n g ca n cer -s p ecific q uesti o ns 
i nc or p orate d i nt o o ne m ulti-ite m scale desi g ne d t o e val uate d ys p nea a n d a series of si n gl e ite ms 
assessi n g differe nt t y pes of  pai n, as well as, c o u g h, he m o pt ysis, d ys p h a gia, s ore m o ut h, al o pec ia, 
a n d peri p heral ne ur o p at h y.  
Gl o bal Versi o n I D: C CI
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 9 /1 0 2  
 
 
F or  b ot h Q L Q -C 3 0 a n d Q L Q -L C 1 3 q uesti o n nair es, a li near tr a nsf or mati o n is t o be a p plie d f or 
eac h m ulti -ite m scale a n d si n gle ite m t o sta n dar dize t he ra w sc ore t o a ra n ge fr o m 0 t o 1 0 0 as 
f oll o ws: 
F or f u n cti o nal scales: F i nal sc ore = ( 1 –  (( R S –  1) / Ite m ra n ge )) x 1 0 0 
F or s y m pt o m a n d Gl o bal Healt h Stat us/ Q o L scales: Fi nal sc ore = (( R S –  1) / Ite m ra n ge) x 1 0 0  
R S is t he ra w sc ore calc ulate d as t he mea n of it e ms c o ntri b uti n g t o t he scale. A sc ore of 1 0 0 
re pres e nts t he best p ossi ble f u ncti o n/ q ualit y of life, a n d t he hi g hest b ur de n of s y m pt o ms f or 
s y m pt o m scales a n d si n gle ite ms.  
T a ble 7  
Sc ori n g r ules f or E O R T C Q L Q -C 3 0 a n d Q L Q -L C 1 3   
Q uesti o n n aire  
T y pe of sc ale  
Sc ale  
N u m ber 
of ite ms  
Ite ms 
n u m bers  
Ite m 
r a n ge  
Mi ni m u m n u m b er of n o n -
missi n g ite ms t o c alc ul ate 
t he 0-1 0 0 sc o re  
Q L Q -C 3 0  
Gl o bal Healt h 
Stat us/ Q o L  
Gl o bal Healt h 
Stat us/ Q o L  
2  
2 9, 3 0  
6  
1  
F u ncti o nal 
scales 
P h ysical F u ncti o ni n g  
5  
1 t o 5  
3  
3  
R ole F u ncti o ni n g  
2  
6, 7  
3  
1  
E m oti o nal F u ncti o ni n g  
4  
2 1 t o 2 4  
3  
2  
C o g niti ve F u ncti o ni n g  
2  
2 0, 2 5  
3  
1  
S ocial F u ncti o ni n g  
2  
2 6, 2 7  
3  
1  
S y m pt o m 
scales / ite ms 
Fati g ue  
3  
1 0, 1 2, 1 8  
3  
2  
Na usea a n d v o miti n g  
2  
1 4, 1 5  
3  
1  
P ai n  
2  
9, 1 9  
3  
1  
D ys p nea  
1  
8  
3  
1  
I ns o m nia 
1  
1 1  
3  
1  
A p petite l oss  
1  
1 3  
3  
1  
C o nsti pati o n  
1  
1 6  
3  
1  
Diarr hea  
1  
1 7  
3  
1  
Fi na ncial Diffic ulties   
1  
2 8  
3  
1  
Q L Q -L C 1 3  
S y m pt o m 
scales / ite ms 
D ys p nea  
3  
3, 4, 5  
3  
3  
C o u g hi n g  
1  
1  
3  
1  
Hae m o pt ysis  
1  
2  
3  
1  
S ore m o ut h  
1  
6  
3  
1  
D ys p ha gia  
1  
7  
3  
1  
P eri p heral ne ur o pat h y  
1  
8  
3  
1  
Al o pecia  
1  
9  
3  
1  
P ai n i n c hest  
1  
1 0  
3  
1  
P ai n i n ar m or s h o ul der  
1  
1 1  
3  
1  
P ai n i n ot her parts  
1  
1 2  
3  
1  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 0 /1 0 2  
 
 
Q uesti o n n aire  
T y pe of sc ale  
Sc ale  
N u m ber 
of ite ms  
Ite ms 
n u m bers  
Ite m 
r a n ge  
Mi ni m u m n u m b er of n o n -
missi n g ite ms t o c alc ul ate 
t he 0-1 0 0 sc o re  
T a ke a n y me dicati o n 
f or pai n 
1  
1 3  
3  
1  
F or Q L Q -C 3 0 m o d ule, o nl y Gl o bal Healt h stat us a n d f u ncti o nal scal es will be i ncl u de d i n t he 
a nal ysis. F or s y m pt o m scale relat e d a nal ysis t he S y m pt o m Scales/Ite ms i n t he Q L Q -L C 1 3 m o d ule 
will be use d.   U nless s pecificall y st ate d ot her wise, all a nal yses will i ncl u d e d ata c ollect e d o n or 
bef ore t h e start date f or n e w a nti -ca ncer t hera p y.  
T he f oll o wi n g a n al ys es will be perf or me d f or eac h of t he E Q -5 D, Q L Q -C 3 0 Gl o bal Healt h stat us 
a n d f u ncti o nal sc ales  a n d  Q L Q -L C 1 3  scal e: 
•  Descri pti ve s u m mar y of n u m ber of s u bjects w h o c o m plete d pa p er H R Q o L e ntr y, el ectr o nic 
H R Q o L e ntr y a n d t otal at eac h sc h e d ule d visit;  
•  C o m plia nce, a n d c o m pleti o n rates:  
E Q -5 D, Q L Q -C 3 0 a n d Q L Q -L C 1 3  ass ess me nts of c o m plia nce, a n d c o m pleti o n r ates will be 
s u m marize d f or eac h sc h e d ule d a d mi nistrati o n, c o nsi deri n g t he f oll o wi n g d efi niti o ns:  
%  𝑑𝑎𝑡𝑒𝑜𝑓𝑑𝑜𝑠𝑒= 1 0 0  ×
n u m b e r  of  s u bj e ct s  wit h  at  l e a st o n e  e v al u a bl e  H R Q o L  q u e sti o n n ai r e
n u m b e r  of  s u bj e ct s  i n t h e F A S ,M F A S  or  ass oci at e d  P D −L 1  e x pr essi o n  s u bs ets   
% 𝑜𝑓𝑙𝑙 𝑐𝑜𝑚𝑝𝑙𝑒𝑡𝑖𝑜𝑛 𝑟𝑎𝑡𝑒= 1 0 0  ×
n u m b er  of  s u bj ects wit h  all  it e ms i n H R Q o L  q u esti o n ni ar e  a v ail a bl e
n u m b er  of  s u bj ects  i n t h e F A S ,M F A S  or  ass oci at e d  P D −L 1  e x pr essi o n  s u bs ets 
T he c o m plia nce a n d f ull c o m pleti o n rate f or eac h q uesti o n na ire will be dis pla ye d usi n g a li ne 
pl ot wit h ti me o n t he x -a xis a n d c o m pleti o n rate o n t he y-a xis. Se parate li n es will be pres e nte d 
f or eac h treat me nt ar m. 
•  H R Q o L q u esti o n naires d escri pti ve statisti cs 
F or E Q -5 D sc ores, eac h of Q L Q -C 3 0 Gl o bal Healt h stat us a n d f u ncti o nal sc ores a n d eac h of 
Q L Q -L C 1 3 s y m pt o ms/ite ms sc ores , descri pti ve statistics will be re p orte d f or eac h sc h e d ule d 
visit  b y tr eat me nt gr o u p  (f or visits wit h ≥ 1 0 s u bjects i n eac h tr eat me nt gr o u p). A d diti o nall y, 
c ha n ge fr o m baseli ne will als o be re p orte d at eac h sc he d ule d visit b y treat me nt gr o u p  (f or visits 
wit h ≥ 1 0 s u bjects i n eac h tr eat me nt gr o u p) . Descri pti ve statistics i ncl u de mea n, sta ndar d 
de viati o n, me dia n, mi ni m u m, ma xi m u m, a n d perce nt missi n g. A d diti o nall y, t he perce nt of 
s u bjects at t he w orst p ossi ble sc ore (e. g., 1 0 0 i n s y m pt o m scales a n d 0 o n f u ncti o nal scales a n d 
q ualit y of life) a n d at t he best p ossi ble sc ore (e. g., 0 i n s y m pt o m  scales a n d 1 0 0 o n f u ncti o nal 
a n d q ualit y of lif e ) will b e re p ort e d. 
C ha n ge fr o m bas eli ne will als o be dis pla ye d i n a pl ot wit h ti me o n t he x -a xis, mea n c ha n ge 
sc ore o n t he y-a xis, a n d sta n dar d err ors ar o u n d eac h mea n sc ore. M ea n c ha n ge fr o m baseli n e  
will be prese nte d f or eac h treat me nt ar m.  
 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 1 /1 0 2  
 
 
If t here are m ulti ple c o m plete assess me nts f or a n y sc he d ule d visit, t he assess me nt t hat is 
cl osest t o t he pla n ne d visit per pr ot oc ol will be use d i n t he a nal ysis.  If t here are m ulti ple 
c o m plete assess me nts at Disc o nti n uati o n visit a n d E n d of Treat me nt visit, t he o ne cl osest t o 
t he treat me nt disc o nti n uati o n date will be use d i n t he a nal ysis.  
•  L o n git u di nal a nal ysis of c ha n ge fr o m baseli ne  
A mi x e d -effect m o del re peate d meas ures ( M M R M) a nal ysis will e val uate l o n git u di nal c h a n ge 
fr o m baseli ne i ncl u di n g meas ure me nts after treat me nt disc o nti n uati o n o n t he Q L Q -C 3 0 
p h ysical f u ncti o n s cale a n d t he Q L Q -L C 1 3 c o u g h, he m o pt ysis, d ys p n ea, a n d pai n i n c hest 
sc ores. T hes e f o ur Q L Q -L C 1 3 s c ores are m ost pr o ne f or c h a n ges rel ate d t o t he dis ease 
s y m pt o m ( w hile ot her Q L Q-L C 1 3 s c ores are m or e rel ate d t o treat me nt) a n d t heref ore are of 
t he m ost i nterest i n M M R M a nal ysis. C o variates will i ncl u de t he baseli ne sc ore f or t he d o mai n 
sc ore bei n g e val uate d a n d ra n d o mizati o n stratificati o n fact ors, a n d t he q uesti o n naire e ntr y ti me 
p oi nt i ncl u di n g b ot h sc he d ule d a n d u nsc he d ul e d visits wit h ≥ 1 0 s u bjects i n eac h treat me nt 
gr o u p will be a nal yze d as a c o nti n u o us varia ble. T w o -si de d p-val ues, wit h o ut a dj ust me nt f or 
m ulti plicit y, will be calc ulate d f or t he dif fere nce bet wee n t he M M R M traject ori es f or t he 
treat me nt ar ms.  
•  E m pirical c u m ulati ve distri b uti o n f u ncti o n (e C D F)  
F or t he H R Q o L d o m ai n sc ores a n al yze d usi n g M M R M, a n e C D F will dis pla y t he pr o p orti o n 
of s u bjects w h o e x perie nce d s pecifi c c ha n ges fr o m baseli ne  t o e n d of treat me nt. F or eac h 
e C D F, t he c ha n ge sc ore f or eac h scale will be dis pla ye d o n t he x -a xis, a n d t he c u m ulati ve 
perce nt a ge of p atie nts ac hie vi n g t h at c h a n ge s c ore or better will be dis pla ye d o n t he y -a xis. 
T he e C D F m a y be i nter prete d b y c h o osi n g a  c ha n ge sc ore m a g nit u de t hat ma y be c o nsi dere d 
cli nicall y m ea ni n gf ul o n t he x -a xis a n d c o m pari n g t he rat e of s u bjects w h o ac hie ve d at least 
t hat a m o u nt of c ha n ge i n t he treat me nt ar ms o n t he y-a xis. 
•  Ti me u ntil defi niti v e deteri orati o n ( T U D D) a n al ysis  
T U D D a n al ysis will be p erf or me d f or t h e Q L Q -C 3 0 p h ysic al f u ncti o ni n g s cale a n d t he Q L Q -
L C 1 3 c o u g h, h e m o pt ysis, d ys p nea, a n d p ai n i n c hest sc ores . T he d ata c ollecte d at b ot h 
sc he d ule d a n d u ns c he d ul e d visits will be i ncl u de d i n t he T U D D a n al ysis.  
T U D D is d efi ne d as t h e ti me bet w ee n ra n d o mizati o n a n d t he occ urre nce of defi niti ve 
deteri orati o n ( D D) c o m pare d t o t he baseli ne sc ore. D D is defi ne d as a H R Q o L sc ore c ha n ge 
greater t ha n or e q u al t o t he Mi ni mal Cli nicall y I m p orta nt C ha n ge ( M CI C) c o m pare d t o 
baseli ne   a n d s uc h c h a n ge is c o nfir me d b y n o f urt her i m pr o ve me nt of H R Q o L sc ore  as 
c o m pare d t o t he pre vi o us sc ore  e x cee di n g M CI C ma g nit u de at ne xt assess me nt  or n o f urt her 
a vaila ble H R Q o L d ata d ue t o deat h , occ urri n g wit hi n 2 sc he d ule d P R O assess me nts .  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 2 /1 0 2  
 
 
T h e MC IC  is defi ne d i n Osa ba et.al. (8 ) as: 
-  Q L Q -C 3 0 p h ysi cal f u n cti o ni n g scal e sc ore: A c ha n ge of 1 0 n or malize d sc ore p oi nts   
-  Q L Q -C 3 0 or Q L Q -L C 1 3 s y m pt o m scale: A c ha n ge of 1 0 n or malize d p oi nts  
T he treat me nt effect will be esti mate d usi n g a C o x pr o p orti o nal -hazar ds m o del stratifie d b y 
t he ra n d o mizati o n strata t o calc ulate t he hazar d rati o a n d its 9 5 % CI. I n a d diti o n, t he res ults 
will be dis pla ye d us i n g f orest pl ots, prese nti n g H R a n d 9 5 % CI f or eac h s cale/ite m. 
Ka pla n -Mei er esti mate a n d its 9 5 % CI will be calc ulate d at t he ti me of sc h e d ule d assess me nt.  
Ce ns ori n g R ules f or T U D D A n al ysis  
T he ce ns or r ules is liste d i n Ta ble 8 . 
T a ble 8 : 
O utc o me a n d e ve nt d ates f or T U D D a n al yses   
 
Sce n ari o  
D ate of e ve nt/ce ns ori n g  
O utc o me  
N o baseli ne assess me nt  
Date of ra n d o mizati o n  
Ce ns ore d  
Baseli ne b ut n o a de q uate P R O assess me nt after 
baseli ne  
Date of ra n d o mizati o n + 1  
Ce ns ore d  
T U D D e ve nt:  
H R Q o L d o mai n sc ore c ha n ge gr eater t h a n or e q ual 
t o t h e Mi ni mal Cli nicall y I m p orta nt C ha n ge ( M CI C) 
c o m pare d t o baseli ne ( = T U D e ve nt) A N D  
c o m pare d t o t his e ve nt, n o f urt her i m pr o ve me nt of 
H R Q o L d o mai n sc ore e xc ee di n g M CI C ma g nit u de 
at a s u bse q ue nt assess me nt, at le ast 2 0 da ys b ut n ot 
m ore t h a n 8 4 da ys later O R n o f urt h er a vaila ble 
H R Q o L data d ue t o deat h, b ut deat h occ urri n g wit hi n 
8 4 da ys ( = 2 sc he d ule d P R O assess me nts) A N D n o 
ne w a nti -ca ncer t h era p y a d mi nist ere d i n -bet wee n.  
Date 
of 
deteri orati o n  (first 
e ve nt 
q ualif yi n g as T U D D)  
E ve nt  
H R Q o L d o mai n sc ore c ha n ge gr eater t h a n or e q ual 
t o t h e Mi ni mal Cli nicall y I m p orta nt C ha n ge ( M CI C) 
c o m pare d t o baseli ne A N D  
N o s u bse q ue nt H R Q o L assess me nt a vaila ble b ut 
deat h di d n ot yet occ ur or occ urre d m ore t h a n 8 4 
da ys later 
Date of last a de q uate P R O assess me nt 
d oc u me nti n g n o deteri orati o n bef ore 
ne w a nti -ca ncer t hera p y is gi ve n or 
misse d H R Q o L assess me nts  
Ce ns or  
N o T U D D e ve nt A N D n o ne w a ntica ncer t h era p y 
a d mi nistere d  
Date of last a de q uate P R O assess me nt.  
Ce ns or  
Ne w a nti -ca ncer t h era p y a d mi nistere d b ut n o T U D D 
bef ore start of ne w a nti -ca ncer t h era p y  
Date of last a de q uate P R O assess me nt 
pri or t o start of ne w a nti -ca ncer t h era p y  
Ce ns or  
1 5. 2. 3  
Se nsiti vit y A n al yses of Sec o n d ar y Effic ac y E n d p oi nts   
A n alysis sets: F A S / m F A S, by P D -L 1  ex pressi o n  st at us 
F or t he sec o n dar y effi cac y e n d p oi nt of B O R, t he f oll o wi n g se nsiti vit y a n al ys es will be perf or m e d 
t o assess t he r o b ust ness of t he pri mar y a nal ysis res ults. T hese a nal yses are re gar de d as p urel y 
e x pl orat or y. T he u n a dj uste d 9 5 % CI will be calc ul ate d f or all t he se nsiti vit y a nal ys es of B O R.  
•  B O R acc or di n g t o I n vesti gat or assess me nt will be a nal yze d. F or t his se nsiti vit y a nal ysis, 
t he date of t u m or assess me nt will be deri ve d fr o m t he “ Assess me nt of Disease Bas e d o n 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 3 /1 0 2  
 
 
I ma gi n g” e C R F pa ge. T h e earliest t u m or assess me nt date c orres p o n di n g t o t he res pecti ve 
visit t hat is c ollecte d o n t his pa ge will be use d f or date of disease pr o gressi o n a n d date of 
res p o nse.  
•  A m ulti varia ble l o gistic re gressi o n a n al ysis will be perf or me d o n c o nfir m e d B O R bas e d o n 
I E R C assess me nt t o assess a n d a dj ust t he treat me nt effect f or rele va nt bas eli ne fact ors of 
p ote ntial pr o g n ostic i m pact. T he s u b gr o u p varia bles defi ne d i n Secti o n 8. 2  “ S u b gr o u p 
A nal ysis Sets” will be i n cl u de d i n t he m o d el. A st e p wise selecti o n pr oce d ure will ser ve t o 
i de ntif y e x pla nat or y v aria bles of p ote ntial pr o g n ostic val u es a d diti o nal t o t he 
ra n d o mizati o n strata w hic h will be i ncl u de d i n all m o dels d uri n g t he selecti o n pr oce d ure. 
T he le vel of si g nifica nce f or a n e x pla nat or y varia ble t o e nter t he m o d el is set t o 0. 1 5 ( p -
val ue of Sc ore test) a n d t he si g nifica n ce le vel f or re m o vi n g it is set t o 0. 4 0 ( p -val ue of 
Wal d test). O nce t his pr oce d ure st o ps, t he fact or 'treat me nt gr o u p' will be a d de d t o t he last 
selecte d m o del i n or der t o e val uate t he effect of tr eat me nt o n B O R w he n a dj uste d f or t he 
selecte d e x pla nat or y vari a bles. T he o d d rati os of all selecte d e x pla nat or y v aria bles a n d of 
treat me nt effects will be re p orte d i nclu di n g 2 -si de d 9 5 % c o nfi de nce i nter vals. N o 
i nteracti o ns will be c o nsi dere d. P ost-baseli ne fact ors will n ot be c o nsi dere d f or t he m o del.  
•  A s u m mar y of c o nc or da nce of B O R bet wee n I R C a n d i n vesti gat or assess me nt will be 
pr o vi de d  (s hift ta ble b y tr eat me nt ar m).  
1 5. 2. 4  
S u b gr o u p A n al ysis o n Sec o n d ar y Effic ac y E n d p oi nts   
A n alysis sets: F A S / m F A S, by P D -L 1  ex pressi o n  st at us 
A nal ysis o n s u b gr o u ps as defi ne d i n Secti o n 8. 2  will be perf or me d f or t he sec o n d ar y efficac y 
e n d p oi nt of B O R.  
T o assess t he heter o ge n eit y of treat me nt effect acr oss t he s u b gr o u p le vels f or t he sec o n dar y 
e n d p oi nt of B O R, a l o gistic re gressi o n m o del will be fitte d wit h B O R as t he de pe n d e nt varia ble 
( = 1 f or s u bjects wit h a c o nfir me d B O R of P R or C R; = 0 ot her wise); s u b gr o u p, treat me nt, a n d wit h 
a n d wit h o ut t he treat me nt -b y -s u b gr o u p i nteracti o n as e x pla nat or y v aria bles. A p-v al ue f or t he 
i nteracti o n ter m ( Wal d C hi-S q uare test) will be pr o vi de d t o get her wit h t he o d ds rati o a n d 
c orres p o n di n g 9 5 % CI of t he i nteracti o n m o del para meter.  
I n a d diti o n, t he O R R al o n g wit h t he t w o-si de d e xact Cl o p per -Pears o n 9 5 % CIs will be calc ulate d 
f or eac h s u b gr o u p. T he res ults will be dis pla ye d usi n g a f orest pl ot, prese nti n g t he o d ds rati o  a n d 
9 5 % CI f or eac h s u b gr o u p. 
 
T he p -val ue f or t he i nteracti o n test ( Li keli h o o d Rati o test) will be pr o vi d e d t o get her wit h t he H R 
f or O S / o d ds rati o  f or O R R a n d 9 5 % CI of t he i nt eracti o n m o del para meter. T his a nal ysis will be 
d o ne i n t he F A S  ( A v ers us B) a n d m F A S  ( C vers us B). 
Gl o bal Versi o n I D: C CI
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 4 /1 0 2  
 
 
1 5. 3  
Ot her E n d p oi nt A n al yses   
A n alysis sets: F A S / m F A S, by P D -L 1  ex pressi o n  st at us 
Gl o bal Versi o n I D: C CI
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 5 /1 0 2  
 
 
Gl o bal Versi o n I D: C CI
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 6 /1 0 2  
 
 
Gl o bal Versi o n I D: C CI
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 7 /1 0 2  
 
 
Gl o bal Versi o n I D: C CI
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 8 /1 0 2  
 
 
Gl o bal Versi o n I D: C CI
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 9 /1 0 2  
 
 
1 6  
S afet y E v al u ati o n   
A n alysis sets: S afety A n alysis Set  / m o difie d S afety A n alysis Set/  S afety C o h ort A n alysis Set  
T he s u bsecti o ns i n t his secti o n i ncl u de s pecifi cati o ns f or s u m marizi n g safet y e n d p oi nts t hat are 
c o m m o n acr oss cli nical trials s uc h as a d v erse e ve nts, la b orat or y tests a n d vita l si g ns. 
Safet y a n al yses will be perf or me d o n t he Safet y a nal ysis set  or m o difie d Safet y a nal ysis set  
acc or di n g t o t h e as -tr eat e d pri nci ple. T h e safet y e n d p oi nts will be ta b ulate d usi n g descri pti ve 
statistics. 
1 6. 1  
A d verse E ve nts   
T he 3 -tier a p pr oac h is a s yste matic wa y t o s u m marize a n d a nal yze a d v erse e ve nts ( A Es) i n cli nical 
st u dies. A Es i n differe nt tiers are a nal yz e d usi n g differe nt le v els of statisti cal a nal yses.  
 
A n al ysis  
( A n al ysis 
P o p ul ati o n)  
S afet y 
Tier  
Deri v ati o n  
St atistic al A n al ysis M et h o ds  
Sec o n d ar y e n d p oi nt: Occ ur re nce of T E A Es, tre at me nt -r el ate d A Es a n d seri o us A Es  
Sec o n dar y  
( S A F) 
Tier 1  
T he A Es i d e ntifie d f or Tier 1 re p orti n g i n t his 
st u d y are t h e c o m p osite ter ms of p ne u m o nia 
a n d l o wer res pirat or y tra ct i nfecti o ns as 
defi n e d i n Ta ble 1 0 . C o m p osites are base d o n 
selecte d P Ts fr o m t h e Me d D R A H L Ts 
“ Bacterial l o wer res pirat or y tract i nfecti o ns”, 
“ F u n gal l o wer res pirat or y tract i nfe cti o ns”, 
“ L o wer res pirat or y tract i nfecti o ns N E C”, 
“ Res pirat or y tract i nfecti o ns N E C”, “ Viral 
l o wer res pirat ory i nfecti o ns” a n d “ L o wer 
res pirat or y tract a n d l u n g i nfecti o ns”. 
T he Tier 1 a n d Tier 2 A Es will be assesse d wit h 
a 9 5 % CI f or bet wee n -gr o u p c o m paris o ns. F or 
t h e differe nce i n i n ci d e nce pr o p orti o ns, t h e CIs 
will be base d o n t h e met h o d pr o p ose d b y 
Mietti ne n & N ur mi n e n (9 ). W hile a nal ys es will 
be d o ne f or all Tier 2 A Es, o nl y A Es wit h 
i n ci d e nce pr o p orti o n [ ≥5 %] i n at least o ne 
gr o u p will be prese nte d i n t he b o d y of cli nical 
st u d y re p ort. 
N o m ulti plicit y a dj ust me n t will be a p plie d. 
F or t his trial, differe nce i n E AI R will als o be 
s u m marize d as e x p os ure peri o ds are e x pecte d 
t o s h o w lar ge differ e nce bet wee n st u d y 
i nter ve nti o n gr o u ps or bet wee n partici p a nts 
wit hi n a st u d y i nter ve nti o n gr o u p. T he CIs will 
be base d o n t h e Wal d -t y pe met h o d pr o p ose d b y 
Li u et al. (1 0 ). 
 
Tier 2  
A Es will be f urt h er classifie d i nt o Tier 2 or 
Tier 3 (i n cl u di n g A Es i n Tier 1 bei n g t o o rare) 
base d o n t h e R ule -of -4. If t h ere are 4 or m ore 
partici p a nts wit h t he re p orte d ter m i n a n y 
st u d y i nter ve nti o n gr o u p, t hat ter m will be 
i n cl u de d i n Tier 2. Ot her wise, it will be 
i n cl u de d i n Tier 3. 
 
Tier 3  
T he Tier 3 A Es will be assesse d via s u m mar y 
statistics a n d ris k differe nces. 
F or t his trial, differe nce i n E AI R will als o be 
s u m marize d as e x p os ure peri o ds are e x pecte d 
t o s h o w lar ge differ e nce bet wee n st u d y 
i nter ve nti o n gr o u ps. 
E AI R: E x p os ure A dj uste d I nci de nce Rate ( d efi niti o n pr o vi d e d bel o w i n secti o n)  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 0 /1 0 2  
 
 
T a ble 1 0  
 C ate g ories a n d Preferre d Ter ms f or Tier 1 E ve nts   
C ate g or y  
M e d D R A Ter ms  
P ne u m o ni a  
At y pical p ne u m o nia, P ne u m o nia, P ne u m o nia c yt o me gal o viral, P ne u m o nia 
p ne u m oc occal, 
P ne u m o nia res pirat or y 
s y nc ytial 
vir al, 
P ne u m o nia 
i nfl ue nzal, P ne u m o nia parai nfl ue nzae viral, P ne u m o nia st a p h yl oc o ccal, 
P ne u m o nia stre pt oc occal, 
P ne u m o nia viral, 
P ne u m o nia nec r otisi n g, 
P ne u m o nia bacterial, L u n g a bscess, P ul m o nar y se psis, Br o nc h o p ul m o nar y 
as per gill osis,  P ne u m o nia f u n gal ,Hae m orr ha gic p ne u m o nia , a n d C O VI D-1 9 
p ne u m o nia  
L o w er res pir at or y  
tr a ct i nfecti o ns 
Br o nc hitis, L o wer res pirat or y tract i nfecti o n, Br o nc hitis viral, Res pirat or y 
tract i nfecti o n f u n gal, Res pirat or y tract i nfecti o n bacterial, Br o nc hitis 
bacterial, 
Br o nc hitis f u n gal, Br o nc hitis p ne u m oc occal,  Se vere ac ute 
res pirat or y s y n dr o me, Res pir at or y tract i nfecti o n viral, Res pirat or y tract 
i nfecti o n, L o wer res pirat or y tract i nfecti o n bacterial, L o wer res pirat or y 
tract i nfecti o n f u n gal a n d L o wer res pirat or y tract i nfecti o n viral 
M e d D R A v er si o n 2 4. 0   
Treat me nt e mer ge nt a d v erse e ve nts ( T E A Es) are t h ose e ve nts wit h o nset dates occ urri n g d uri n g 
t he o n-treat me nt peri o d or if t he w orse ni n g of a n e ve nt is d uri n g t he o n-tr eat me nt peri o d as defi ne d 
i n Secti o n 1 0 . 
All a nal ys es descri be d i n Secti o n s 1 6. 1  a n d 1 6. 2  will be base d o n T E A Es if n ot ot her wise s pecifi e d. 
T he A E listi n gs will i ncl u de all A Es ( w h et her treat me nt -e mer ge nt or n ot ). A Es o utsi de t he o n -
treat me nt peri o d will be fla g ge d i n t he listi n gs.  
A s e parate listi n g will als o be pr o vi de d f or  A Es t hat starte d d uri n g sec o n d peri o d of a vel u ma b 
treat me nt (f or s u bjects i n t he a vel u ma b  ar m w h o re-i nitiate d treat me nt after P D) 
T he f oll o wi n g cate g ories of T E A Es are defi n e d f or re p orti n g:  
•  Rel ate d A d ve rse E ve nts : a d verse e ve nts wit h rel ati o ns hi p t o st u d y treat me nt (as rec or de d 
o n t he A E e C R F pa ge, Relati o ns hi p wit h st u d y treat me nt = Rel ate d) re p orte d b y t h e 
i n vesti gat or a n d t h ose of u n k n o w n relati o ns hi p (i.e. n o a ns wer t o t he q uesti o n “ Relati o ns hi p 
wit h st u d y treat me nt ”).  
•  Seri o us A d verse E ve nts ( S A E) : seri o us a d verse e ve nts (as rec or de d o n t he A E e C R F pa ge, 
Seri o us A d verse E v e nt = Yes ). 
•  A d verse E ve nts Le a di n g t o Tre at me nt Disc o nti n u ati o n:  a d verse e ve nts lea di n g t o 
per ma ne nt disc o nti n uati o n of st u d y treat me nt (as rec or de d o n t he A E e C R F pa ge, Acti o n 
ta ke n wit h st u d y tr eat me nt = Dr u g wit h dra w n). 
•  A d verse E ve nts Le a di n g t o De at h: a d verse e ve nt lea di n g t o deat h (as rec or de d o n t he A E 
e C R F pa ge, O ut c o me = Fatal, as well as A Es of Gra de 5).  
•  I m m u ne R el ate d A d verse E ve nts (ir A E): ir A Es are i de ntifie d b ase d o n a list of Me d D R A 
P Ts a n d ot her q ualif yi n g criteria (f or det ails see A p pe n di x V ).  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 1 /1 0 2  
 
 
•  I nf usi o n Rel ate d Re acti o n (I R R): I R Rs are i d e ntifie d base d o n a list of Me d D R A P Ts. T he 
detaile d criteria of t he ti mi n g relati o ns hi p t o i nf usi o n are s pecifi e d i n T a ble 1 6  i n A p pe n di x 
V .  
F or t he c he m ot hera p y ar m, a n a d verse e ve nt will be c o nsi dere d as a relate d a d verse e v e nt if it is 
relate d t o at least o ne of t he treat me nts i n t he ar m. I n t he sa me wa y, a n a d verse e ve nt will be 
c o nsi dere d as l ea di n g t o treat me nt disc o nti n uati o n if it le d t o t he disc o nti n uati o n of at least o ne 
c he m ot hera p y treat me nt.  
U nless ot her wise s pecifie d, A Es will be dis pla ye d i n ter ms of fre q u e nc y ta bl es b y tr eat me n t gr o u p 
b y desce n di n g fre q u e nc y of pri mar y s yste m or ga n cl ass ( S O C)  a n d desce n di n g fre q u e nc y of 
preferre d t er m ( P T) i n a v el u ma b ar m A  wit hi n S O Cs . W he n t he fre q ue n c y i n t he S O C or P T is t he 
sa me i n t he a v el u ma b Ar m A tr eat me nt gr o u p, t h e S O C or P T will be dis pla ye d i n al p ha betical 
or der.   
Eac h s u bject will be c o u nte d o nl y o nce wit hi n eac h S O C  or P T . If a s u bject e x perie nces m or e t ha n 
o ne A E wit hi n a S O C  or P T  f or t he sa m e s u m mar y peri o d, o nl y t h e A E wit h t he str o n gest 
relati o ns hi p or t he w orst se verit y, as a p pr o pri ate, will be i ncl u de d i n t he s u m maries of relati o ns hi p 
a n d se verit y.  
F or a n al ysis p ur p os es, A E relate d t o st u d y tr eat m e nt are defi ne d as t h ose A E wit h relati o ns hi p t o 
st u d y treat me nt as re p ort e d as “relate d”, missi n g or u n k n o w n o n t he “ A d verse E ve nts Details” 
e C R F pa ge.  
C ha n ges i n t o xicit y gra d e, seri o us ness or o utc o m e of A Es are rec or de d as se parate e ntri es i n t he 
e C R F wit h ass ociate d e n d a n d start dates (start date e q uals e n d date of pre vi o us e ntr y). S uc h e ntries 
re p orti n g t he sa me e v e nt i n s uc h im me diatel y c o ns ec uti ve peri o ds will be c o nsi dere d as o ne e ve nt 
i n t he a nal ysis i n case of a n i m pr o ve me nt i n t o xicit y gra de. T hes e e v e nts will be ke pt as se parate 
rec or ds i n t he data bas e i n or der t o mai ntai n t he f ull detaile d hist or y of t he e v e nts. T he start date of 
t he i nitial rec or d i n t he se q ue nce is ta ke n as start date of t he e ntire e ve nt. D urati o n of t he A E a n d 
t he T E A E fla g will be a dj uste d acc or di n gl y i n t he a nal ysis. 
1 6. 1. 1  
All A d verse E ve nts   
A d verse e v e nts will be s u m marize d b y w orst gra de  (acc or di n g t o N CI-C T C A E versi o n 4. 0 3) per 
s u bject, usi n g t he latest versi o n of Me d D R A P T as e ve nt cate g or y a n d M e d D R A pri mar y S O C 
b o d y ter m as B o d y S yste m cate g or y.  
I n cas e a s u bject has e v e nts wit h missi n g a n d n o n -missi n g gra des, t h e ma xi m u m of t he n o n -missi n g 
gra des will be dis pla ye d.  N o i m p utati o n of missi n g gra des will be perf or m e d.  
T he f oll o wi n g fre q u e nc y ta bles will be create d:  
•  T he o verall s u m mar y of A Es ta ble will i ncl u de t he fre q u e nc y ( n u m ber a n d perce nta ge) of 
s u bjects wit h eac h of t h e f oll o wi n g b y treat me nt gr o u p:  
-  T E A Es  
-  T E A Es, gra de ≥ 3  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 2 /1 0 2  
 
 
-  Relate d T E A Es  
-  Relate d T E A Es, gra de ≥ 3  
-  T E A Es lea di n g t o per ma ne nt treat me nt disc o nti n uati o n  
-  Relate d T E A Es lea di n g t o per ma ne nt treat me nt disc o nti n uat i o n  
-  Seri o us T E A Es  
-  Relate d seri o us T E A Es  
-  T E A Es lea di n g t o deat h  
-  Relate d T E A Es lea di n g t o de at h  
-  Treat me nt -e mer ge nt p ote ntial ir A Es  
-  Treat me nt -e mer ge nt ir A Es  (f or a v el u ma b treat me nt ar m o nl y) 
-  Treat me nt -e mer ge nt I R Rs  
-  Relate d treat me nt -e mer ge nt I R Rs  
•  T E A Es b y S O C a n d P T a n d w orst gra de  
•  Relate d T E A Es b y S O C a n d P T a n d w orst gra d e  
•  T E A Es lea di n g t o deat h b y S O C a n d P T  
•  Relate d T E A Es lea di n g t o deat h b y S O C a n d P T  
•  T E A Es b y S O C a n d P T: dis pla yi n g i n s e parate c ol u m ns t he All T E A Es / Relate d T E A Es / 
Gra de ≥3 T E A Es / Relate d Gra d e ≥3 T E A Es  
•  T E A Es E x cl u di n g S A Es wit h fre q ue n c y ≥ 5 % i n a n y treat me nt ar m  b y S O C a n d P T  
F or s u bjects w h o s witc h t o a vel u ma b usi n g t he c orres p o n di n g o n -treat me nt peri o d defi niti o n, a 
se parat e o verall s u m mar y of A Es ta bl e will be pr o vi de d f or A Es occ urri n g i n t his peri o d. As l o n g 
as less t ha n 2 0 s u bjects i n t he st u d y are a vaila ble i n t his s u bset, o nl y a listi n g will be pr o vi de d. At 
t he ti me w he n at le ast 2 0 s u bjects ha ve s witc h e d t o a vel u ma b, t he s u m mar y of A Es ta ble will als o 
be pr o vi de d, wit h o nl y a ‘s witc h t o a vel u ma b’ c ol u m n.  
A d verse e v e nts will be ill ustrate d i n se parate ta bl es b y tier acc or di n g t o t he 3 -tier a p pr oac h. A Es 
i n all tiers will be s orte d i n desce n di n g or der acc or di n g t o t he ris k differe n ce. 
T he f oll o wi n g t a bles will be pr o vi de d  i n a d diti o n als o f or t he m Safet y-A S:  
•  O ver all s u m mar y of A Es as descri be d a b o ve  
•  T E A Es b y S O C a n d P T: dis pla yi n g i n s e parate c ol u m ns t he All T E A Es / Relate d T E A Es / 
Gra de ≥3 T E A Es / Relate d Gra d e ≥3 T E A Es  
•  T E A Es lea di n g t o deat h b y S O C a n d P T  
•  Ta bles b y tier acc or di n g t o t he 3 -tier a p pr oac h (o nl y Ar m B vs. Ar m C)  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 3 /1 0 2  
 
 
E x p os ure A dj uste d I nci de nce R ate  
E x p os ure A dj uste d I n ci d e nce Rat es ( E AI Rs) are calc ulate d as n u m ber of p artici pa nts wit h a n A E 
di vi de d b y t he s u m of t he i n di vi d ual ti mes at ris k f or t he first occ urre nce of a n A E of all partici pa nts 
i n t he safet y p o p ulati o n fr o m start of st u d y i nter ve nti o n t o first o nset of A E, e n d of treat me nt 
peri o d, c ut -off or deat h, w hic he ver occ urs first.  
E x p os ure will be calc ulat e d as ti me at ris k:  
•  F or a s u bj ect wit h A E: st u d y da y of  first e ve nt o n st u d y i nter ve nti o n –  st u d y da y st art of st u d y 
i nter ve nti o n + 1 
•  S u bjects wit h o ut A E: st u d y da y of e n d of tr eat me nt peri o d –  st u d y da y start of st u d y i nter ve nti o n 
+ 1  
E AI Rs of first occ urre n ce of a n A E of t o xicit y gra de > = 3 is deri ve d i n a si milar ma n ner. 
T he f oll o wi n g t a bles will be pr o vi de d:  
•  E x p os ure a dj uste d i nci de nce rat es of A Es b y S yste m Or ga n Class a n d Preferre d T er m  
•  E x p os ure a dj uste d i nci de nce rat es of relate d A Es b y S yste m Or ga n Class a n d Preferre d Ter m  
•  E x p os ure a dj uste d i nci de nce r ates of N CI-C T C A E t o xicit y gra de 3 A Es b y S yste m Or ga n 
Class a n d Preferre d T er m  
•  E x p os ure a dj uste d i nci de nce rates of relate d [ N CI -C T C A E t o xicit y gra de 3] A Es b y S yste m 
Or ga n Class a n d Preferre d Ter m  
•  E x p os ure a dj uste d i nci de nce rates of N CI -C T C A E t o xicit y  gra de 4  A Es b y S yste m Or ga n 
Class a n d Preferre d T er m  
•  E x p os ure a dj uste d i nci de nce rates of relate d [ N CI -C T C A E t o xicit y gra de ] A Es b y S yste m 
Or ga n Class a n d Preferre d Ter m  
1 6. 1. 2  
A d verse 
E ve nts 
Le a di n g 
t o 
Per m a ne nt 
Tre at me nt 
Disc o nti n u ati o n   
T he f oll o wi n g o verall fre q ue nc y ta bles will be pre pare d f or t he a d verse e v e nt acti o ns t hat lea d t o 
per ma ne nt tr eat me nt disc o nti n uati o n ( dr u g wit h dr a wal): 
•  T E A Es lea di n g t o treat m e nt disc o nti n uati o n b y S O C a n d P T  
•  Relate d T E A Es lea di n g t o treat me nt disc o nti n uati o n b y S O C a n d P T  
T he f oll o wi n g t a ble will be pr o vi de d i n a d diti o n als o f or t he m Safet y -A S:  
•  T E A Es lea di n g t o treat m e nt disc o nti n uati o n b y S O C a n d P T  
T he listi n g of T E A Es lea di n g t o treat me nt disc o nti n uati o n will als o be pr o vi de d wit h t he rele va nt 
i nf or mati o n.  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 4 /1 0 2  
 
 
1 6. 2  
De at hs, Ot her Seri o us A d verse E ve nts, a n d Ot her Si g nific a nt 
A d verse E ve nts   
1 6. 2. 1  
De at hs   
All deat hs, deat hs wit hi n 3 0 da ys after last d os e of st u d y dr u g, deat h wit hi n 6 0 da ys after first d ose 
as well as t he pri mar y reas o n f or deat h, will be t a b ulate d base d o n i nf or m ati o n fr o m t he “ Re p ort 
of S u bject Deat h” a n d “ S ur vi val F oll o w -U p” eC R Fs.  
•  N u m ber of D eat hs  
•  N u m ber of D eat hs wit hi n 3 0 da ys after l ast d ose of  st u d y treat me nt 
•  N u m ber of D eat hs wit hi n 6 0 da ys after first d ose of st u d y tr eat me nt 
•  Pri mar y Reas o n of Deat h  
•  Dise ase pr o gressi o n  
•  A d verse e ve nt rel ate d t o st u d y treat me nt  
•  A d verse e ve nt n ot relat e d t o st u d y treat me nt  
•  Ot her  
•  U n k n o w n  
I n a d diti o n, date a n d ca us e of deat h will be pr o vi de d i n i n di vi d ual s u bject data listi n g t o get her wit h 
selecte d d osi n g i nf or m ati o n (st u d y tr eat me nt recei ve d, date of first / last a d mi nistrati o n, d ose a n d 
n u m ber of i nf usi o ns recei ve d f or treat me nt) a n d will i ncl u de t he f oll o wi n g i nf or mati o n:  
•  A Es wit h fatal o utc o m e (list preferre d t er ms of A Es wit h o utc o me = Fatal , as well as A Es of 
Gra de 5 ),  
•  F la g f or d eat h wit hi n 3 0 da ys of last st u d y tr eat me nt  
•  Fla g f or d eat h wit hi n 6 0 da ys of first st u d y treat m e nt  
1 6. 2. 2  
Seri o us A d verse E ve nts   
T he f oll o wi n g o v erall fre q ue nc y t a bles will b e pre pare d f or tr eat me nt-e mer ge nt s eri o us a d verse 
e ve nts ( S A Es):  
•  Seri o us A Es b y S O C a n d P T  
•  Relate d seri o us A Es b y S O C a n d P T  
T he f oll o wi n g t a ble will be pr o vi de d i n a d diti o n  als o f or t he m Safet y -A S:  
•  Seri o us A Es b y S O C a n d P T  
T he listi n gs of S A Es will als o be pr o vi de d wit h t h e rele va nt i nf or mati o n.  
 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 5 /1 0 2  
 
 
1 6. 2. 3  
Ot her Si g nific a nt A d verse E ve nt   
1 6. 2. 3. 1  
I m m u ne-Rel ate d A d verse E ve nts   
T he f oll o wi n g ta bl es will be creat e d f or tr eat me nt -e mer ge nt ir A Es b y tr eat me nt gr o u p. Se parate 
s u m mar y ta bles will prese nt p ote ntial ir A Es (t h ose i de ntifie d s olel y b y M e d D R A preferre d t er m) 
a n d al g orit h micall y-ass esse d ir A Es ( w hi c h meet t he criteria o utli ne d i n A p pe n di x V ). F or t h e 
p ote ntial ir A E ta bles,  all t hree treat me nt ar ms will be pres e nte d wit h c o u nts, as a p plica ble. O nl y 
t he c o u nts f or t he a vel u m a b ar m will be dis pla ye d i n t he classifi e d  ir A E s u m mar y ta bles. “ Cl uster” 
is a c o m pilati o n of P Ts t hat are cate g orize d b y i m m u ne-relat e d e ve nt of s p ecial i nterest. 
•  T he o verall s u m mar y of treat me nt e mer ge nt ir A Es ta ble will i ncl u de t he f oll o wi n g 
cate g ories : 
-  
All ir A Es 
-  
Seri o us ir A E s 
-  
ir A Es, gra de ≥ 3 
-  
ir A Es lea di n g t o per ma n e nt treat me nt disc o nti n uati o n  
-  
ir A Es lea di n g t o deat h  
•  ir A Es lea di n g t o deat h, b y Cl uster a n d P T 
•  irA Es b y Cl uster a n d P T  
•  ir A Es, gra de ≥ 3, b y Cl uster a n d P T 
•  ir A Es lea di n g t o per ma n e nt treat me nt disc o nti n uati o n b y Cl uster a n d P T 
•  ir A Es b y Cl uster, P T , a n d w orst gra de  
T he listi n g of all p ote ntial ir A Es will als o be pr o vi de d wit h all rele va nt i nf or mati o n i ncl u di n g a 
fla g f or ir A Es wit h o nset o utsi de of t he o n-tr eat me nt peri o d. T h e f oll o wi n g i nf or mati o n will be 
pr o vi de d f or eac h ir A E: 
•  T he ti me fr o m first st u d y treat me nt t o start of irA E  
•  T he ti me fr o m m ost rece nt st u d y treat me nt u ntil start of irA E  
•  T he d urati o n of t he irA E  
T he ir A Es i de ntifie d p er b y t h e al g orit h m defi ne d b y st u d y m e dical p ers o n nel t hat are o nl y 
a p plica ble t o a vel u ma b treat me nt ar ms will als o be fla g ge d i n t h e listi n g. A se p arate listi n g of 
ir A Es wit h o nset after t h e o n-treat me nt peri o d will als o be pr o vi de d. 
1 6. 2. 3. 2  
I nf usi o n Rel ate d Re acti o n s  
T he o verall s u m mar y of treat me nt e mer ge nt I R R ta ble will i ncl u de t he f oll o wi n g s u m maries: 
-  Treat me nt e mer ge nt I R R  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 6 /1 0 2  
 
 
-  Relate d treat me nt e m er ge nt I R R 
-  Seri o us treat me nt e mer ge nt I R R 
-  Relate d seri o us treat me nt e mer ge nt I R R 
-  Treat me nt e mer ge nt I R R, gra de ≥ 3  
-  Relate d treat me nt e m er ge nt I R R, gra de ≥ 3 
-  Treat me nt e mer ge nt I R R lea di n g t o d eat h  
-  Relate d treat me nt e m er ge nt I R R lea di n g to de at h  
-  Treat me nt e mer ge nt I R R lea di n g t o p er ma ne nt treat me nt disc o nti n uati o n  
-  Relate d treat me nt e m er ge nt I R R lea di n g t o per ma ne nt treat me nt disc o nti n uati o n  
-  Ti me relate d t o first o nset of a n I R R (c ycl e 1/ c ycl e 2/ c ycle 3/ c ycle 4 or later).  T he e ve nts 
s h o ul d be assi g ne d t o t he act ual dr u g i nf usi o ns t hat t he s u bject recei ve d, n ot t o t he pla n ne d 
dates. A n I R R is assi g ne d t o a dr u g c ycle if its o nset is at t he sa m e date ( b ut n ot bef ore 
d osi n g) or t h e f oll o wi n g da y of dr u g i nf usi o n. F or a vel u ma b ar ms, a c ycl e will b e assi g ne d 
f or eac h a vel u ma b i nf usi o n. F or c he m ot hera p y ar m, a c ycl e will be assi g ne d f or eac h 
a d mi nistrati o n of at least o ne c he m ot hera p y pr o d u ct . 
T he f oll o wi n g o v erall fre q ue nc y ta bles will be pre pare d f or I R Rs:  
•  I R Rs lea di n g t o de at h, b y P T  
•  Relate d I R R s le a di n g t o deat h, b y P T  
•  I R Rs, b y P T  
•  I R Rs, Gra de ≥ 3, b y P T  
•  Relate d I R Rs, b y P T  
•  Relate d I R Rs, Gra de ≥ 3, b y P T  
•  I R Rs lea di n g t o per m a ne nt treat me nt disc o nti n uati o n, b y P T  
•  Relate d I R Rs le a di n g t o per ma ne nt treat me nt disc o nti n uati o n, b y P T  
•  Seri o us I R R s, b y P T  
•  Relate d seri o us I R Rs, b y P T  
T he listi n g of all I R Rs will als o be pr o vi de d wit h t he rele va nt i nf or mati o n wit h a fla g f or I R Rs 
wit h o nset o utsi de of t he o n -treat me nt peri o d. 
1 6. 2. 4  
I m m u n o ge nicit y S u b gr o u p A n al ysis of A d verse E ve nts   
A n alysis sets: S afety a n alysis set, avel u m a b ar ms o nly  
A listi n g of i m m u n o ge nicit y data a n d T E A Es will be pr o vi de d c o ntai ni n g s u bject I D,  treat me nt 
ar m, a ge, ge n d er, st u d y treat me nt start a n d st o p d ate, all dat es wit h p ositi ve A D A res ult, all d ates 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 7 /1 0 2  
 
 
wit h p ositi ve n A b res ults, preferre d ter m of T E A E, T E A E start  d ate, st o p date, C T C A E t o xicit y 
gra de a n d fl a gs f or i m m u ne -relat e d a d v erse e v e nt or i nf usi o n relate d reacti o n or reas o n f or 
per ma ne nt treat me nt disc o nti n uati o n, as well as A D A stat us gr o u p.  
O nl y s u bjects w hic h are pre -e xisti n g p ositi ve, tra nsie nt treat me nt -e mer ge nt p ositi ve, or persiste nt 
treat me nt-e mer ge nt p ositi ve will be liste d).  
1 6. 3  
Cli nic al L a b or at or y E v al u ati o n   
A n alysis sets: S afety a n alysis set  
1 6. 3. 1  
He m at ol o g y a n d C he mistr y P ar a me ters  
La b orat or y res ults will be classifie d acc or di n g t o t he N CI -C T C A E criteria versi o n 4. 0 3. N o n -
n u merical q ualifiers ( wit h t he e x ce pti o n of fasti n g fla gs) will n ot be ta ke n i nt o  c o nsi derati o n i n t he 
deri vati o n of C T C A E criteria (e. g., h y p o kale mia Gra de 1 a n d Gra de 2 are o nl y disti n g uis he d b y a 
n o n -n u merical q ualifier a n d t heref ore Gra de 2 will n ot be deri ve d).  A d diti o nal la b orat or y res ults 
t hat are n ot p art of N CI-C T C A E will be p res e nte d acc or di n g t o t he cate g ories: bel o w n or mal li mits, 
wit hi n n or mal li mits a n d a b o ve n or mal li mits (acc or di n g t o t he la b orat or y n or mal ra n ges).  
If b ot h ce ntral a n d l ocal la bs are c ollect e d f or a s u bject, a n y s u m mar y statistics b y visit will be 
base d o nl y o n t he ce ntral la b res ults, w hile s u m maries of w orst o n -treat me nt gra de will be bas e d 
o n b ot h ce ntral a n d l ocal la b res ults.  
Q ua ntitati ve data will be s u m marize d usi n g si m ple descri pti ve statistics ( m ea n, sta n dar d de viati o n, 
me dia n, Q 1, Q 3, mi ni m u m, a n d ma xi m u m) of act ual val ues a n d c h a n ges fr o m baseli ne f or eac h 
n o mi nal visit o ver ti me ( u nsc he d ule d meas ure m e nts w o ul d t heref ore n ot be i ncl u de d i n t hese 
s u m maries). E n d of Treat me nt visit will be s u m marize d se paratel y. T he c ha n ges c o m p ute d will be 
t he differe n ces fr o m baseli ne. Q ualitati ve data base d o n refere nce ra n ges will be descri be d 
acc or di n g t o t he cate g ories (i.e. L o w, N or mal, Hi g h) . 
T he w orst gra d e d uri n g t h e o n -tr eat me nt p eri o d will be s u m marize d b y treat me nt gr o u p 
c o nsi deri n g o nl y s u bjects wit h p ost baseli ne l a b orat or y s a m ples: La b orat or y tests b y N CI -C T C A E  
gra de ( 0, 1, 2, 3, 4).   
Se parate la b orat or y res ults ta bles f or s u bjects w h o s witc h t o a vel u ma b usi n g t he c orres p o n di n g 
o n -treat me nt peri o d defi niti o n will be pr o vi de d f or sa m ples ta ke n d uri n g this peri o d ( wit h o nl y a 
‘s witc h t o a vel u ma b’ c ol u m n), w he n at least 2 0 s u bjects ha ve s witc he d t o a vel u ma b. If less t ha n 
2 0 s u bjects, res pecti ve la b orat or y res ults will be prese nte d i n a listi n g . 
A b n or malities classifie d acc or di n g t o N CI -C T C A E t o xicit y gra di n g v ersi o n 4. 0 3 will be descri be d 
usi n g t he w orst gra d e. F or t h ose para met ers w hic h are gra de d wit h t w o t o xicities s uc h as p otassi u m 
( h y p o k ale mia/ h y per kale mia), t he t o xicities will be s u m marize d se paratel y. L o w directi o n t o xicit y 
(e g. h y p o k ale mia) gra des at baseli ne a n d p ost baseli ne will be set t o 0 w he n t he varia bles are 
deri ve d f or s u m marizi n g hi g h directi o n t o xicit y (e g. h y per kale mia), a n d vice versa.   
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 8 /1 0 2  
 
 
F or c alci u m, C T C A E gra di n g is base d o n C orrecte d Calci u m. C orrecte d Calci u m is cal c ulate d 
fr o m Al b u mi n a n d Calci u m as f oll o ws base d o n t he I nter n ati o nal S yste m of U nits ( SI): 
C orrecte d calci u m ( m m ol/ L) = m eas ure d t otal Calci u m ( m m ol/ L) + 0. 0 2 ( 4 0 –  ser u m al b u mi n 
[ g/ L]). 
Li ver f u ncti o n tests : 
Al a ni ne a mi n otra nsferase ( A L T), as partate a mi n otra nsferase ( A S T), a n d t otal bilir u bi n are us e d t o 
assess p ossi ble dr u g i n d uce d li ver t o xicit y. T he rati os of t est res ult o v er u p per li mit of n or mal 
( U L N) will be calc ulate d a n d classifi e d f or t hese t hree p ara m eters d uri n g t he o n-treat me nt peri o d.  
S u m mar y of li ver f u ncti o n test will i ncl u de t h e f oll o wi n g cate g ori es. T he n u m ber a n d perce nta ge 
of s u bjects wit h eac h of t he f oll o wi n g d uri n g t he o n -tr eat me nt peri o d will be s u m marize d b y 
treat me nt gr o u p: 
•  A L T: ≥3 × U L N /  ≥5 × U L N / ≥1 0 × U L N / ≥2 0 × U L N.  
•   A S T: ≥3 × U L N / ≥5 × U L N / ≥1 0 × U L N / ≥2 0 × U L N.  
•  ( A L T or A S T): ≥3 × U L N / ≥5 × U L N / ≥1 0 × U L N / ≥2 0 × U L N. 
•  T otal bilir u bi n: ≥2 × U L N.  
•  A L T ≥3 × U L N c o nc urre ntl y wit h t otal bilir u bi n ≥2 × U L N.  
•  A S T ≥3 × U L N c o n c urre ntl y wit h t otal bilir u bi n ≥2 × U L N.  
•  ( A L T or A S T) ≥3 × U L N c o nc urre ntl y wit h t otal bilir u bi n ≥2 × U L N. 
•  ( A L T or A S T) ≥3 × U L N c o nc urre ntl y wit h t otal bilir u bi n ≥2 × U L N a n d A L P > 2 × U L N. 
•  ( A L T or A S T) ≥3 × U L N c o nc urre ntl y wit h t otal bilir u bi n ≥2 × U L N a n d (A L P ≤2 × U L N or 
missi n g ). 
C o nc urre nt meas ure me nts are  t h ose occ urri n g o n t he sa me date. 
Cate g ories will be c u m ulati ve, i.e a s u bject wit h a n ele vati o n of A S T ≥1 0 × U L N will als o a p pear 
i n t he cat e g ories ≥5 × U L N a n d ≥3 × U L N. Li v er f u ncti o n ele vati o n a n d p ossi ble H y’s La w cases 
will be s u m mariz e d usi n g fre q ue n c y a n d p erce nta ge.  
A n e val uati o n of Dr u g -I n d uce d Seri o us He pat ot o xicit y (e DI S H) pl ot will als o be create d, wit h 
differe nt s y m b ols f or differe nt treat me nt gr o u ps, b y gra p hicall y dis pla yi n g  
•  pea k ser u m A L T(/ U L N) vs pea k  t otal bilir u bi n (/ U L N) i ncl u di n g refere n ce li nes at A L T 
= 3 × U L N a n d t otal bilir u bi n = 2 × U L N.  
•  pea k ser u m A S T(/ U L N) vs pea k  t otal bilir u bi n (/ U L N) i ncl u di n g refere n ce li nes at A S T 
= 3 × U L N a n d t otal bilir u bi n = 2 × U L N.  
I n a d diti o n, a listi n g of all T BI LI, A L T, AS T a n d A L P v al ues f or patie nts wit h a p ost -baseli ne 
T BI LI ≥ 2 × U L N, A L T ≥ 3 × U L N or A S T ≥ 3 × U L N will be pr o vi de d.  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 9 /1 0 2  
 
 
P ar a meters wit h N CI -C T C A E  gr a des a v ail a ble:  
T he la b orat or y t o xicities will be ta b ulate d usi n g descri pti ve statistics (c o u nt a n d perce nta ge) 
d uri n g t he o n -treat me nt p eri o d. T he s u m mar y statistics will be b ase d o n s u bjects w h o h a ve at l east 
o ne p ost -baseli ne la b orat or y assess me nt.  
•  T he s u m mar y of la b orat or y p ara m eters b y C T C A E gra de t a ble will i ncl u de n u m ber a n d 
perce nt a ge of s u bjects wit h t he w orst o n -treat me nt Gra de > = 0, Gra de > = 3, a n d Gra de > = 4  
d uri n g t he o n -treat me nt p eri o d. 
•  T he s hift ta ble will s u m marize baseli ne C T C A E gra de v ers us t he w orst o n -treat me nt 
C T C A E gra d e. T he hi g h est C T C A E gra d e d uri n g t he o n -treat me nt peri o d is c o nsi dere d as 
t he w orst gra d e f or t he s u m mar y.  
T he a b o v e a n al ys es a p pl y t o h e mat ol o g y a n d c he mistr y e val uati o ns w hic h ca n be gra de d per 
C T C A E, i.e.:  
•  He mat ol o g y:  
He m o gl o bi n ( H B), Le u k oc yt es ( w hite bl o o d cell decreas e d), L y m p h oc yt es (l y m p h oc yte 
c o u nt i ncreas e d/ decreas e d), Ne u tr o p hils / A bs ol ute Ne utr o p hils C o u nt ( A N C) ( ne utr o p hil 
c o u nt decrease d), Platelet C o u nt  ( P L T) ( platel et c o u nt decrease d). 
•  Ser u m C he mistr y:  
Al b u mi n ( h y p oal b u mi n e mia), 
Al kali ne 
P h os p hatase ( A L P ) (al kali ne 
p h os p hatase 
i ncreas e d), Ala ni ne A mi n otra nsferase ( A LT) ( A L T i ncreas e d), A m ylase (ser u m a m ylase 
i ncreas e d), As partate A mi n otra nsferas e ( A S T) ( A S T i ncrease d), T otal Bilir u bi n ( bl o o d 
bilir u bi n i ncrease d), C h olester ol (c h olester ol hi g h), Creati ni ne (creati ni ne i ncrease d), 
Creati ne 
Ki nas e ( C P K i ncreas e d), 
P otassi u m ( h y p o kale mia/ h y per kale mia), S o di u m 
( h y p o n atre mia/ 
h y per natre mia), 
Ma g nesi u m ( h y p o ma g n ese mia/ h y p er ma g nes e mia), 
Calci u m ( h y p o calc e mia/ h y percal ce mia), Gl uc ose ( h y p o gl yce mia/  h y per gl yce mia), Ga m ma 
Gl uta m yl Tra nsferase ( G G T) ( G G T i ncreas e d), Li p ase  (li pas e i ncreas e d), P h os p hates 
( h y p o p h os p h ate mia), Tri gl yceri des ( h y p ertri gl yceri de mia). 
P ar a meters wit h N CI -C T C A E  gr a des n ot a v ail a ble:  
He mat ol o g y a n d c h e mistr y e v al uati o ns w hic h ca n’t be gra de d p er C T C A E criteria will be 
s u m marize d as:  
•  N u m ber a n d p erce nta ge of s u bjects wit h s hifts fr o m baseli ne n or mal t o at least o ne res ult 
a b o ve n or mal d uri n g o n -treat me nt peri o d  
•  N u m ber a n d p erce nta ge of s u bjects wit h s hifts fr o m baseli ne n or mal t o at least o ne res ult 
bel o w n or mal d uri n g o n -treat me nt peri o d 
I n t his st ud y, t hese a p pl y t o t he f oll o wi n g para met ers:  
•  He mat ol o g y:  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 0 /1 0 2  
 
 
He mat ocrit, Er yt hr oc ytes , M o n oc yt es, E osi n o p hils, Bas o p hils, Retic ul oc yt es, Er y. M ea n 
C or p usc ular 
He m o gl o bi n, 
Er y. M ea n C or p usc ular 
V ol u me, 
Er y. Mea n C or p usc ular 
He m o gl o bi n C o nce ntrati o n.  
•  Ser u m C he mistr y:  
C hl ori de, C -Reacti ve Pr otei n, Lactate De h y dr o ge n ase ( L D H), T otal Pr otei n, Urate .  
1 6. 3. 2  
Ot her L a b or at or y P ar a meters   
All ot her para meters c ollecte d o n t h e e C R F will be  liste d i n d e dicate d listi n gs pres e nti n g all 
c orres p o n di n g c ollecte d i nf or mati o n o n t he e C R F.  
•  C oa g ulati o n: acti vat e d partial t hr o m b o plasti n ti me (a P T T) a n d pr ot hr o m bi n ti me (I N R).  
•  Uri nal ysis: all uri nal ysis para meters  
•  Ot her para meters: h or m o ne, a n d i m m u n o l o g y para meters 
•  Pre g n a nc y test  
T he listi n gs of la b orat or y res ults will be pr o vi de d f or all la b orat or y para meters. T he listi n gs will 
be s orte d b y para meters a n d assess me nt dates or visits f or eac h s u bject. La b orat or y v al ues t hat are 
o utsi de t he n or mal ra n ge will als o be fla g ge d i n t he da ta listi n gs, al o n g wit h c orres p o n di n g n or mal 
ra n ges.  
I n a d diti o n, listi n gs of a b n or mal val ues will be pr o vi de d f or he mat ol o g y, c he mistr y, uri n al ysis, 
c oa g ulati o n para m eters. If t here is at least o ne a b n or mal assess me nt f or a n y para meter, all t he data 
f or t hat la b orat or y para meter will be i ncl u de d i n t he listi n g.  
F or all tests n ot me nti o ne d a b o ve b ut prese nt i n t he cli nical data, a listi n g of s u bjects wit h at least 
o ne res ult f or t he rele v a nt test will be pr o vi de d.  
1 6. 4  
Vit al Si g ns   
A n alysis sets: S afety a n alysis set  
Vital si g n s u m maries will i ncl u de all vital si g n assess me nts fr o m t he o n -treat me nt peri o d.  All vital 
si g n assess me nts will be liste d, a n d t h ose c ollecte d o utsi de t he o n-treat me nt peri o d will be fla g ge d 
i n t he listi n g, wit h differe nt fla gs f or t h ose c ollecte d d uri n g t h e sec o n d a vel u ma b o n-treat me nt 
peri o d (i.e. s witc h t o a v el u ma b) a n d t h ose c ollecte d o utsi de t he sec o n d a vel u ma b o n -tr eat me nt 
peri o d .  
T he ma xi m u m c ha n ges of vi tal si g n meas ure me nts fr o m scree ni n g/ bas eli ne t o ma xi m u m c ha n ges 
after ra n d o mizati o n  will be gr o u pe d as f oll o ws:  
P ar a meters  
C ate g ories of C h a n ge fr o m B as eli ne  
B o d y te m perat ure i n crease  
< 1 C , 1 -< 2 C , 2 -< 3 C, 3 C  
Wei g ht i n crease  
< 1 0 %,  1 0 %  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 1 /1 0 2  
 
 
P ar a meters  
C ate g ories of C h a n ge fr o m B as eli ne  
Wei g ht decreas e  
< 1 0 %,  1 0 %  
Heart rate i ncrease fr o m baseli ne  
< 1 0 0 b p m ; ≥ 1 0 0 b p m  
2 0 b p m, > 2 0 –  4 0 b p m, > 4 0 b p m  
Heart rate decreas e fr o m baseli ne  
< 1 0 0 b p m ; ≥ 1 0 0 b p m  
2 0 b p m, > 2 0 –  4 0 b p m, > 4 0 b p m  
S B P i n crease fr o m baseli ne  
< 1 4 0 m m H g; ≥ 1 4 0 m m H g  
2 0 m m H g, > 2 0 –  4 0 m m H g, > 4 0 m m H g  
S B P decrease fr o m baseli ne  
< 1 4 0 m m H g; ≥ 1 4 0 m m H g,  
2 0 m m H g, > 2 0 –  4 0 m m H g, > 4 0 m m H g  
D B P i ncrease fr o m baseli ne  
< 9 0 m m H g; ≥ 9 0 m m H g  
2 0 m m H g, > 2 0 –  4 0 m m H g, > 4 0 m m H g  
D B P decrease fr o m baseli ne  
< 9 0 m m H g; ≥ 9 0 m m H g,  
2 0 m m H g, > 2 0 –  4 0 m m H g, > 4 0 m m H g  
Res pirati o n rate i ncrease fr o m baseli ne < 2 0 b p m ; ≥ 
2 0 b p m  
5 b p m, > 5 –  1 0 b p m, > 1 0 b p m  
Res pirati o n rate decrease fr o m baseli ne < 2 0 b p m ; ≥ 
2 0 b p m  
5 b p m, > 5 –  1 0 b p m, > 1 0 b p m  
F or eac h patie nt t he w orst o n -treat me nt val ue will be calc ulate d. Missi n g val ues will defi ne a 
se parat e cat e g or y. 
T he f oll o wi n g s u m maries will be pre pare d f or vital si g n para meters as gr o u pe d a b o ve b y treat me nt 
ar m c o nsi deri n g o nl y s u bjects wit h p ost baseli ne val ues:  
•  Ma xi mal S hifts (c ha n ges i n cate g ories)  
All vital si g n para met ers will be s u m marize d usi n g descri pti ve statistics ( mea n, sta n dar d d e viati o n, 
me dia n, Q 1, Q 3, mi ni m u m, a n d ma xi m u m) of act ual val ues a n d c h a n ges fr o m baseli ne f or eac h 
visit o ver ti me. E n d of tr eat me nt visit will be s u m ma rize d se paratel y. T h e c ha n ges c o m p ute d will 
be t he differe nces fr o m b aseli ne.   
A n a d diti o nal s u bject data listi n g will prese nt all c ha n ges fr o m baseli ne re p orte d i n t h e hi g hest 
cate g ories.  
1 6. 5  
Ot her S afet y or T oler a bilit y E v al u ati o ns   
1 6. 5. 1  
E C G   
A n alysis sets: S afety a n alysis set  
 
T he 1 2 -le a d El ectr ocar di o gra m ( E C G) ass ess me nt will be p erf or me d d uri n g s cree ni n g ( baseli ne) 
a n d at t he Disc o nti n uati o n / E n d -of -Treat me nt visit. F or eac h of t he E C G para meters, descri pti ve 
statistics at baseli ne a n d at t he Disc o nti n uati o n / E n d-of -Treat me nt visit  a n d c ha n ges fr o m baseli n e 
will be prese nte d.  
T he i nci de n ce a n d p erce nta ge of s u bjects wit h p ote ntiall y cli nicall y si g nifica nt a b n or malities 
( P C S A) f or E C G para meters will be s u m mari ze d d uri n g t he o n -treat me nt peri o d (i ncl u di n g 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 2 /1 0 2  
 
 
u nsc he d ule d meas ur e me nts)  as defi ne d i n Secti o n  1 0 , as well as f or s u bjects w h o s witc he d t o 
a vel u ma b usi n g t h e c orres p o n di n g o n -tr eat me nt peri o d defi niti o n ( w he n t here are m or e t ha n 2 0 
s u bjects w h o s witc he d t o a vel u ma b). Eac h s u bject will be c o u nte d o nl y o nce wit hi n eac h cate g or y. 
As E C G assess me nts are pla n ne d t o be perf or me d at scree ni n g a n d Disc o nti n uati o n/ E n d -of -
Treat me nt visits, t he de n o mi nat or t o calc ulate perce nta ges f or eac h P C S A cate g or y is t he n u m ber 
of s u bjects wit h a Disc o nti n uati o n/ E n d of Treat me nt visit. T he P C S A criteria are pr o vi de d i n Ta bl e 
1 1  bel o w.  
T a ble 1 1  
P ote nti all y Cli nic all y Si g nific a nt A b n or m alities criteri a f or E C G   
Test  
P ote nti all y Cli nic all y Si g nific a nt A b n or m alities ( P C S A) Criteri a  
Heart Rate ( H R)  
≤ 5 0 b p m a n d decrease fr o m bas eli ne ≥ 2 0 b p m  
≥ 1 2 0 b p m a n d i n crease fr o m baseli ne ≥ 2 0 b p m 
P R  I nter val 
≥ 2 2 0 ms a n d i n crease fr o m baseli n e ≥ 2 0 ms  
Q R S  
 ≥ 1 2 0 ms  
Q Tc F a n d Q Tc B a bs ol ute  
> 4 5 0 ms  
> 4 8 0 ms  
> 5 0 0 ms  
Q Tc F a n d Q Tc B  c ha n ge 
fr o m baseli ne 
I ncrease fr o m baseli ne > 3 0 ms 
I ncrease fr o m baseli ne > 6 0 ms 
Q T will be c orrect e d bas e d o n Fri dericia’s f or m ul a ( Q Tc F = Q T/  √𝑑𝑎
3
) a n d Bazett's f or m ula f or 
Q Tc B ( Q T c B = Q T/  √𝑡𝑒
2
) wit h R R = 6 0/ H R . Bas eli ne Q Tc F a n d Q Tc B will be deri ve d fr o m t he 
visit t hat ot her E C G para meters are fla g ge d as bas eli ne.  
Listi n gs of 1 2 -lea d E CGs will be pr o vi de d wit h all rele va nt i nf or m ati o n a n d deri ve d varia bles.  
U nsc he d ule d E C G m eas ure me nts will n ot be us e d i n c o m p uti n g t he descri pti ve statistics f or 
c ha n ge fr o m bas eli ne at eac h p ost -bas eli ne ti me p oi nt. H o we ver, t he y will be use d i n t he a nal ysis 
of n ota ble E C G c ha n ges.  
1 6. 5. 2  
E C O G Perf or m a nce St at us   
A n alysis sets: S afety a n alysis set  
T he E C O G s hift fr o m bas eli ne t o hi g hest sc ore d uri n g t he o n -tr eat me nt peri o d will be su m marize d  
b y tr eat me nt gr o u p . E C O G perf or ma nce stat us wit h s hift fr o m E C O G = 0 or 1 t o E C O G 2 or hi g her 
will als o be prese nte d i n a data listi n g  wit h s u bject i de ntifier  a n d ot her rele va nt i nf or mati o n . 
Gl o bal Versi o n I D: C CI
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 3 /1 0 2  
 
 
Gl o bal Versi o n I D: C CI
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 4 /1 0 2  
 
 
Gl o bal Versi o n I D: C CI
C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 5 /1 0 2  
 
 
1 7  
Refere nces   
1.  H o m mel G, Bretz F, Ma urer 
W. P o werf ul s h ort ‐c uts f or m ulti ple testi n g pr oce d ures wit h 
s pecial refere nce t o gate k ee pi n g strate gies. Statistics i n Me dici ne 2 0 0 7; 2 6( 2 2): 4 0 6 3-4 0 7 3.   
2.  J e n nis o n C, T ur n b ull B W. I n: Gr o u p Se q u e ntial Met h o ds wit h A p plicati o ns t o Cli nical T rials. 
C ha p ma n & H all/ C R C, B oca R at o n, 2 0 0 0.   
3.  Br o o k me yer R, Cr o wle y J. A C o nfi de nce I nter v al f or t he Me di a n S ur vi val Ti me. Bi o metrics 
1 9 8 2; 3 8: 2 9 -4 1.   
4.  Kal b ﬂeis c h J D, Pre ntice R L. T he Statistical A nal ysis of Fail ure Ti me Dat a, Ne w Y or k: J o h n 
Wile y & S o ns 1 9 8 0.   
5.  C oc hra n W G. S o me Met h o ds f or Stre n gt he ni n g t he C o m m o n C hi -s q uare Tests. Bi o metrics 
1 9 5 4; 1 0: 4 1 7 -5 1.   
6.  A gresti A. A S ur ve y of E x act I nfere n ce f or C o nti n ge nc y Ta bles. 
Statistical Scie nce 
1 9 9 2; 7: 1 3 1 – 7 7.   
7.  A gresti A. A n I ntr o d u cti o n t o Cate g orical Dat a A nal ysis ( 2 e d.). Ne w Y or k: J o h n Wile y & 
S o ns, 2 0 0 7.   
8.  Os o ba D, R o dri g ues G, M yles J, Zee B, Pater J. I nter preti n g t he si g nifica nce of c h a n ges i n 
healt h -rel ate d q ualit y-of -life sc ores. J o ur nal of cli nical o nc ol o g y. 1 9 9 8 J a n 1; 1 6( 1): 1 3 9-4 4   
9.  Mietti ne n O, N ur mi ne n 
M. C o m parati ve a nal ysis of t w o rates. Stat istics i n 
Me dici ne 
1 9 8 5; 4( 2): 2 1 3 -2 6   
1 0.  Li u  G F, Wa n g J, Li u K, S na vel y D B.  C o nfi de nce i nter vals f or a n e x p os ure a dj uste d i nci de nce 
rate differe n ce wit h a p plicati o ns t o cli nical trials. Statistics i n Me dici ne 2 0 0 6; 3 0; 2 5( 8): 1 2 7 5 -
8 6   
 
 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 6 /1 0 2  
 
 
1 8  
A p pe n dices   
A p pe n di x I  
 R E CI S T 1. 1   
Eise n ha uer E A, T herasse P, B o gaerts J, et al. Ne w  res p o nse e val uati o n criteria i n s oli d t u m o urs: 
Re vise d R E CI S T g ui deli ne ( versi o n 1. 1). E ur J Ca ncer 2 0 0 9; 4 5: 2 2 8 -4 7.  
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 7 /1 0 2  
 
 
A p pe n di x II 
Cli nic all y I m p ort a nt Pr ot oc ol De vi ati o ns   
Pr ot oc ol De vi ati o n  
Pr ot oc ol 
De vi ati o n 
C o de  
Cli nic all y 
I m p ort a nt 
P D  
Pr o p ose d C hec k  
 
I ncl usi o n / E x cl usi o n Crite ri a 
 
 
 
S u bject di d n ot meet i n cl usi o n criteri o n 4 ( T u m or deter mi ne d t o be p ositive f or P D -L 1 
ex pressi o n per t h e ev al u ati o n of a ce ntr al l a b or at ory ) 
I N C E X C 0 1 
y  
Me dical re vie w re q uire d a n d Pr o gra m mi n g 
c hec k o n i n cl usi o n criteri o n  
S u bject di d n ot meet i n cl usi o n criteri o n 6 ( S u bjects wit h hist ol o gic ally c o nfir me d met ast atic or 
rec urre nt N S C L C ( per 7 t h I nter n ati o n al Ass oci ati o n f or t he St u dy of L u n g C a ncer 
cl assific ati o n) ) 
I N C E X C 0 3 
y  
Me dical r e vie w re q uire d a n d Pr o gra m mi n g 
c hec k o n i n cl usi o n criteri o n  
S u bject di d n ot meet i n cl usi o n criteri o n 7 ( S u bjects m ust n ot h ave receive d a ny tre at me nt f or 
syste mic l u n g c a ncer, i n cl u di n g E G F R i n hi bit ors or a n a pl astic ly m p h o m a ki n ase ( A L K) 
i n hi bit ors) 
I N C E X C 0 5 
y  
Me dical re vie w re q uire d a n d Pr o gra m mi n g 
c hec k o n i n cl usi o n criteri o n  
S u bject met e xcl usi o n criteri o n 1  or  2 ( S u bjects w h ose dise ase h ar b ors a n activ ati n g E G F R 
m ut ati o n, or S u bjects wit h n o n -s q u a m o us cell N S C L C w h ose dise ase h ar b ors a n A L K 
re arra n ge me nt ) 
I N C E X C 0 6 
y  
Me dical re vie w re q uire d a n d Pr o gra m mi n g 
c hec k o n e xcl usi o n  criteri o n 
S u bject met e xcl usi o n criteri o n 4 ( Pri or t h er a py wit h a ny a nti b o dy or dr u g t ar geti n g T -cell 
c ore g ul at ory pr otei ns, c o nc urre nt a ntic a ncer tre at me nt, or i m m u n os u p pressive a ge nts) 
I N C E X C 0 8 
y  
Me dical re vie w re q uire d a n d Pr o gra m mi n g 
c hec k o n e xcl usi o n criteri o n 
S u bject met e xcl usi o n criteri o n 5 ( C o nc urre nt a ntic a ncer tre at me nt (f or ex a m ple, cyt ore d uctive 
t h er a py, r a di ot h er a py [ wit h t h e exce pti o n of p alli ative b o ne -directe d r a di ot her a py] , i m m u ne 
t h er a py, or cyt o ki n e t her a py exce pt f or eryt hr o p oieti n)) 
I N C E X C 0 9 
y  
Me dical re vie w re q uire d a n d Pr o gra m mi n g 
c hec k o n e xcl usi o n criteri o n 
S u bject met e xcl usi o n criteri o n 6 ( M aj or s ur gery f or a ny re as o n, exce pt  di a g n ostic bi o psy, 
wit hi n 4 weeks of r a n d o miz ati o n a n d / or if t he s u bject h as n ot f ully rec overe d fr o m t he s ur gery 
wit hi n 4 weeks of r a n d o miz ati o n) ) 
I N C E X C 1 0*  
y *  
Me dical re vie w re q uire d a n d Pr o gra m mi n g 
c hec k o n e xcl usi o n criteri o n 
S u bject met e xcl usi o n criteri o n 1 6 ( Pre g n a ncy or l a ct ati o n ) 
I N C E X C 1 4 
y  
Me dical re vie w re q uire d a n d Pr o gra m mi n g 
c hec k o n e xcl usi o n criteri o n 
C o nc o mit a nt M e dic ati o ns/ Pr oc e d ures  
 
 
 
F or a vel u ma b ar ms, s u bjects t o o k i m m u n ot h era p y, i m m u n os u p pressi ve dr u gs (t hat is, s yste mic 
c ortic oster oi ds e xce pt f or cases s pecifie d i n a pr ot o c ol secti o n 6. 5. 2)  
C O N M E D 0 2  
y  
Me dical re vie w re q uire d  
S u bject ha d a n y a nti -ca ncer treat me nt d uri n g t h e st u d y (s ur ger y, ra di ot hera p y -u nless b o ne 
directe d or ra di ot h era p y t o a s u perficial lesi o n as l o n g as t h ere is n o i d e ntifie d s oft tiss ue 
c o m p o ne nt w hic h has bee n selecte d as tar get lesi o n).  
C O N M E D 0 7  
y  
Me dical re vie w re q uire d  
Pr ot oc ol Pr oc e d ur es  
 
 
 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 3 9 5 3 9 8 4 _ 4 6 4 0 0 1 7


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 8 /1 0 2  
 
 
Pr ot oc ol De vi ati o n  
Pr ot oc ol 
De vi ati o n 
C o de  
Cli nic all y 
I m p ort a nt 
P D  
Pr o p ose d C hec k  
 
St u d y pr oce d ure n ot d o ne/ o mitte d: Scree ni n g C T sca ns n ot perf or me d (l u n g/a b d o me n/ p el vis, 6 
we e ks brai n, b o ne sca n if cli nciall y i n dicate d)  
P R O C E D 1 3  
y  
Me dical re vie w re q uire d  a n d Pr o gra m mi n g 
c hec k o n C T sca n rec or d e d at scree ni n g  
R a n d o miz ati o n  
 
 
 
S u bject ra n d o mise d i n err or or ra n d o misati o n i nter u pte d i n I W R S res ulti n g i n err o ne o us 
a p plicati o n of t h e ra n d o m isati o n c o de 
R A N D O M 0 1  
y  
 
P atie nt ra n d o mi ze d m ore t h a n o nce  
R A N D O M 0 2  
y  
Me dical re vie w re q uire d a n d Pr o gra m mi n g 
c hec k o n p ote ntial se veral s u bjects wit h t h e 
sa me date of birt h, ge n der, race a n d baseli ne 
hei g ht  
* T his mi g ht be, b ut n ot necessaril y is, a CI P D. T his will ha ve t o be deci d e d o n a case -b y -cas e basis d uri n g t h e data re vie w meeti n gs.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 3 9 5 3 9 8 4 _ 4 6 4 0 0 1 7


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 9 /1 0 2  
 
 
A p pe n di x III 
E O R T C Q L Q -C 3 0 versi o n 3. 0   
 
 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 0 0 /1 0 2  
 
 
A p pe n di x I V 
E O R T C Q L Q -C 3 0 -L C 1 3: L u n g C a ncer M o d ule   
  
 
 
 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 0 1 /1 0 2  
 
 
A p pe n di x V  
Descri pti o n of t he C ase Defi niti o n  f or Assess me nt of I m m u ne-Rel ate d 
A Es a n d I R R s   
I m m u ne-Rel at e d A d verse E ve nts  
I m m u ne-relat e d a d v erse e ve nts (ir A Es) will be i de ntifie d pr o gra m maticall y . A Es w hic h satisf y all 
of t he f oll o wi n g criteri a will be fla g ge d as i m m u n e-rel ate d: 
1) T he A E preferre d ter m matc hes a preferre d ter m o n t he list of pre -selecte d Me d D R A ter ms.  
T he list of ter m is re vie we d a n d u p date d, if necessar y, f or eac h ne w versi o n of t he Me d D R A 
dicti o nar y a n d t he c o m plete list of ter ms is i ncl u d e d i n a “l o o k u p ” datas et t hat is i nlc u de d i n t he 
a nal ysis d atasets f or t h e st u d y.  T heref ore, t he list is n ot pr o vi de d i n t his d oc u me nt.  
2) T he A E o nset occ urs after t he first st u d y dr u g a d mi nistrati o n a n d n o m ore t ha n 9 0 da ys after 
last d ose. 
3) O n t he A E e C R F pa ge , t he q uesti o n “Were C ortic oster oi ds, I m m u n os u p presa nts, or h or m o n al 
t hera p y (e. g. T h yr oi d) a p plie d?” has t he a ns wer “ Yes” selecte d.  
4)  O n t he A E e C R F p a ge, eit her:  
a.  T he q uesti o n “ D oes a n y of t he f oll o wi n g pr o vi de a clear eti ol o g y f or t h e e ve nt? ” has t he 
a ns wer “ N o” select e d, i n dicati n g t h at t he A E is n ot attri b uta ble t o u n derl yi n g ca ncer 
disease/ P D, pri or or c o nc o mita nt me dicati o ns/ pr oce d ures, n or a n ot h er m e dical c o n diti o n 
s uc h as a n i nf ecti o n or pre-e xisti n g disease.  
O R  
b.  T he A E e C R F i n dicat es t hat a  bi o ps y was perf or me d a n d t he q u esti o n “ Is t h e 
hist o pat h ol o g y/ bi o ps y c o nsiste nt wit h a n i m m u ne -me diate d e ve nt? ” has t he a ns wer “ Y es” 
selecte d. 
I n t he cas e t hat criteri a ( 1) t hr o u g h ( 3) are m et, a n d e ntries f or c o n diti o n ( 4)  are missi n g, t he 
f oll o wi n g r ules will be a p plie d:  
• If t he a ns wer t o “D oes a n y of t he f oll o wi n g pr o vi d e a clear eti ol o g y f or t he e ve nt? ” ( 4a) 
is missi n g, t he e ve nt will be co nsi dere d as ir A E (irres pecti ve  of bi o ps y res ults).  
• If t h e a ns wer t o “Is t he hist o pat h ol o g y/ bi o ps y c o nsiste nt wit h a n i m m u ne-me diate d 
e ve nt? ” ( 4 b) is missi n g, or if n o bi o ps y was perf or me d, a n d c o n diti o n ( 4a) is n ot satisfie d 
(i.e. “ Yes” is select e d as t he a ns wer t o t he q uesti o n “D oes a n y of t he f oll o wi n g pr o vi de 
a clear eti ol o g y f or t he e ve nt? ”), t he e ve nt will be c o nsi dere d as  a n o n -ir A E. 
I R Rs 
I nf usi o n relate d reacti o ns are i de ntifie d base d o n a list of Me d D R A P Ts a n d criteria o n t he ti mel y 
relati o ns hi p acc or di n g t o T a ble 1 6 . 
Gl o bal Versi o n I D: C CI


A vel u m a b  
A vel u m a b i n First -li ne N o n-S m all Cell L u n g C a ncer  
E M R 1 0 0 0 7 0 -0 0 5  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 0 2 /1 0 2  
 
 
T a ble 1 6  
Criteri a f or i nf usi o n rel ate d re acti o ns   
I nf usi o n relate d reacti o ns 
Re a cti o ns - C o nsi dere d w he n o nset is o n t he d a y of st u d y dr u g 
i nf usi o n ( d uri n g or after t he i nf usi o n) or t he d a y after t he st u d y 
dr u g i nf usi o n (irres pecti ve of res ol uti o n d ate):  
•  
I nf usi o n relate d reacti o n 
•  
Dr u g h y perse nsiti vit y  
•  
A na p h ylactic reacti o n  
•  
H y perse nsiti vit y  
•  
T y pe 1 h y perse nsiti vit y  
 
Si g ns a n d S y m pt o ms - occ urri n g o n t he d a y of st u d y dr u g 
i nf usi o n ( d uri n g or after t he i nf usi o n) a n d res ol ve d o n t h e d a y of 
o nset or t he ne xt d a y  
•  
P yre xia  
•  
C hills  
•  
Fl us hi n g  
•  
H y p ote nsi o n  
•  
D ys p n oea  
•  
W heezi n g  
•  
B ac k pai n  
•  
A b d o mi nal pai n  
•  
Urtic aria 
 
 
Gl o bal Versi o n I D: C CI


Si g nat ure Pa ge f or V V- C LI N- 2 8 0 0 1 4 v 2. 0
Si g nat ure Pa ge f or V V- C LI N- 2 8 0 0 1 4 v 2. 0
A p pr o val
Cli nical
1 1- N o v- 2 0 2 1 1 7: 3 4: 5 5 G M T + 0 0 0 0
Gl o bal Versi o n I D: C CI
P P D