Clinical trial NCT03631706
Conditions: Non-small Cell Lung Cancer
Keywords: M7824 Pembrolizumab PD-L1-tumor Expression INTR@PID Lung 037 Bintrafusp alfa
Sponsor: EMD Serono Research & Development Institute, Inc.
Start date: 2018-10-01; Completion date: 2024-06-25
Enrollment: 304 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to evaluate the efficacy and safety of bintrafusp alfa (M7824) compared with pembrolizumab in participants with advanced NSCLC with high PD-L1-tumor expression, with no epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) translocation. The Phase III adaptive design allows for the option to recruit up to 584 patients based on pre-specified rules.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: M7824 intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Participants received intravenous infusion of M7824 at a dose of 1200 milligrams (mg) once every 2 weeks until confirmed progression of disease, death, unacceptable toxicity, or study withdrawal. intervention 2: Pembrolizumab: Participants received intravenous infusion of Pembrolizumab at a dose of 200 milligrams (mg) once every 3 weeks until confirmed progression of disease, death, unacceptable toxicity, or study withdrawal.

Protocol documents:
Prot_000.pdf: 
Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
Cli nic al St u d y Pr ot oc ol
Title P a ge
Cli nic al St u d y Pr ot oc ol Title:
A n A da pti ve P hase III, M ultice nter, Ra n d o mize d, 
O pe n -La bel , 
C o ntr olle d
St u d y  
of 
M 7 8 2 4
( bi ntraf us p
alfa )
vers us
Pe m br oliz u ma b 
as a 
First -li ne Treat me nt 
i n Patie nts 
wit h
P D -L 1  
E x pressi n g A d va nce d N o n -small Cell L u n g Ca ncer 
St u d y N u m ber:
M S 2 0 0 6 4 7 - 0 0 3 7
Merc k C o m p o u n d N u m ber:
M 7 8 2 4
St u d y P h ase:
III
S h ort Title:
1 L  N S C LC A da pti ve P hase III R C T M 7 8 2 4 vs 
Pe m br oliz u ma b
C o or di n ati n g I n vesti g at or :
S p o ns or N a me a n d Le g al Re gistere d 
A d dress:
F or all c o u ntries e xce pt t he U S a n d Ja pa n :
Merc k K Ga A , Dar msta dt, Ger ma n y
Fra n kf urter Strasse 2 5 0
6 4 2 9 3 Dar msta dt, Ger ma n y
I n Ja pa n:
Merc k Bi o p har ma C o., Lt d. : Ja pa n
( Affiliate of Merc k K Ga A, Dar msta dt, Ger ma ny)
Arc o T o wer, 1 - 8-1 S hi m o me g ur o
Me g ur o -k u, T o k y o 1 5 3 -8 9 2 6, Ja pa n
I n t he U S: 
E M D Ser o n o Researc h a n d 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
Re g ul at or y 
A ge nc y 
I de ntif yi n g 
N u m bers:
E u dra C T 2 0 1 8 - 0 0 1 5 1 7-3 2
Pr ot oc ol Versi o n:
2 2 J u ne 2 0 2 1/ Versi o n 4. 0
D oc u me nt N o.
O bject N o.
C CI
C CI
C CI
P P D
P P D


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
Me dic al 
M o nit or 
N a me a n d C o nt act 
I nf or m ati o n:
 
O ffice p h o ne : 
M o bile p h o ne :
Pr ot oc ol A me n d me nt S u m m ar y of C h a n ges
Pr ot oc ol Hist or y
V er si o n N u m b er
T y p e
V er si o n D at e
1. 0
Ori gi n al Pr ot o c ol
2 3 M a y 2 0 1 8
1. 1 -J P N
C o u ntr y -s p e cifi c a m e n d m e nt ( J a p a n )
0 2 A u g u st 2 0 1 8
1. 2
R e gi o n -s p e cifi c a m e n d m e nt ( E ur o p e a n U ni o n f or 
c o u ntri e s p arti ci p ati n g i n t h e V H P)
2 5 J ul y 2 0 1 8
1. 3 -C H N
C o u ntr y -s p e cifi c a m e n d m e nt ( C hi n a)
0 1 S e pt e m b er 2 0 1 8
2. 0
Gl o b al a m e n d m e nt
0 8 J ul y 2 0 1 9
2. 1
R e gi o n -s p e cifi c a m e n d m e nt ( E ur o p e a n U ni o n f or 
c o u ntri e s p arti ci p ati n g i n t h e V H P)
0 9 S e pt e m b er 2 0 1 9
3. 0
Gl o b al a m e n d m e nt
1 0 F e br u ar y 2 0 2 0
3. 1
R e gi o n -s p e cifi c a m e n d m e nt ( E ur o p e a n U ni o n f or 
c o u ntri e s p arti ci p ati n g i n t h e V H P)
0 6 M a y 2 0 2 0
4. 0
Gl o b al a m e n d m e nt
2 2 J u n e 2 0 2 1
V H P = V ol u nt ar y H ar m o ni s ati o n Pr o c e d ur e .
Pr ot oc ol Versi o n 4. 0 (2 2 J u ne 2 0 2 1 )
T his a me n d me nt is s u bsta ntial base d o n t he criteria i n Article 1 0(a) of Directi ve 2 0 0 1/ 2 0/ E C of 
t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n.
O ver all R ati o n ale f or t he A me n d me nt
T he pri mar y p ur p ose of t his a me n d me nt is t o u p date t he ris k classificati o n a n d mi ni mizati o n 
meas ures . F urt her c ollecti o ns of p har mac o ki netic /a nti-dr u g a nti b o d y s a m ples a n d patie nt re p orte d 
o utc o me data are n o l o n ger nee de d a n d t heref ore re m o ve d fr o m t his a me n d me nt.
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
Titl e P a g e
C h a n g e i n N a m e a n d C o nt a ct 
i nf or m ati o n of M e di c al M o nit or 
R e m o v e d “ A m e n d m e nt N u m b er”, 
“ R e pl a c e s V er si o n” a n d “ A p pr o v al 
D at e” r o w s
R e m o v e d M e di c al R e s p o n si bl e 
i nf or m ati o n
A d mi ni str ati v e c h a n g e
D oc u me nt N o.
O bject N o.
C CI
C CI
P P D
P P D
P P D
P P D


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
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 e cti o n 1. 1 S y n o p si s a n d 
S e cti o n 3 O bj e cti v e s a n d 
E n d p oi nt s
P K, I m m u n o g e ni cit y a n d A D A 
o bj e cti v e s h a v e b e e n r e m o v e d
C oll e cti o n of P K/ A D A s a m pl e s i s n o 
l o n g er r e q uir e d a n d h as b e e n 
r e m o v e d fr o m t h e pr ot o c ol
S e cti o n 1. 2 S c h e m a i n 
Fi g ur e 1
P K a n d A D A h a v e b e e n r e m o v e d 
fr o m k e y s e c o n d ar y e n d p oi nt s
C oll e cti o n of P K/ A D A s a m pl e s i s n o 
l o n g er r e q uir e d a n d h a s b e e n 
r e m o v e d fr o m t h e pr ot o c ol
S e cti o n 1. 3 S c h e d ul e of 
A cti viti e s , T a bl e 1 S c h e d ul e of 
A s s e s s m e nt s – M 7 8 2 4 Ar m, 
T a bl e 2 S c h e d ul e of 
A s s e s s m e nt s –
P e m br oli z u m a b Ar m
P K a n d A D A s a m pli n g h a v e b e e n 
r e m o v e d
C oll e cti o n of P K/ A D A s a m pl e s i s n o 
l o n g er r e q uir e d a n d h as b e e n 
r e m o v e d fr o m t h e pr ot o c ol
S e cti o n 1. 3 S c h e d ul e of 
A cti viti e s , Ta bl e 1 S c h e d ul e of 
A s s e s s m e nt s – M 7 8 2 4 Ar m , 
T a bl e 2 S c h e d ul e of 
A s s e s s m e nt s –
P e m br oli z u m a b Ar m , T a bl e 3
S af et y a n d L o n g -t er m F oll o w-
u p – M 7 8 2 4 a n d 
P e m br oli z u m a b Ar m s
N ot e f or D o c u m e nt ati o n of A E s h a s 
b e e n u p d at e d t o r ef er t o t h e 
A p p e n di x 6 a n d S e cti o n 7. 1 f or 
f urt h er d et ail s o n A E r e p orti n g
T o c l arif y a n d str e a mli n e 
S e cti o n 1. 3 S c h e d ul e of 
A cti viti e s , T a bl e 1 S c h e d ul e of 
A s s e s s m e nt s - M 7 8 2 4 Ar m , 
T a bl e 2 S c h e d ul e of 
A s s e s s m e nt s –
P e m br oli z u m a b Ar m , T a bl e 3
S af et y a n d L o n g -t er m F oll o w-
u p – M 7 8 2 4 a n d 
P e m br oli z u m a b Ar m s , 
S e cti o n 3 O bj e cti v e s a n d 
e n d p oi nt s , S e cti o n 7. 2 
P arti ci p a nt 
Di s c o nti n u ati o n/ Wi t h dr a w al 
fr o m t h e St u d y
P R O a s s e s s m e nt s h a v e b e e n 
r e m o v e d
P R O a s s e s s m e nt ar e n o l o n g er 
r e q uir e d a n d h a v e b e e n r e m o v e d fr o m 
t h e pr ot o c ol
S e cti o n 1. 3 S c h e d ul e of 
A cti viti e s , Pr e vi o u s T a bl e 2
M 7 8 2 4 Ar m P h ar m a c o ki n eti c a n d 
 S a m pli n g t a bl e h a s 
b e e n d el et e d
C oll e cti o n of P K
 
 
S e cti o n 1. 3 S c h e d ul e of 
A cti viti e s, T a bl e 3 S a f et y a n d 
L o n g -t er m F oll o w-u p – M 7 8 2 4 
a n d P e m br oli z u m a b Ar m s
N ot e a h a s b e e n u p d at e d t o cl arif y 
t h at t h e 1 2-w e e k S af et y F oll o w -u p 
a n d L o n g -t er m f oll o w-u p m a y b e 
c o n d u ct e d vi a t el e p h o n e c all s
F or c o n si st e n c y ( w e e k v s. m o nt h) 
el s e w h er e i n t h e d o c u m e nt 
S e cti o n 2. 3 B e n efit/ Ri s k 
A s s e s s m e nt
T e xt h a s b e e n u p d at e d t o r efl e ct 
t h e ri s k cl a s sifi c ati o n a n d 
mi ni mi z ati o n m e a s ur e s, a n d a 
r ef er e n c e t o t h e I B f or d et ail s of 
i d e ntifi e d a n d p ot e nti al ri s k s f or 
M 7 8 2 4 h a s b e e n a d d e d
T o u p d at e t h e ri s k cl a s sifi c ati o n a n d 
mi ni mi z ati o n m e a s ur e s
a n d r ef er t o 
t h e I B f or f ull s af et y d et ail s
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
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 e cti o n 5 St u d y P o p ul ati o n
Cl arifi e d t h at t h e p arti ci p a nt’ s l e g al 
r e pr e s e nt ati v e m a y pr o vi d e c o n s e nt 
w h er e all o w e d b y l o c al l a w s a n d 
r e g ul ati o n s
F or c o n si st e n c y wit h c urr e nt pr ot o c ol 
t e m pl at e
S e cti o n 6. 8 S p e ci al 
Pr e c a uti o n s
T e xt i n A E SI s u b s e cti o n s h a s b e e n 
u p d at e d a n d m o v e d t o S e cti o n 6. 9
A E SI
T o a v oi d r e pl eti o n a n d str e a mli n e 
pr e s e nt ati o n
S e cti o n 6. 8. 1. 1 A d v er s e 
E v e nt s of S p e ci al 
I nt er e st/I d e ntifi e d Ri s k s
T e xt fr o m ori gi n al 6. 8. 1 t o 6. 8. 5 h a s 
b e e n m o v e d t o S e cti o n 6. 9
( M a n a g e m e nt of A E SI); a cr o s s 
r ef er e n c e t o S e cti o n 6. 9 h a s b e e n 
a d d e d
T o a v oi d r e p etiti o n a n d str e a mli n e 
pr e s e nt ati o n
S e cti o n 6. 8. 1. 2 A d diti o n al 
P ot e nti al Ri s k s
T e xt d e s cri bi n g p ot e nti al ri s k s fr om 
ori gi n al S e cti o n 6. 9 ( A E SI) ar e 
m o v e d t o t hi s s e cti o n a n d u p d at e d 
t o r e m o v e mil d t o m o d er at e 
bl e e di n g a n d a n e mi a a s p ot e nti al 
ri s k
T o a v oi d r e p etiti o n a n d str e a mli n e 
pr e s e nt ati o n a n d t o u p d at e t h e ri s k 
cl a s sifi c ati o n
S e cti o n 6. 9 M a n a g e m e nt of 
A d v er s e E v e nt s of S p e ci al 
I nt er e st
T e xt h a s b e e n m o v e d fr o m ori gi n al 
s e cti o n s 6. 8. 1 t o 6. 8. 5 , a n d ri s k 
cl a s sifi c ati o n a n d mi ni mi z ati o n 
m et h o d s h a v e b e e n u p d at e d , 
ori gi n al S e cti o n 6. 9 i s r e m o v e d
T o u p d at e t h e ri s k cl a s sifi c ati o n a n d 
mi ni mi z ati o n m e a s ur e s
S e cti o n 6. 9. 1 I nf u si o n-r el at e d 
R e a cti o n s I n cl u di n g I m m e di at e 
H y p er s e n siti vit y
T e xt h a s b e e n a d d e d t o cl arif y I R R 
i s A E SI a n d i d e ntifi e d ri s k s f or 
M 7 8 2 4
T o c o n s oli d at e a n d cl arif y t h e t e xt.
S e cti o n 6. 9 . 2 I m m u n e-r el at e d 
A d v er s e E v e nt s
T e xt h a s b e e n u p d at e d t o pr o vi d e 
t h e li st of i m m u n e-r el at e d A Es
A d d e d a r ef er e n c e t o t h e c urr e nt 
N C C N g ui d eli n e
T o u p d at e t h e ri s k cl a s sifi c ati o n
S e cti o n 6. 9 . 3 T G Fβ i n hi biti o n 
m e di c at e d s ki n r e a cti o n s
R e m o v e “ P ot e nti al” fr o m s e cti o n 
titl e.
Cl arifi e d t h at s ki n a s s e s s m e nt s will 
b e p erf or m e d f or all p arti ci p a nt s, 
a n d f or p arti ci p a nt s r e st arti n g 
tr e at m e nt aft er tr e at m e nt 
di s c o nti n u ati o n, a r e b a s eli n e s ki n 
a s s e s s m e nt s h o ul d b e d o n e.
Cl arifi e d t h at s ki n A E s ar e al s o 
A E SI s.
T o u p d at e t h e ri s k cl a s sifi c ati o n a n d 
mi ni mi z ati o n m e a s ur e s
S e cti o n 6. 9. 4 A n e mi a
R e m o v al of “tr e at m e nt -r el at e d” 
fr o m d efi niti o n of a n e mi a A E SI
T o u p d at e t h e ri s k cl a s sifi c ati o n 
S e cti o n 6. 9 . 5 M a n a g e m e nt of 
Bl e e di n g E v e nt s
T e xt r e vi s e d t o s p e cif y t h at 
Bl e e di n g A E s ar e A E SI s a n d ar e 
c o n si d er e d i m p ort a nt i d e ntifi e d r i s k 
f or M 7 8 2 4, a n d n ot a p ot e nti al ri s k
T o u p d at e t h e ri s k cl a s sifi c ati o n a n d 
mi ni mi z ati o n m e a s ur e s
S e cti o n 6. 9. 5. 1 M u c o s al/ N o n-
t u m or bl e e di n g
Cl arifi e d t h at p arti ci p a nt s tr e at e d 
wit h M 7 8 2 4 w er e c o m m o nl y 
r e p ort e d wit h mil d t o m o d er at e 
m u c o s al A E s.
A cti o n s t o b e t a k e n wit h st u d y 
i nt er v e nti o n i n t h e e v e nt of bl e e di n g 
A E s h a v e b e e n u p d at e d
T o u p d at e t h e ri s k cl a s sifi c ati o n a n d 
mi ni mi z ati o n m e a s ur e s
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
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 e cti o n 6. 9 . 5. 2 T u m or 
Bl e e di n g
T e xt a d d e d t o st at e t h at 
p arti ci p a nt s tr e at e d wit h M 7 8 2 4 
w er e r e p ort e d i n l o w er fr e q u e n ci e s
wit h Gr a d e ≥3 h e m orr h a g e 
i n cl u di n g t u m or bl e e di n g
T o u p d at e t h e ri s k cl a s sifi c ati o n a n d 
mi ni mi z ati o n m e a s ur e s
S e cti o n 8. 5 P h ar m a c o ki n eti c s
Pr e vi o u s d e s cri pti o n of P K 
s a m pli n g d el et e d a n d t e xt a d d e d t o 
cl arif y t h at P K s a m pl e s ar e n o 
l o n g er c oll e ct e d i n t h e st u d y
C oll e cti o n of P K s a m pl e s ar e n o 
l o n g er r e q uir e d a n d h a v e b e e n 
r e m o v e d fr o m t h e pr ot o c ol
S e cti o n 8. 9 I m m u n o g e ni cit y 
A s s e s s m e nt s 
Pr e vi o u s d e s cri pti o n of A D A 
s a m pli n g d el et e d a n d t e xt a d d e d t o 
cl arif y t h at A D A s a m pl e s ar e n o 
l o n g er c oll e ct e d i n t h e st u d y
C oll e cti o n of A D A s a m pl e s ar e n o 
l o n g er r e q uir e d a n d h a v e b e e n 
r e m o v e d fr o m t h e pr ot o c ol
S e cti o n 8. 1 0 P ati e nt -r e p ort e d 
O ut c o m e s
S e cti o n h a s b e e n d el et e d 
P R O e v al u ati o n s ar e n o l o n g er 
p erf or m e d i n t hi s st u d y
S e cti o n 9. 3 P o p ul ati o n s f or 
A n al y s e s
P K p o p ul ati o n h a s b e e n r e m o v e d 
fr o m T a bl e 1 3 A n al y si s P o p ul ati o n s
C oll e cti o n of P K/ A D A s a m pl e s i s n o 
l o n g er r e q uir e d a n d h as b e e n 
r e m o v e d fr o m t h e pr ot o c ol
S e cti o n 9. 4. 3 Ot h er A n al y s e s
D e s cri pti o n of P K a n al y s e s 
r e m o v e d a n d t e xt a d d e d t o cl arif y 
t h at P K a n al y s e s will b e p erf or m e d 
o n s a m pl e s c oll e ct e d i n t hi s st u d y 
a s d e s cri e d i n pr e vi o u s v er si o n s of 
t h e pr ot o c ol
C oll e cti o n of P K/ A D A s a m pl e s i s n o 
l o n g er r e q uir e d a n d h as b e e n 
r e m o v e d fr o m t h e pr ot o c ol
A p p e n di x 2 St u d y G o v er n a n c e 
I nf or m e d C o n s e nt Pr o c e s s 
d e s cri pti o n u p d at e d
F or c o n si st e n c y wit h c urr e nt pr ot o c ol 
t e m pl at e
A p p e n di x 6 A d v er s e E v e nt s: 
D efi niti o n s a n d Pr o c e d ur e s f or 
R e c or di n g, E v al u ati n g, F oll o w -
u p, a n d R e p orti n g
T h e c at e g ori e s f or A E SI s h a v e 
b e e n u p d at e d
T o u p d at e t h e ri s k cl a s sifi c ati o n 
- C o nfi d e nti al –
T hi s d o c u m e nt i s t h e pr o p ert y of M er c k K G a A , D ar m st a dt, G er m a n y, or o n e of it s s u b si di ari e s. It i s i nt e n d e d f or 
r e stri ct e d u s e o nl y a n d m a y n ot – i n f ull or p art – b e p a s s e d o n, r e pr o d u c e d, p u bli s h e d or u s e d wit h o ut e x pr e s s 
p er mi s si o n of M er c k K G a A, D ar m st a dt, G er m a n y, or it s s u b si di ar y. C o p yri g ht © 2 0 2 1 b y M er c k K G a A, D ar m st a dt, 
G er m a n y, or it s s u b si di ar y. All ri g ht s r e s er v e d.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
T a ble of C o nte nts
Title Pa ge
.............................................................................................................. 1
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 Hist or y
.............................................................................................................. 2
Pr ot oc ol Versi o n 4. 0 ( 2 2 J u ne 2 0 2 1) ................................................................................... 2
Ta ble of C o nte nts
.............................................................................................................. 6
List of Ta bles
............................................................................................................ 1 0
List of Fi g ures
............................................................................................................ 1 1
1
Pr ot oc ol S u m mar y .............................................................................. 1 2
1. 1
S y n o psis ..............................................................................................1 2
1. 2
Sc he ma ................................................................................................ 1 5
1. 3
Sc he d ule of Acti vi ties......................................................................... 1 6
2
I ntr o d ucti o n......................................................................................... 2 8
2. 2
Bac k gr o u n d .........................................................................................3 0
2. 3
Be nefit/ Ris k Assess me nt.................................................................... 3 2
3
O bje cti ves a n d E n d p oi nts ................................................................... 3 4
4
St u d y  Desi g n....................................................................................... 3 6
4. 1
O verall Desi g n .................................................................................... 3 6
4. 1. 1
Treat me nt Be y o n d Pr o gressi o n ........................................................... 3 7
4. 1. 2
C o nti n uati o n of St u d y  Inter ve nti o n After L ocal Treat me nt of 
Disease Pr o gressi o n ............................................................................ 3 8
4. 2
Scie ntific Rati o nale f or St u d y  Desi g n ................................................ 3 9
4. 2. 1
Re q uire me nt f or P D -L 1 Hi g h Stat us .................................................. 3 9
4. 2. 2
Pe m br oliz u ma b as C o m parat or ........................................................... 3 9
4. 2. 3
O pe n -la bel Desi g n ..............................................................................4 0
4. 2. 4
Stratificati o n ................................ .......................................................4 0
4. 2. 5
P F S a n d O S as t he Pri mar y  E n d p oi nts ...............................................4 0
4. 2. 6
A da pti ve P hase III Desi g n................................ ..................................4 0
4. 3
J ustificati o n f or D ose ..........................................................................4 1
4. 4
E n d of St u d y  Defi niti o n......................................................................4 3
5
St u d y  P o p ulati o n.................................................................................4 3
5. 1
I ncl usi o n Criteria................................ ................................................4 3
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
5. 2
E xcl us i o n Criteria...............................................................................4 6
5. 3
Lifest y le C o nsi derati o ns..................................................................... 4 9
5. 4
Scree n Fail ures .................................................................................... 5 0
6
St u d y  Inter ve nti o n(s) .......................................................................... 5 0
6. 1
St u d y  I nter ve nti o n(s) A d mi nistrati o n................................................. 5 0
6. 2
St u d y  Inter ve nti o n(s) Pre parati o n, Ha n dli n g, St ora ge, a n d 
Acc o u nta bilit y ..................................................................................... 5 1
6. 2. 1
M 7 8 2 4 ................................................................................................. 5 2
6. 2. 2
Pe m br oliz u ma b ................................................................................... 5 2
6. 3
Meas ures t o Mi ni mize Bias: St u d y  Inter ve nti o n Assi g n me nt a n d 
Bli n di n g ..............................................................................................5 2
6. 3. 1
St u d y  Inter ve nti o n Assi g n me nt .......................................................... 5 2
6. 3. 2
Bli n di n g ..............................................................................................5 3
6. 4
St u d y  Inter ve nti o n C o m plia nce .......................................................... 5 3
6. 5
C o nc o mita nt T hera p y ......................................................................... 5 3
6. 5. 1
Per mitte d Me dici nes ........................................................................... 5 3
6. 5. 2
Pr o hi bite d Me dici nes .......................................................................... 5 4
6. 5. 3
Per mitte d/ Pr o hi bite d Pr oce d ures ........................................................ 5 4
6. 5. 4
Ot her I nter ve nti o ns ............................................................................. 5 5
6. 6
D ose Selecti o n a n d M o dificati o n ........................................................ 5 5
6. 7
St u d y  Inter ve nti o n After t he E n d of t he St u d y ................................... 5 5
6. 8
S pecial Preca uti o ns ............................................................................. 5 5
6. 8. 1
S pec ific Pla n ne d Assess me nts............................................................ 5 5
6. 8. 1. 1
A d verse E ve nts of S pecial I nterest/I de ntifie d Ris ks .......................... 5 5
6. 8. 1. 2
A d diti o nal P ote ntial Ris ks .................................................................. 5 5
6. 8. 2
A d verse Dr u g Reacti o ns Re q uiri n g Treat me nt Disc o nti n uati o n ........5 6
6. 9
Ma na ge me nt of A d verse E ve nts of S pecial I nterest ........................... 5 8
6. 9. 1
I nf usi o n-relate d Reacti o ns Incl u di n g I m me diate H y perse nsiti vit y .... 5 8
6. 9. 2
I m m u ne-relate d A d verse E ve nts.........................................................6 0
6. 9. 3
T G F β I n hi biti o n Me diate d S ki n Reacti o ns......................................... 6 2
6. 9. 4
A ne mia ................................................................................................6 3
6. 9. 5
Blee di n g E ve nts ..................................................................................6 4
6. 9. 5. 1
M uc osal/ N o n -t u m or Blee di n g............................................................ 6 4
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
6. 9. 5. 2
T u m or Blee di n g ..................................................................................6 5
7
Disc o nti n uati o n of St u d y I nter ve nti o n a n d Partici pa nt 
Disc o nti n uati o n/ Wit h dra wal ...............................................................6 5
7. 1
Disc o nti n uati o n of St u d y I nter ve nti o n ................................................ 6 5
7. 2
Partici pa nt Disc o nti n uati o n/ Wit h dra wal fr o m t he St u d y ................... 6 6
7. 3
L ost t o F oll o w -u p ............................................................................... 6 7
8
St u d y  Assess me nts a n d Pr oce d ures .................................................... 6 7
8. 1
Efficac y  Assess me nts a n d Pr oce d ures................................................ 6 8
8. 2
Safet y  Assess me nts a n d Pr oce d ures................................................... 6 9
8. 2. 1
Cli nical Safet y  La b orat or y Assess me nts............................................ 6 9
8. 2. 2
Vital Si g ns, P h y sical E xa mi nati o ns, a n d Ot her Assess me nts............. 7 0
8. 3
A d verse E ve nts a n d Seri o us A d verse E ve nts ..................................... 7 1
8. 3. 1
Ti me Peri o d a n d Fre q ue nc y  f or C ollecti n g A d verse E ve nt a n d 
Seri o us A d verse E ve nt I nf or mati o n .................................................... 7 1
8. 3. 2
Met h o d of Detecti n g A d verse E ve nts a n d Seri o us A d verse E ve nts ... 7 1
8. 3. 3
F oll o w -u p of A d verse E ve nts a n d Seri o us A d verse E ve nts ............... 7 1
8. 3. 4
Re g ulat or y  Re p orti n g Re q uireme nts f or Seri o us A d verse E ve nts ..... 7 2
8. 3. 5
Pre g na nc y ........................................................................................... 7 3
8. 4
Treat me nt of O ver d ose ....................................................................... 7 3
8. 5
P har mac o ki netics ................................................................................ 7 4
8. 1 0
Patie nt -re p orte d O utc o mes .................................................................7 8
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
9. 3
P o p ulati o ns f or A nal y ses .................................................................... 8 1
9. 4
Statistical A nal y ses ............................................................................. 8 2
9. 4. 1
Efficac y  A nalys es ............................................................................... 8 2
9. 4. 2
Safe t y A nalys es .................................................................................. 8 6
9. 4. 3
Ot her A nal ys es .................................................................................... 8 7
9. 4. 4
Se q ue nce of A nal ys es ......................................................................... 8 7
1 0
Refere nces ........................................................................................... 8 7
1 1
A p pe n dices ......................................................................................... 9 0
A p pe n di x 1
A b bre viati o ns ...................................................................................... 9 1
A p pe n di x 2
St u d y  G o ver na nce............................................................................... 9 4
A p pe n di x 3
C o ntrace pti o n .................................................................................... 1 0 0
A p pe n di x 4
Pr o hi bite d Tra diti o nal C hi nese Me dici nes ....................................... 1 0 2
A p pe n di x 5
T he Rec o m me n dati o ns f or ir A E Ma na ge me nt, i n Acc or da nce wit h 
t he J oi nt A merica n S ociet y of Cli nical O nc ol o g y Cli nical Practice 
G ui deli nes a n d Nati o nal C o m pre he nsi ve Ca ncer Net w or k ..............1 0 3
Ta ble of Ta bles
1 0 4
A p pe n di x 6
A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E val uati n g, F oll o w -u p, a n d Re p orti n g .............................................. 1 4 2
A p pe n di x 7
Cli nical L a b orat or y Tests ................................................................. 1 4 6
A p pe n di x 9
Pr ot oc ol A me n d me nt Hist or y ........................................................... 1 4 8
A p pe n di x 1 0
S p o ns or Si g nat ure Pa ge .................................................................... 1 5 7
A p pe n di x 1 1
C o or di nati n g I n vesti gat or Si g nat ure Pa ge ........................................ 1 5 8
A p pe n di x 1 2
Pri nci pal I n vesti gat or Si g nat ure Pa ge ............................................... 1 5 9
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
List of T a bles
Ta ble 1
Sc he d ule of Assess me nts – M 7 8 2 4 Ar m ............................................ 1 6
Ta ble 2
Sc he d ule of Assess me nts – Pe m br oliz u ma b Ar m .............................. 2 1
Ta ble 3
Safet y  a n d L o n g-ter m F oll o w-u p – M 7 8 2 4 a n d Pe m br oliz u ma b 
Ar ms ................................................................................................... 2 6
Ta ble 4
Res p o nse Rates of M 7 8 2 4 i n E M R 2 0 0 6 4 7- 0 0 1 Sec o n d -li ne 
N S C L C C o h ort ................................................................................... 2 9
Ta ble 5
Res p o nse Rates of Pe m br oliz u ma b, Ni v ol u ma b, a n d 
Atez oliz u ma b as First -li ne M o n ot hera py f or N S C L C........................ 3 1
Ta ble 6
Res p o nse Rates of Ni v ol u ma b, Pe m br oliz u ma b, a n d 
Atez oliz u ma b as Sec o n d -li ne M o n ot hera py f or N S C L C ................... 3 2
Ta ble 7
St u d y  O bjecti ves a n d E n d p oi nts......................................................... 3 4
Ta ble 8
Treat me nt M o dificati o n f or S y m pt o m s of I nf usi o n-relate d 
Reacti o ns ............................................................................................. 5 9
Ta ble 9
E val uati o n G ui da nce of S us pecte d A ne mia A d verse E ve nts ............. 6 4
Ta ble 1 3
A nal y sis P o p ulati o ns .......................................................................... 8 2
Ta ble 1 4
Efficac y  E n d p oi nts a n d Statistical A nal ysis Met h o ds ........................ 8 4
Ta ble 1 5
Safet y  E n d p oi nts a n d Statistical A nal ysis Met h o ds ........................... 8 6
Ta ble 1 6
Pr ot oc ol -Re q uire d Cli nical La b ora t or y Assess me nts....................... 1 4 6
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
List of Fi g ures
Fi g ure 1
Dia gra m of St u d y Desi g n ................................................................... 1 5
Fi g ure 2
Al p ha re -all ocati o n i n t he c o nfir mat or y h yp ot hesis testi n g ( das he d 
li nes i n dicate t hat all ocati o n is d o ne o nl y w he n t he ori gi nati n g 
h y p ot hesis was reje cte d) ..................................................................... 8 3
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
1
Pr ot oc ol S u m m ar y
1. 1
S y n o psis
Pr ot oc ol Title: A n A da pti ve P hase III, M ultice nter, Ra n d o mize d, O pe n-La bel , C o ntr olle d St u d y 
of M 7 8 2 4 ( bi ntraf us p alfa) vers us Pe m br oliz u ma b as a First -li ne Treat me nt i n Patie nts wit h P D -L 1  
E x pressi n g A d va n ce d N o n -S mall Cell L u n g Ca ncer
S h ort Title: 1 L  N S C L C A da pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u ma b
R ati o n ale: Base d o n t he acce pta ble safet y pr ofile a n d pr o misi n g acti vit y t hat is e n ha nce d at hi g her 
pr o gra m me d deat h -li ga n d 1 ( P D -L 1 ) e x pressi o n le vels i n t u m or cells, t his a da pti ve P hase III st u d y 
is t o e val uate w het her M 7 8 2 4 
i m pr o ves pr o gressi o n -free s ur vi val (P F S ) ti me a n d/ or o verall 
s ur vi val ( O S) c o m pare d wit h pe m br oliz u ma b as a first-li ne (1 L ) treat me nt f or partici pa nts wit h ,
a d va nce d n o n- s mall cell l u n g ca ncer (N S C L C ) wit h P D -L 1  tu m or e x pressi o n . 
 
 
 
 
 
 
 
 
 
 
 
B ot h d ual pri mar y  en d p oi nts P F S a n d O S are e val uate d 
i n a c o nfir mat or y anal ys is t o de m o nstrate t he s u peri orit y of M 7 8 2 4 vers us p e m br oliz u ma b usi n g 
o ne -si de d stratifie d l o g-ra n k tests ta ki n g t he ra n d o mizati o n strata i nt o acc o u nt a n d c o ntr olli n g t he 
o verall si g nifica nce le vel at 2. 5 % o ne -si de d. T he partici pa nts i n t his st u d y m ust n ot ha ve recei ve d 
pri or s y ste mic t hera p y treat me nt f or t heir a d va nce d N S C L C a n d m ust n ot ha ve e pi der mal gr o wt h 
fact or rece pt or ( E G F R) se nsitizi n g (acti vati n g) m utati o n, a na plastic l ym p h o ma ki nase ( A L K) 
tra nsl ocati o n, R O S 1 m utati o n, or B R A F V 6 0 0 E m utati o n, w her e tar gete d t hera p y is l ocall y 
a p pr o ve d.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
O bjecti ves a n d E n d p oi nts:
O bj e cti v e s
E n d p oi nt s ( O ut c o m e M e a s ur e s)
Pri m ar y
T o d e m o n str at e i m pr o v e m e nt i n P F S wit h 
M 7 8 2 4 c o m p ar e d wit h p e m br oli z u m a b 
T o d e m o n str at e i m pr o v e m e nt i n O S wit h M 7 8 2 4 
c o m p ar e d wit h p e m br oli z u m a b
P F S a c c or di n g t o R E CI S T 1. 1 a s s e s s e d b y I R C
O S
S e c o n d ar y
S af et y
T o e v al u at e t h e s af et y a n d t ol er a bilit y of M 7 8 2 4 
c o m p ar e d wit h p e m br oli z u m a b
O c c urr e n c e of T E A E s a n d tr e at m e nt -r el at e d A E s
Effi c a c y
T o e v al u at e t h e o bj e cti v e r e s p o n s e of M 7 8 2 4 
c o m p ar e d wit h p e m br oli z u m a b
O bj e cti v e r e s p o n s e a c c or di n g t o R E CI S T 1. 1 a s s e s s e d b y I R C
T o e v al u at e t h e D O R of M 7 8 2 4 c o m p ar e d wit h 
p e m br oli z u m a b
D O R a s s e s s e d fr o m C R or P R a c c or di n g t o R E CI S T 1. 1 
a s s e s s e d b y I R C u ntil P D, d e at h, or l a st t u m or a s s e s s m e nt
A E = a d v er s e e v e nt; C R = c o m pl et e r e s p o n s e; D O R = d ur ati o n of r e s p o n s e; I R C = I n d e p e n d e nt R e vi e w 
C o m mitt e e; O S = o v er all s ur vi v al; P D = pr o gr e s si v e di s e a s e; P F S = pr o gr e s si o n -fr e e s ur vi v al; P R = p arti al 
r e s p o n s e; R E CI S T = R e s p o n s e E v al u ati o n Crit eri a i n S oli d T u m or s; T E A E = tr e at m e nt- e m er g e nt a d v er s e e v e nt.
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
O ver all Desi g n: T his is a m ultice nter, a da pti ve P hase III, i nter nati o nal, ra n d o mize d, o pe n -la bel, 
c o ntr olle d st u d y of i ntra ve n o us M 7 8 2 4 m o n ot hera p y  vers us pe m br oliz u ma b as 1 L treat me nt f or 
partici pa nts wit h a d va nce d N S C L C wit h hi g h P D -L 1 t u m or e x pressi o n . T he st u d y will recr uit 
partici pa nts w h o ha ve n ot recei ve d pre vi o us treat me nt f or t heir a d va nce d N S C L C f or e xa mi nati o n 
of t he efficac y an d safet y o f M 7 8 2 4 vers us pe m br oliz u ma b .Partici pa nts will be ra n d o mly assi g ne d 
t o treat me nt ar m i n a 1: 1 rati o. P D -L 1 hi g h is defi ne d as ≥ 8 0 % P D -L 1 p ositi ve t u m or cells as 
deter mi ne d b y  t he P D -L 1 i m m u n o hist oc he mistr y (I HC) 7 3- 1 0 assa y. T hese partici pa nts m ust n ot 
ha ve E G F R se nsitizi n g m utati o n or A L K tra nslocati o n, R O S 1 m utati o n, or B R A F V 6 0 0 E m utati o n 
if tar gete d t hera py i s l ocall y a p pr o ve d. Pri mar y  efficac y a nalys is p o p ulati o n is t he f ull a nalys is set 
( F A S) acc or di n g t o t he i nte nti o n-t o-treat (IT T) pri nci ple, i.e., all ra n d o mize d partici pa nts . T he 
a da pti ve trial desi g n pr o vi des pres pecifie d a nal ysis r ules, w hic h all o ws the I n de pe n de nt Data 
M o nit ori n g C o m mittee (I D M C) t o rec o m me n d a n e x pa nsi o n fr o m a n i nitial 3 0 0 partici pa nts i nt o 
a lar ger st u d y wit h a sa m ple size of 5 8 4 partici pa nts i n t otal, i.e. a d di n g 2 8 4 partici pa nts. T he 
I D M C e val uates o bjecti ve res p o nse as assesse d b y the I n de pe n de nt Re vie w C o m mittee (I R C) o n 
t he 7 3- 1 0 P D -L 1 hi g h a nal ysis set restricte d t o partici pa nts ra n d o mize d at least 6 m o nt hs bef ore 
t he data c ut off date. T hat i nteri m a nal ysis ( O R I A) c ut off date is 6 m o nt hs after e nr olli n g t he 1 0 0t h 
partici pa nt teste d 7 3- 1 0 P D -L 1  hi gh. I n t his a nal ysis, t he I D M C will deci de , base d o n O R R 
differe nce bet wee n treat me nt ar ms per st u d y  desi g n, t o eit her kee p t he st u d y r u n ni n g at t he i nitial 
sa m ple size ( N = 3 0 0), e x pa n d t he sa m ple size ( N = 5 8 4), or st o p f or f utilit y. Details of t he 
pre defi ne d criteri a t o e x pa n d t he st u d y t o lar ger sa m ple size will be gi ve n i n t he I D M C c harter.
N u m ber of P artici p a nts: T he i nitial sa m ple size of 3 0 0 ra n d o mize d partici pa nts ma y  be e x pa n de d 
t o a t otal of 5 8 4 ra n d o mize d partici pa nts u p o n pre defi ne d a da ptati o n criteri o n base d o n t he O R I A  
e val uate d b y t he I D M C.
St u d y I nter ve nti o n Gr o u ps a n d D ur ati o n:
Partici pa nts w h o meet t he st u d y criteria will be 
ra n d o ml y assi g ne d i n a 1: 1 rati o t o recei ve eit her:

M 7 8 2 4 at a d ose of 1 2 0 0 m g per i nf usi o n o nce e ver y  2 wee ks, or

Pe m br oliz u ma b at a d ose of 2 0 0 m g per i nf usi o n o nce e ver y  3 wee ks.
I n v ol ve me nt of S peci al C o m mittee(s): Yes
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
1. 2
Sc he m a
Fi g ure 1
Di a gr a m of St u d y Desi g n
Pri or t o 
Pr ot o c ol V . 3. 0, p arti ci p a nt s wit h T P S ≥ 5 0 % a s d et er mi n e d b y t h e P D -L 1 I H C 2 2 C 3 a s s a y p erf or m e d a c c or di n g t o 
l o c al l a b or at or y r e g ul ati o n s pri or t o st u d y e nr oll m e nt w er e al s o eli gi bl e .
N r ef er s t o p arti ci p a nt s r a n d o mi z e d a n d i n cl u d e d i n t h e F A S p o p ul ati o n.
E P = e n d p oi nt; F A S = f ull a n al y si s s et; 1 L = fir st- li n e; I H C = i m m u n o hi st o c h e mi str y; I A = i nt eri m a n al y si s; 
I D M C = I n d e p e n d e nt D at a M o nit ori n g C o m mitt e e; i v = i ntr a v e n o u sl y; N S C L C = n o n -s m all c ell l u n g c a n c er;
O R = o bj e cti v e r e s p o n s e; O R R = o bj e cti v e r e s p o n s e r at e; O S = o v er all s ur vi v al; P D -L 1 = pr o gr a m m e d d e at h- li g a n d 
1; P F S = pr o gr e s si o n -fr e e s ur vi v al; q 2 w = e v er y 2 w e e k s; q 3 w = e v er y 3 w e e k s; R = r a n d o mi z ati o n; 
s q u a m = s q u a m o u s; T P S = t u m or pr o p orti o n s c or e; ℵa d a pt ati o n d e ci si o n b o u n d ar y .
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
1. 3
Sc he d ule of Acti vities
T a ble 1
Sc he d ule of Assess me nts –
M 7 8 2 4 Ar m
M 7 8 2 4 
A s s e s s m e nt
S cr e e ni n g/
B a s eli n e 
A s s e s s m e
nt s
Tr e at m e nt P h a s e
( ±3 d a y s)
E n d -of -Tr e at m e nt
Vi sit
N ot e s
D a y -2 8 t o 
R a n d o mi z a
ti o n
V 1 
V 2 
V 3 
V 4 
V 5 
V 6 
V 7
U ntil 
P D
O n t h e D a y  of or 
Wit hi n 7
D a y s of 
D e ci si o n 
W 1  
W 3  
W 5  
W 7  
W 9
W 1 1  
W 1 3
D 1
D 1 5  
D 2 9  
D 4 3  
D 5 7  
D 7 1  
D 8 5
A d mi ni str ati v e Pr o c e d ur e s
Wr itt e n i nf or m e d 
c o n s e nt
X
T o d et er mi n e t h e m ai n st u d y eli gi bilit y crit eri a 
a h e a d of f ull s cr e e ni n g pr o c e d ur e s, a n I C F will b e 
u s e d .
I n cl u si o n/ 
e x cl u si o n/ 
E nr oll m e nt (if 
eli gi bl e)
X 
X a
E nr oll m e nt will b e aft er t h e c o nfir m ati o n of 
f ulfilli n g all i n cl u si o n crit eri a a n d wit h o ut m at c hi n g 
a n y e x cl u si o n crit eri o n. 
a: C o nfir m ati o n of eli gi bilit y vi a a n a b br e vi at e d 
c h e c kli st i s r e q uir e d pri or t o d o si n g o n W 1 D 1.
D e m o gr a p hi c 
d at a
X
M e di c al hi st or y 
X
D o c u m e nt ati o n 
c o n c o mit a nt 
t h er a p y
X 
X 
X 
X 
X 
X 
X 
X 
2- w e e kl y
X
Pri or a nti c a n c er 
dr u g/r a di ot h er a p y
/ pr o c e d ur e s
X
Vir ol o g y s er ol o g y
( H B V a n d H C V)
X
X b
X b
6 w e e kl y b
b: O nl y a p pli c a bl e t o p arti ci p a nt s wit h a hi st or y of 
H B V or H C V i nf e cti o n
D oc u me nt N o.
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
M 7 8 2 4 
A s s e s s m e nt
S cr e e ni n g/
B a s eli n e 
A s s e s s m e
nt s
Tr e at m e nt P h a s e
( ±3 d a y s)
E n d -of -Tr e at m e nt
Vi sit
N ot e s
D a y -2 8 t o 
R a n d o mi z a
ti o n
V 1 
V 2 
V 3 
V 4 
V 5 
V 6 
V 7
U ntil 
P D
O n t h e D a y  of or 
Wit hi n 7
D a y s of 
D e ci si o n 
W 1  
W 3  
W 5  
W 7  
W 9
W 1 1  
W 1 3
D 1
D 1 5  
D 2 9  
D 4 3  
D 5 7  
D 7 1  
D 8 5
T u m or Bi o p si e s/ Ar c hi v al Ti s s u e C oll e cti o n
Pr etr e at m e nt a n d M 7 8 2 4 Dr u g A d mi ni str ati o n
Pr etr e at m e nt a n d 
M 7 8 2 4 dr u g 
a d mi ni str ati o n
X 
X 
X 
X 
X 
X 
X 
2- w e e kl y
O pti o n al p r e m e di c ati o n wit h a n a nti hi st a mi n e a n d 
wit h p ar a c et a m ol ( a c et a mi n o p h e n) a p pr o xi m at el y 
3 0 t o 6 0 mi n ut e s pri or t o e a c h d o s e (f or e x a m pl e, 
2 5 - 5 0 m g di p h e n h y dr a mi n e a n d 5 0 0-6 5 0 m g 
p ar a c et a m ol i v or or al e q ui v al e nt).
S af et y  As s e s s m e nt s
D o c u m e nt ati o n of 
A E s 
X 
X 
X 
X 
X 
X 
X 
X 
2- w e e kl y
X
S e e A p p e n di x 6 f or s af et y r e c or di n g a n d r e p orti n g
a n d s e e S e cti o n  7. 1 i n c a s e of di s c o nti n u ati o n 
fr o m t h e st u d y i nt er v e nti o n.
P h y si c al 
e x a mi n ati o n
X 
X 
X 
X 
X 
X 
X 
X
6 w e e kl y
X
C o m pl et e P E at s cr e e ni n g; s u b s e q u e nt f o c u s e d 
P E s t o b e p erf or m e d a s p er l o c al st a n d ar d
pr a cti c e.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
M 7 8 2 4 
A s s e s s m e nt
S cr e e ni n g/
B a s eli n e 
A s s e s s m e
nt s
Tr e at m e nt P h a s e
( ±3 d a y s)
E n d -of -Tr e at m e nt
Vi sit
N ot e s
D a y -2 8 t o 
R a n d o mi z a
ti o n
V 1 
V 2 
V 3 
V 4 
V 5 
V 6 
V 7
U ntil 
P D
O n t h e D a y  of or 
Wit hi n 7
D a y s of 
D e ci si o n 
W 1  
W 3  
W 5  
W 7  
W 9
W 1 1  
W 1 3
D 1
D 1 5  
D 2 9  
D 4 3  
D 5 7  
D 7 1  
D 8 5
S ki n a s s e s s m e nt
X
X
X
6 w e e kl y
X
Vit al si g n s
X 
X 
X 
X 
X 
X 
X 
X 
2- w e e kl y
X
I n cl u di n g w ei g ht a n d h ei g ht ( h ei g ht at S cr e e ni n g 
o nl y)
E C O G P S d
X 
X d
X 
X 
X 
X 
X 
X 
2- w e e kl y
X 
d : E C O G P S 0 or 1 i s r e q uir e d at W1 D 1
1 2 -l e a d E C G
X
L a b or at or y  As s e s s m e nt s
H e m at ol o g y a n d 
h e m o st a s e ol o g y
X 
X
X
X
X 
4- w e e kl y
X
D et ail s o n bl o o d t e st s u n d er t hi s c at e g or y i s li st e d 
i n T a bl e 1 6 . S a m pl e s m u st al s o b e dr a w n a n d 
r e s ult s f or c or e c h e mi str y, h e m at ol o g y, a n d 
pr e g n a n c y t e st r e vi e w e d pri or t o d o s e 
a d mi ni str ati o n. F or p arti ci p a nt s w h o m et st u d y 
crit eri a at s cr e e ni n g, b ut W 1 D 1 v al u e s ar e n ot 
wit hi n st u d y crit eri a a n d st u d y c o nti n u ati o n i s 
d e sir e d, di s c u s s wit h t h e M e di c al M o nit or .
C or e s er u m 
c h e mi str y
X
X
X
X 
4- w e e kl y
C or e s er u m c h e mi str y ar e li st e d i n  T a bl e 1 6 .
S a m pl e s m u st al s o b e dr a w n a n d r e s ult s f or c or e 
c h e mi str y, h e m at ol o g y, a n d pr e g n a n c y t e st 
r e vi e w e d pri or t o d o s e a d mi ni str ati o n. F or 
p arti ci p a nt s w h o m et st u d y crit eri a at s cr e e ni n g, 
b ut W 1 D 1 v al u e s ar e n ot wit hi n st u d y crit eri a a n d 
st u d y c o nti n u ati o n i s d e sir e d, di s c u s s wit h t h e 
M e di c al M o nit or.
F ull s er u m 
c h e mi str y P a n el A
X
X
X
X 
4- w e e kl y
X
S e e  T a bl e 1 6 f or i n di vi d u al t e st s i n e a c h 
l a b or at or y p a n el. Bl o o d s a m pl e s m u st al s o b e 
dr a w n a n d r e s ult s f or c or e c h e mi str y p ar a m et er s, 
h e m at ol o g y, a n d pr e g n a n c y t e st r e vi e w e d pri or t o 
d o s e a d mi ni str ati o n.
F ull s er u m 
c h e mi str y P a n el B
X
S e e  T a bl e 1 6 f or i n di vi d u al t e st s i n e a c h 
l a b or at or y p a n el.
Uri n al y si s
X
A s cli ni c all y i n di c at e d
D oc u me nt N o.
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
M 7 8 2 4 
A s s e s s m e nt
S cr e e ni n g/
B a s eli n e 
A s s e s s m e
nt s
Tr e at m e nt P h a s e
( ±3 d a y s)
E n d -of -Tr e at m e nt
Vi sit
N ot e s
D a y -2 8 t o 
R a n d o mi z a
ti o n
V 1 
V 2 
V 3 
V 4 
V 5 
V 6 
V 7
U ntil 
P D
O n t h e D a y  of or 
Wit hi n 7
D a y s of 
D e ci si o n 
W 1  
W 3  
W 5  
W 7  
W 9
W 1 1  
W 1 3
D 1
D 1 5  
D 2 9  
D 4 3  
D 5 7  
D 7 1  
D 8 5
β- h C G pr e g n a n c y 
t e st ( o nl y 
a p pli c a bl e t o 
W O C B P)
X e
X
X
X
X 
4- w e e kl y
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 a uri n e or s er u m s a m pl e 
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 d o si n g of st u d y 
i nt er v e nti o n.
e : If a c o nfir m ati o n of a p arti ci p a nt’ s 
p o st m e n o p a u s al st at u s i s n e c e s s ar y, 
f olli cl e-sti m ul ati n g h or m o n e a n d e str a di ol t e st s will 
b e p erf or m e d at S cr e e ni n g.
Fr e e T 4 a n d T S H
X
X
X
6 w e e kl y
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
M 7 8 2 4 
A s s e s s m e nt
S cr e e ni n g/
B a s eli n e 
A s s e s s m e
nt s
Tr e at m e nt P h a s e
( ±3 d a y s)
E n d -of -Tr e at m e nt
Vi sit
N ot e s
D a y -2 8 t o 
R a n d o mi z a
ti o n
V 1 
V 2 
V 3 
V 4 
V 5 
V 6 
V 7
U ntil 
P D
O n t h e D a y  of or 
Wit hi n 7
D a y s of 
D e ci si o n 
W 1  
W 3  
W 5  
W 7  
W 9
W 1 1  
W 1 3
D 1
D 1 5  
D 2 9  
D 4 3  
D 5 7  
D 7 1  
D 8 5
A E = a d v er s e e v e nt; β- h C G = b et a -h u m a n c h ori o ni c g o n a d otr o pi n; C R = c o m pl et e r e s p o n s e; C R T = c h e m or a di ot h er a p y; 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 o T = E n d -of - Tr e at m e nt; 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 = pr o gr e s si v e di s e a s e; P D -L 1 = pr o gr a m m e d 
d e at h -li g a n d 1; P E = p h y si c al e x a mi n ati o n; P R = p arti al r e s p o n s e; R T = r a di ati o n t h er a p y; 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 = V i sit; W = W e e k ; W O C B P = w o m a n of c hil d b e ari n g p ot e nti al.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
T a ble 2
Sc he d ule of Assess me nts – Pe m br oliz u m a b Ar m
P e m br oli z u m a b 
A s s e s s m e nt
S cr e e ni
n g/
B a s eli n e 
A s s e s s-
m e nt s
Tr e at m e nt P h a s e
( ±3 d a y s)
E n d -of -
Tr e at m e nt
Vi sit
N ot e s
D a y -2 8 
t o 
R a n d o m
i-z ati o n
V 1 
V 2 
V 3 
V 4 
V 5 
V 6 
V 7
U ntil 
P D
O n t h e D a y  of 
or Wit hi n 7 
D a y s  of 
D e ci si o n 
W 1  
W 4  
W 7
W 1 0  
W 1 3  
W 1 6  
W 1 9
D 1
D 2 2  
D 4 3  
D 6 4  
D 8 5
D 1 0 6
D 1 2 7
A d mi ni str ati v e Pr o c e d ur e s
Wr itt e n i nf or m e d 
c o n s e nt
X
T o d et er mi n e t h e m ai n st u d y eli gi bilit y crit eri a 
a h e a d of f ull s cr e e ni n g pr o c e d ur e s, a n I C F will
b e u s e d.
I n cl u si o n/ e x cl u si o n/ 
E nr oll m e nt (if eli gi bl e)
X 
X a
E nr oll m e nt will b e aft er t h e c o nfir m ati o n of 
f ulfilli n g all i n cl u si o n crit eri a a n d wit h o ut 
m at c hi n g a n y e x cl u si o n crit eri o n.
a: C o nfir m ati o n of eli gi bilit y vi a a n a b br e vi at e d 
c h e c kli st i s r e q uir e d pri or t o d o si n g o n W 1 D 1.
D e m o gr a p hi c d at a
X
M e di c al hi st or y 
X
D o c u m e nt ati o n 
c o n c o mit a nt t h er a p y
X 
X 
X 
X 
X 
X 
X 
X 
3- w e e kl y
X
Pri or a nti c a n c er 
dr u g/r a di ot h er a p y/
pr o c e d ur e s
X
Vir ol o g y s er ol o g y
( H B V a n d H C V)
X
X b
X b
X b
6 w e e kl y b
b: O nl y a p pli c a bl e t o p arti ci p a nt s wit h a hi st or y 
of H B V or H C V i nf e cti o n . 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
P e m br oli z u m a b 
A s s e s s m e nt
S cr e e ni
n g/
B a s eli n e 
A s s e s s-
m e nt s
Tr e at m e nt P h a s e
( ±3 d a y s)
E n d -of -
Tr e at m e nt
Vi sit
N ot e s
D a y -2 8 
t o 
R a n d o m
i-z ati o n
V 1 
V 2 
V 3 
V 4 
V 5 
V 6 
V 7
U ntil 
P D
O n t h e D a y  of 
or Wit hi n 7 
D a y s  of 
D e ci si o n 
W 1  
W 4  
W 7
W 1 0  
W 1 3  
W 1 6  
W 1 9
D 1
D 2 2  
D 4 3  
D 6 4  
D 8 5
D 1 0 6
D 1 2 7
Pr etr e at m e nt a n d P e m br oli z u m a b Dr u g A d mi ni str ati o n
P e m br oli z u m a b 
a d mi ni str ati o n
X 
X 
X 
X 
X 
X 
X 
3- w e e kl y
S af et y  As s e s s m e nt s
D o c u m e nt ati o n 
of A E s 
X 
X 
X 
X 
X 
X 
X 
X 
3- w e e kl y
X
S e e A p p e n di x 6 f or s af et y r e c or di n g a n d 
r e p orti n g a n d s e e S e cti o n  7. 1 i n c a s e of 
di s c o nti n u ati o n fr o m t h e st u d y i nt er v e nti o n .
P h y si c al e x a mi n ati o n
X 
X 
X 
X 
X 
X 
X 
X
6 w e e kl y
X
C o m pl et e P E at s cr e e ni n g; s u b s e q u e nt f o c u s e d 
P E s t o b e p erf or m e d a s p er l o c al st a n d ar d
pr a cti c e.
S ki n a s s e s s m e nt
X
X
X
X
6 w e e kl y
X
Vit al si g n s
X 
X 
X 
X 
X 
X 
X 
X 
3- w e e kl y
X
I n cl u di n g w ei g ht a n d h ei g ht ( h ei g ht at S cr e e ni n g 
o nl y)
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
P e m br oli z u m a b 
A s s e s s m e nt
S cr e e ni
n g/
B a s eli n e 
A s s e s s-
m e nt s
Tr e at m e nt P h a s e
( ±3 d a y s)
E n d -of -
Tr e at m e nt
Vi sit
N ot e s
D a y -2 8 
t o 
R a n d o m
i-z ati o n
V 1 
V 2 
V 3 
V 4 
V 5 
V 6 
V 7
U ntil 
P D
O n t h e D a y  of 
or Wit hi n 7 
D a y s  of 
D e ci si o n 
W 1  
W 4  
W 7
W 1 0  
W 1 3  
W 1 6  
W 1 9
D 1
D 2 2  
D 4 3  
D 6 4  
D 8 5
D 1 0 6
D 1 2 7
E C O G P S d
X 
X d
X 
X 
X 
X 
X 
X 
3- w e e kl y
X
d: E C O G P S 0 or 1 i s r e q uir e d at W 1 D 1
1 2 -l e a d E C G
X
L a b or at or y  As s e s s m e nt s
H e m at ol o g y a n d 
h e m o st a s e ol o g y
X 
X 
X 
X 
X 
X
X
6 w e e kl y
X
D et ail s o n bl o o d t e st s u n d er t hi s c at e g or y i s 
li st e d i n T a bl e 1 6 . S a m pl e s m u st al s o b e dr a w n
a n d r e s ult s f or c or e c h e mi str y, h e m at ol o g y, a n d 
pr e g n a n c y t e st r e vi e w e d pri or t o d o s e 
a d mi ni str ati o n. F or p arti ci p a nt s w h o m et st u d y 
crit eri a at s cr e e ni n g, b ut W 1 D 1 v al u e s ar e n ot 
wit hi n st u d y crit eri a a n d st u d y c o nti n u ati o n i s 
d e sir e d, di s c u s s wit h t h e M e di c al M o nit or.
C or e s er u m c h e mi str y
X
X
X
X
6 w e e kl y
C or e s er u m c h e mi str y ar e li st e d i n  T a bl e 1 6 . 
S a m pl e s m u st al s o b e dr a w n a n d r e s ult s f or 
c or e c h e mi str y, h e m at ol o g y, a n d pr e g n a n c y t e st 
r e vi e w e d pri or t o d o s e a d mi ni str ati o n. F or 
p arti ci p a nt s w h o m et st u d y crit eri a at s cr e e ni n g, 
b ut W 1 D 1 v al u e s ar e n ot wit hi n st u d y crit eri a 
a n d st u d y c o nti n u ati o n i s d e sir e d, di s c u s s wit h 
t h e M e di c al M o nit or.
F ull s er u m c h e mi str y
P a n el A
X
X
X
X
6 w e e kl y
X
S e e  T a bl e 1 6 f or i n di vi d u al t e st s i n e a c h 
l a b or at or y p a n el. Bl o o d s a m pl e s m u st al s o b e 
dr a w n a n d r e s ult s f or c or e c h e mi str y 
p ar a m et er s, h e m at ol o g y, a n d pr e g n a n c y t e st 
r e vi e w e d pri or t o d o s e a d mi ni str ati o n. 
F ull s er u m c h e mi str y 
P a n el B
X
S e e  T a bl e 1 6 f or i n di vi d u al t e st s i n e a c h 
l a b or at or y p a n el.
Uri n al y si s
X
A s cli ni c all y i n di c at e d
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
P e m br oli z u m a b 
A s s e s s m e nt
S cr e e ni
n g/
B a s eli n e 
A s s e s s-
m e nt s
Tr e at m e nt P h a s e
( ±3 d a y s)
E n d -of -
Tr e at m e nt
Vi sit
N ot e s
D a y -2 8 
t o 
R a n d o m
i-z ati o n
V 1 
V 2 
V 3 
V 4 
V 5 
V 6 
V 7
U ntil 
P D
O n t h e D a y  of 
or Wit hi n 7 
D a y s  of 
D e ci si o n 
W 1  
W 4  
W 7
W 1 0  
W 1 3  
W 1 6  
W 1 9
D 1
D 2 2  
D 4 3  
D 6 4  
D 8 5
D 1 0 6
D 1 2 7
β- h C G pr e g n a n c y t e st 
( o nl y a p pli c a bl e t o 
W O C B P)
X e
X 
X 
X 
X 
X 
X 
X 
3- w e e kl y
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 a uri n e or s er u m s a m pl e 
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 
d o si n g of st u d y i nt er v e nti o n.
e: If a c o nfir m ati o n of a p arti ci p a nt’ s 
p o st m e n o p a u s al st at u s i s n e c e s s ar y, f olli cl e -
sti m ul ati n g h or m o n e a n d e str a di ol t e st s will b e 
p erf or m e d at S cr e e ni n g.
Fr e e T 4 a n d T S H
X
X
X
X
6 w e e kl y
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
P e m br oli z u m a b 
A s s e s s m e nt
S cr e e ni
n g/
B a s eli n e 
A s s e s s-
m e nt s
Tr e at m e nt P h a s e
( ±3 d a y s)
E n d -of -
Tr e at m e nt
Vi sit
N ot e s
D a y -2 8 
t o 
R a n d o m
i-z ati o n
V 1 
V 2 
V 3 
V 4 
V 5 
V 6 
V 7
U ntil 
P D
O n t h e D a y  of 
or Wit hi n 7 
D a y s  of 
D e ci si o n 
W 1  
W 4  
W 7
W 1 0  
W 1 3  
W 1 6  
W 1 9
D 1
D 2 2  
D 4 3  
D 6 4  
D 8 5
D 1 0 6
D 1 2 7
A E = a d v er s e e v e nt; β - hC G = b et a -h u m a n c h ori o ni c g o n a d otr o pi n; C R = c o m pl et e r e s p o n s e; C R F = c a s e r e p ort f or m; C R T = c h e m or a di ot h er a p y; 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 o T = E n d -of - Tr e at m e nt; 
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; 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
= pr o gr e s si v e di s e a s e; P E = p h y si c al 
e x a mi n ati o n; P R = p arti al r e s p o n s e; R T = r a di ati o n t h er a p y; 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 ; W O C B P = w o m a n of c hil d b e ari n g p ot e nti al .
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
T a ble 3
S afet y a n d L o n g -ter m F oll o w-u p – M 7 8 2 4 a n d Pe m br oliz u m a b Ar ms
M 7 8 2 4 a n d P e m br oli z u m a b
A s s e s s m e nt
S af et y  F oll o w-u p Vi sit
L o n g -t er m F oll o w -u p
N ot e s
2 8 D a y s 
( ± 5 d a ys) aft er 
L a st Tr e at m e nt
1 2 W e e k s 
( ± 2 w e e k s) aft er 
L a st Tr e at m e nt
E v er y  
6 w e e k s 
( ± 1 w e e k)
E v er y  
1 2 w e e k s
( ± 1 w e e k)
D o c u m e nt ati o n c o n c o mit a nt 
t h er a p y
X
X
X
D o c u m e nt ati o n of A E s 
X
X
X
a , b
S e e A p p e n di x 6 f or s af et y r e c or di n g a n d r e p orti n g a n d s e e 
S e cti o n  7. 1 i n c a s e of di s c o nti n u ati o n fr o m t h e st u d y 
i nt er v e nti o n
a: T h e 1 2 -w e e k S af e t y F oll o w -u p a n d L o n g -t er m F oll o w-u p
m a y b e c o n d u ct e d vi a t el e p h o n e c all s
b: S e e S e cti o n  8. 3. 1 f or d efi niti o n of t h e A E R e p orti n g P eri o d 
a n d S e cti o n  8. 3. 3 f or F oll o w- u p of A E s/ S A E s
P h y si c al e x a mi n ati o n
X
F o c u s e d P E s t o b e p erf or m e d a s p er l o c al st a n d ar d pr a cti c e.
S ki n a s s e s s m e nt
X
Vit al si g n s
X
I n cl u di n g w ei g ht 
E C O G P S
X
1 2 -l e a d E C G
X
H e m at ol o g y a n d 
h e m o st a s e ol o g y
X
D et ail s o n bl o o d t e st s u n d er t hi s c at e g or y ar e li st e d i n 
T a bl e 1 6 . S a m pl e s m u st al s o b e dr a w n a n d r e s ult s f or c or e 
c h e mi str y, h e m at ol o g y, a n d pr e g n a n c y t e st r e vi e w e d pri or t o 
d o s e a d mi ni str ati o n
F ull s er u m c h e mi str y P a n el A
X
S e e  T a bl e 1 6 f or i n di vi d u al t e st s i n e a c h l a b or at or y p a n el. 
Uri n al y si s
X
β- h C G pr e g n a n c y t e st
X
β- h C G s h o ul d b e d et er mi n e d fr o m uri n e or s er u m.
Fr e e T 4 a n d T S H
X
S u b s e q u e nt a nti c a n c er 
t h er a p y ( a n y li n e)
X
X
X
S ur vi v al f oll o w -u p
X
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
M 7 8 2 4 a n d P e m br oli z u m a b
A s s e s s m e nt
S af et y  F oll o w-u p Vi sit
L o n g -t er m F oll o w -u p
N ot e s
2 8 D a y s 
( ± 5 d a ys) aft er 
L a st Tr e at m e nt
1 2 W e e k s 
( ± 2 w e e k s) aft er 
L a st Tr e at m e nt
E v er y  
6 w e e k s 
( ± 1 w e e k)
E v er y  
1 2 w e e k s
( ± 1 w e e k)
A E = a d v er s e e v e nt; β- h C G = b et a -h u m a n c h ori o ni c g o n a d otr o pi n; C R F = c a s e r e p ort f or m; C T = c o m p ut e d t o m o gr a p h 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; M RI
= m a g n eti c r e s o n a n c e i m a gi n g; P E
= p h y si c al e x a mi n ati o n; 2 L = s e c o n d -li n e; 
S A E = s eri o u s a d v er s e e v e nt; T 4 = fr ee t h yr o xi n e; 3 L = t hir d li n e; T S H = t h yr oi d-sti m ul ati n g h or m o n e.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
2 8 /1 5 9
2
I ntr o d ucti o n
Bi ntraf us p alfa (M 7 8 2 4 ) is a first-i n-class bif u ncti o nal f usi o n pr otei n t hat c o m bi nes a pr o gra m me d 
deat h -li ga n d 1 ( P D-L 1) a nti b o d y a n d tra nsf or mi n g gr o wt h fact or β ( T G F β) rece pt or II as a T G F β 
ne utralizi n g ‘tra p’ i nt o a si n gle m olec ule.
M 7 8 2 4 is desi g ne d t o tar get P D -L 1 a n d T G F β, 2 maj or mec ha nis ms of i m m u n os u p pressi o n i n t he 
t u m or micr oe n vir o n me nt. T he precli nical data s u g gest t hat M 7 8 2 4 str o n gl y en ha nces a ntit u m or 
acti vit y an d pr ol o n gs s ur vi val i n m o use t u m or m o dels a b o ve the effect of eit her t he a nti-P D -L 1  
a nti b o d y a vel u ma b or t he T G F β Tra p c o ntr ol al o ne (at t he sa me m olarit y as M 7 8 2 4). 
T his o pe n -la bel, a da pti ve P hase III, ra n d o mize d, c o ntr olle d st u d y is t o e val uate w het her M 7 8 2 4 
i m pr o ves pr o gressi o n -free s ur vi val (P F S )
a n d / or o verall s ur vi val (O S )
c o m pare d wit h 
pe m br oliz u ma b . M 7 8 2 4 is i n dicate d as m o n ot hera p y f or partici pa nts wit h a d va nce d n o n- s mall cell 
l u n g ca ncer ( N S C L C) w h ose t u m ors ha ve hi g h P D -L 1 e x pressi o n, wit h n o pri or s yste mic treat me nt 
f or metastatic N S CL C .
C o m plete i nf or mati o n o n t he c he mistr y, p har mac ol o g y , efficac y,  an d safet y of M 7 8 2 4
is i n t he
I n vesti gat or’s Br oc h ure.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
 
 
 
 
 
 
 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
2. 2
B ac k gr o u n d
L u n g ca ncer is t he lea di n g ca use of ca ncer deat h i n t he U S A a n d res ults i n m ore ca ncer deat hs t ha n 
breast ca ncer, pr ostate ca ncer, a n d c ol orectal ca ncer c o m bi ne d. N o n -s mall cell l u n g ca ncer 
acc o u nts f or a p pr o xi matel y 8 0 % of all cases of l u n g ca ncer. It is esti mate d i n 2 0 1 8 t here w o ul d be 
2 3 4, 0 3 0 ne w cases of l u n g a n d br o nc h us ca ncer a n d 1 5 4, 0 5 0 pe o ple w o ul d die fr o m t heir l u n g 
ca ncers i n t he U S A al o ne ( Sie gel, 2 0 1 8). I n the E U, 2 7 5, 7 0 0 deat hs d ue t o l u n g ca ncer were 
pre dicte d i n 2 0 1 7 (Mal vezzi, 2 0 1 7 ). W orl d wi de, a n esti mate d 1. 8 milli o n ne w cases of l u n g ca ncer 
were dia g n ose d i n 2 0 1 2, a p pr o xi matel y 13 % of t he t otal of all ne w ca ncers dia g n ose d (Ferla y , 
2 0 1 3 ). 
I m m u ne c hec k p oi nt i n hi bit ors ha ve s h o w n i m pr o ve d treat me nt o utc o me i n patie nts wit h N S C L C;
h o we ver, t here is r o o m t o f urt her i m pr o ve be nefits. 
Pe m br oliz u ma b has bee n a p pr o ve d as a 1 L m o n ot hera p y  for patie nts wit h metastatic N S C L C
w h ose T P S is ≥ 5 0 % (as deter mi ne d b y  t he P D -L 1 I HC 2 2 C 3 p har m D x assa y) a n d ne gati ve f or 
E G F R a n d A L K ge n o mic t u m or a berrati o ns base d o n t he K E Y N O T E -0 2 4 st u d y. I n t his P D -L 1
hi g h p o p ulati o n, pe m br oliz u ma b s h o we d 1- ye ar O S of 7 0 %, me dia n P F S of 1 0. 3 m o nt hs a n d O R R 
of 4 5 % (Rec k, 2 0 1 6 ). Preli mi nar y  res ults fr o m t he K E Y N O T E -0 4 2 ( P hase III st u d y of 
pe m br oliz u ma b vers us c he m ot hera p y i n P D -L 1 + a d va nce d N S C L C) i n dicate t hat t he st u d y met its 
pri mar y  e n d p oi nt of O S a n d wo ul d be s u b mitte d t o re g ulat or y  a ut h orities (Merc k, 2 0 1 8 ).
F urt her st u d y data f or K E Y N O T E -0 4 2 were n ot discl ose d at t he ti me of t his pr ot oc ol. T he k n o w n 
res ults of pe m br oliz u ma b, ni v ol u ma b , a n d atez oliz u ma b as 1 L m o n ot hera p y f or N S C L C are 
s u m marize d i n Ta ble 5 .
D oc u me nt N o.
O bject N o.
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
T a ble 5
Res p o nse R ates of Pe m br oliz u m a b, Ni v ol u m a b, a n d Atez oliz u m a b as
First -li ne M o n ot her a p y f or N S C L C
K E Y N O T E -0 2 4 
C h e c k m at e -0 2 6
BI R C H
T P S ≥ 5 0 %
N = 1 5 4
≥5 %
P D -L 1 +
N = 2 0 8
≥5 0 %
P D -L 1 +
N = 8 8
≥5 %  P D-L 1 +
( T C or I C)
N = 1 3 9
≥5 0 %  P D-L 1 +
( T C or I C)
N = 6 5
O R R 
( 9 5 % CI)
4 4. 8 %
( 3 6. 8 t o 5 3. 0)
2 6 %
( 2 0 t o 3 3)
3 4 %
( 2 4 t o 4 5)
2 2 %
( 1 5 t o 2 9)
3 1 %
( 2 0 t o 4 3)
m P F S ( m o nt h s) 
( 9 5 % CI)
1 0. 3
( 6. 7 t o N R )
4. 2
( 3. 0 t o 5. 6)
5. 4
5. 4
( 3. 0 t o 6. 9)
5. 6
( 2. 7 t o 8. 3)
m O S ( m o nt h s)
( 9 5 % CI)
N R
1 4. 4
( 1 1. 7 t o 1 7. 4)
1 5. 9
2 0. 1
( 2 0. 1 t o N E)
N R
(R e c k, 2 0 1 6 ; C ar b o n e, 2 0 1 7 ; P et er s, 2 0 1 7 )
I C = t u m or i nfilt r ati n g i m m u n e c ell s; m O S
= m e di a n o v er all s ur vi v al; m P F S
= m e di a n pr o gr e s si o n- fr e e s ur vi v al;
N E = n ot e v al u at e d; N R = n ot r e p orte d ; O R R = o bj e cti v e r e s p o n s e r at e ; 
 
T C = t u m or c ell s; T P S = t u m or pr o p orti o n s c or e.
I n t he 2 L setti n g w here partici pa nts ha d disease pr o gressi o n f oll o wi n g plati n u m -c o ntai ni n g 
c he m ot hera p y a n d, if a p pr o priate, tar gete d t hera p y f or E G F R or A L K ge n o mic t u m or a berrati o ns, 
a nti-P D - 1 a nti b o dies, O p di v o ® ( ni v ol u ma b) a n d Ke y tr u da ® ( pe m br oliz u ma b), a n d 
 
a nti b o dies, Tece ntri q ™ (atez oliz u ma b) ha ve bee n a p pr o ve d as m o n ot hera p y . T he res p o nse rates 
of t he a p pr o ve d P D -( L) i n hi bit ors use d as t he 2 L  treat me nt f or N S C L C partici pa nts are 
s u m marize d i n Ta ble 6 .
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
T a ble 6
Res p o nse R ates of Ni v ol u m a b, Pe m br oliz u m a b, a n d Atez oliz u m a b as 
Sec o n d- li ne M o n ot her a p y f or N S C L C
C h e c k m at e -0 5 7
C h e c k m at e -0 1 7
K E Y N O T E -0 1 0
P O P L A R
All 
C o m er
N = 2 9 2
> 5 0 %  
P D -L 1 + 
N = 6 6
All 
C o m er
N = 1 3 5
> 5 0 %  
P D -L 1 + 
N = 1 7
T P S ≥ 1 %
2, 1 0 m g/ k g
N = 3 4 4, 3 4 6
T P S ≥ 5 0 %
2, 1 0 m g/ k g
N = 1 3 9, 1 5 1
All C o m er
N = 1 4 4
≥ 5 0 %  P D-
L 1 +
T C or I C)
O R R 
1 9 %
( 1 5 t o 
2 4)
4 1 
( 2 9 t o 
5 4)
2 0 %
( 1 4 t o 
2 8)
2 9 % 
( 1 0 t o 
5 6)
1 8. 0 %, 1 9 %
3 0 %, 2 9 %
1 4. 6 % 
3 7. 5 %
m P F S 
2. 1
( 1. 2 t o 
8. 6)
N R
3. 5
( 2. 1 t o 
4. 9)
N R
3. 9 
( 3· 1 t o 4· 1),
4. 0 
( 2· 7 t o 4· 3)
5. 0 
( 4· 0 t o 6· 5),
5. 2
( 4· 1 t o 8· 1)
2. 7
( 2 t o 4. 1)
7. 8
( 2. 7 t o 1 2. 3)
m O S
( 9 5 % CI)
1 2. 2
( 9. 7 t o 
1 5. 0)
N R
9. 2
( 7. 3 t o 
1 3. 3)
N R
1 0. 4
( 9· 4 t o 1 1· 9),
1 2. 7
( 1 0· 0 t o 
1 7· 3)
1 4. 9
( 1 0· 4 t o N E)
1 7. 3
( 1. 8 t o N E)
1 2· 6
( 9· 7 t o 
1 6· 4)
1 5· 5
( 9· 8 t o N E)
(Br a h m er, 2 0 1 5 ; B or g h a ei, 2 0 1 5 ; H er b st, 2 0 1 6 ; F e hr e n b a c h er, 2 0 1 6 )
I C = t u m or i nfiltr ati n g i m m u n e c ell s; m O S =
m e di a n o v er all s ur vi v al; m P F S = m e di a n pr o gr e s si o n -fr e e s ur vi v al; 
N E = n ot e v al u at e d; N R = n ot r e p ort e d; O R R = o bj e cti v e r e s p o n s e r at e ;
 
T C = T u m or c ell s; T P S = t u m or pr o p orti o n s c or e.
T he cli nical pr ofile of M 7 8 2 4 is bei n g e val uate d i n 2 o n g oi n g P hase I st u dies (E M R 2 0 0 6 4 7 - 0 0 1
a n d M S 2 0 0 6 4 7 -0 0 0 8) i n partici pa nts wit h vari o us s oli d t u m ors. See t he M 7 8 2 4 I nvesti gat or’s 
Br oc h ure f or a s u m mar y  of cli nical st u dies c o n d ucte d t o date. M 7 8 2 4 c o nsiste ntl y  s h o we d hi g her 
O R Rs i n 2 L  NS C L C all-c o mers, 
 
c o m pare d wit h 
t h ose of ot her patie nt deri ve d xe n o graft 
(P D x )
i n hi bit ors, i ncl u di n g 
pe m br oliz u ma b, t h us j ustif yi n g t he cli nical i n vesti gati o n of M 7 8 2 4 
i n 1 L  NS C L C. D ura ble 
res p o nses wit h M 7 8 2 4 were o bser ve d.
2. 3
Be nefit/ Ris k  Assess me nt
M 7 8 2 4 is a first-i n-class bif u ncti o nal m olec ule tar geti n g 2 i m m u n os u p pressi ve pat h wa y s i n t he 
t u m or micr oe n vir o n me nt: t he P D -1/ P D -L 1 a xis a n d T G F β. I n E M R 2 0 0 6 4 7 - 0 0 1, t he res p o nse rates 
i n be nefit of M 7 8 2 4 i n 2 L N S C L C partici pa nts are s u bsta ntiall y better tha n hist orical c o ntr ols a n d 
are f urt her i m pr o ve d wit h hi g her P D -L 1  tu m or e x pressi o n. It is a ntici pate d t hat res p o nse rates 
w o ul d i m pr o ve f urt her w he n m o vi n g fr o m pretreate d disease t o treat me nt-naï ve partici pa nts, as 
was see n i n pe m br oliz u ma b bet wee n K E Y N O T E - 0 1 0 a n d K E Y N O T E -0 2 4. I mpr o vi n g res p o nse 
a n d s ur vi val i n t his patie nt p o p ulati o n will be mea ni n gf ul as res p o nses t o i m m u n ot hera p y are 
k n o w n t o be d ura ble, a n d t hera pe utic, n o n- c yt ot o xic o pti o ns are li mite d i n t hese patie nts wit h o ut 
acti o na ble t u m or m utati o ns. 
T his st u d y  will ra n d o ml y assi g n participa nts 1: 1 bet wee n M 7 8 2 4 a n d pe m br oliz u ma b t o e val uate 
w het her cli nical efficac y ca n be i m pr o ve d si nce K E Y N O T E -0 2 4. T his gl o bal st u d y will i ncl u de 
c o u ntries wit h a n d wit h o ut a p pr o val of 1 L  pe m br oliz u ma b, i ncreasi n g access t o t his life-e xte n di n g 
class of dr u gs. A n earl y f utilit y anal y sis base d o n res p o nse rate is pla n ne d 6 m o nt hs after t he 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
e nr oll me nt of t he first 1 0 0 partici pa nts wit h hi g h P D -L 1  ex pressi o n acc or di n g t o 7 3 - 1 0 assa y t o 
e ns ure M 7 8 2 4 acti vit y is at least c o m para ble t o pe m br oliz u ma b i n t his 1 L  setti n g. If pre -s pecifie d
efficac y
res ults are
o bser ve d at t his a nal ysis, t he sa m ple size ma y 
be i ncrease d u p o n 
rec o m me n dati o n of t he I n de pe n de nt Data M o nit ori n g C o m mittee I D M C (Secti o n  9 ).
Pri or t o 2 4 Se pte m ber 2 0 1 9, partici pa nts c o ul d be e nr olle d i n t his st u d y base d o n P D -L 1  ex pressi o n 
res ults usi n g eit her pre -e xisti n g l ocal 2 2 C 3 res ults or 7 3- 1 0 ce ntral res ults. As t he st u d y pr ot oc ol 
all o we d t o li mit t he n u m ber of partici pa nts e nr olle d wit h pri or l ocal 2 2 C 3 P D -L 1  test res ults (see 
S ecti o n 9. 2 ), o n 2 4 Se pte m ber 2 0 1 9, i n vesti gat ors were n otifie d t hat ne w partici pa nts c o ul d be 
e nr olle d o nl y  base d o n t he 7 3- 1 0 assa y ce ntral res ults. T here is a p ote ntial ris k t hat s o me 
partici pa nts wit h a hi g h P D -L 1  res ult usi n g t he 7 3 -1 0 assa y wo ul d ha ve a res ult of < 5 0 % T P S 
usi n g t he 2 2 C 3 assa y gi ve n t he p ositi ve perce nt a gree me nt bet wee n t he 2 assa ys i n pr oc ure d 
N S C L C t u m or sa m ples is 8 0 % ( 9 5 % c o nfi de nce i nter val [CI ]: 6 3. 1, 9 1. 6) w he n usi n g 7 3 - 1 0 as t he 
n o n- refere nce sta n dar d (see Secti o n 2. 1). T his ma y  res ult i n treat me nt of partici pa nts ra n d o mize d 
t o t he pe m br oliz u ma b ar m at a P D -L 1  le vel of < 5 0 % T P S o utsi de of t he c urre nt E U la bel f or 
pe m br oliz u ma b ; h o we ver, t his ris k f or partici pa nts is mi ni mal: t u m or sa m ples fr o m partici pa nts 
e nr olle d i n St u d y M S 2 0 0 6 4 7 -0 0 3 7 wit h hi g h P D -L 1 e x pressi o n base d o n ce ntral 7 3- 1 0 assa y 
res ults were retr os pecti vel y teste d wit h t he V E N T A N A P D -L 1 Assa y  (S P 2 6 3 Assa y ), w hic h has 
si milar a nal ytical perf or ma nce c haracteristics i n N S C L C c o mpare d wit h t he 2 2 C 3 assa y an d is 
C E -mar ke d i n t he E U f or use wit h pe m br oliz u ma b i n 1 L  NS C L C. T he retr os pecti ve testi n g was 
c o n d ucte d i n sa m ples fr o m 6 9 partici pa nts ra n d o mize d i n t his st u d y o n or bef ore 2 3 Oct o ber 2 0 1 9 
( data o n file). Of t he 6 9 sa m ples teste d, 6 6 ge nerate d vali d res ults wit h t he S P 2 6 3 assa y, w hic h 
i ncl u de d 6 5 p ositi ve res ults a n d 1 ne gati ve res ult. T he p ositi ve perce nt a gree me nt bet wee n t he 
7 3- 1 0 assa y an d t he S P 2 6 3 assa y usi n g 7 3 - 1 0 as t he n o nrefere nce sta n dar d is 9 8. 5 % ( 9 5 % CI : 9 1. 8, 
1 0 0. 0).  T he 1 disc or da nt sa m ple ha d P D -L 1  e x pressi o n i n 9 0 % of t u m or cells base d o n t he 7 3-1 0 
assa y an d 3 0 % of t u m or cells base d o n t he S P 2 6 3 assa y. T he hi g h p ositi ve perce nt a gree me nt 
( 9 8. 5 %) bet wee n t he 7 3- 1 0 assa y an d t he S P 2 6 3 
assa y in partici pa nts e nr olle d i n 
St u d y M S 2 0 0 6 4 7 - 0 0 3 7 s u g gests t hat usi n g t he 7 3- 1 0 assa y for partici pa nt selecti o n i n t his st u d y 
has ver y  lo w ris k of e nr olli n g partici pa nts o utsi de of t he c urre nt E U la bel f or pe m br oliz u ma b 
treat me nt.
T he i de ntifie d a n d p ote ntial safet y ris ks wit h M 7 8 2 4 were o verall ma na gea ble a n d m o nit ora ble. 
N o ne w safety si g nals e mer ge d i n t he E M R 2 0 0 6 4 7 - 0 0 1/M S 2 0 0 6 4 7 - 0 0 0 8 st u dies c o m pare d wit h 
pri or t hera pies tar geti n g P D -L 1  or T G F β. T he e mer ge nce of a n ir A E is a n i de ntifie d ris k f or b ot h 
M 7 8 2 4 a n d pe m br oliz u ma b. T he fre q ue nc y an d se verity of ir A Es were c o m para ble bet wee n 
partici pa nts treate d wit h M 7 8 2 4 at 5 0 0 m g a n d 1 2 0 0 m g, a n d si milar t o ot her P D -( L) 1 tar geti n g 
dr u gs, i ncl u di n g pe m br oliz u ma b. N o i ncrease d ir A E ris k was o bser ve d wit h M 7 8 2 4 
d ue t o 
bl oc ki n g 2 i m m u n os u p pressi ve pat h wa ys. 
Der mat ol o gic A Es relate d t o T G F β -i n hi biti o n (i ncl u di n g kerat oaca nt h o mas ( K A) a n d c uta ne o us 
s q ua m o us cell ca ncers) are a n i de ntifie d ris k wit h M 7 8 2 4 n ot see n wit h pe m br oliz u ma b . T hese 
lesi o ns were pre vi o usly o bser ve d i n i n di vi d uals wit h ge netic m utati o ns i n t he T G F β rece pt or (i .e.,
Fer g us o n -S mit h S y n dr o me), a n d partici pa nts treate d wit h t he T G F β -tar geti n g a ge nt, fres oli m u ma b 
(G o u die, 2 0 1 1 ; M orris, 2 0 1 4 ). I n t he E M R 2 0 0 6 4 7 - 0 0 1/M S 2 0 0 6 4 7 - 0 0 0 8 st u dies, t hese lesi o ns 
were o bser ve d i n a p pr o xi matel y  7 % of partici pa nts , were well- ma na ge d wit h si m ple e xcisi o n ( or 
s p o nta ne o us res ol uti o n) a n d di d n ot re q uire a n y p artici pa nt t o disc o nti n ue treat me nt. T he ris k of 
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
t hese lesi o ns wit h M 7 8 2 4 was c o nsi dere d ma na gea ble o n t his st u d y, es peciall y in t he c o nte xt of 
cli nical acti vit y a gai nst a n a d va nce d ca ncer.
T he ris ks f or M 7 8 2 4 are u p date d base d o n t he p o ole d safety data fro m 7 6 5 patie nts treate d wit h 
M 7 8 2 4 
m o n ot hera p y  i n t he I nvesti gat or’s Br oc h ure
Versi o n 
7. 0 ( A pril 2 0 2 1). T he ris k 
classificati o ns are re vise d i n t his a me n d me nt, see Secti o n 6. 9 f or s pecifics.
I de ntifie d a n d p ote ntial ris ks of t hese dr u gs will be cl osel y mo nit ore d i n b ot h treat me nt ar ms, al o n g 
wit h t he m o nit ori n g of all A Es . Ma na ge me nt g ui da nce is o utli ne d i n t his pr ot oc ol f or s pecific ris ks, 
b ut direct g ui da nce via c o m m u nicati o n wit h st u d y me dics is al wa y s a vaila ble. O verall, t he safety 
pr ofile of b ot h dr u gs is ma na gea ble . C o nsi deri n g t he o bser ve d efficac y  of M 7 8 2 4
i n N S C LC a n d 
acce pta ble safet y pr ofile, t he be nefit/ris k assess me nt a p pears fa v ora ble t o c o n d uct t his st u d y .
M ore 
detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d reas o na bly 
e x pecte d A Es
of M 7 8 2 4
ma y  be f o u n d i n Secti o n 4. 2 a n d t he I nvesti gat or’s Br oc h ure.
See 
Secti o ns 6. 9 a n d 6. 8 f or ma na ge me nt of A E SI s a n d s pecial preca uti o ns, res pecti vel y.
Base d o n t he a vaila ble n o ncli nical a n d cli nical data t o date, t he c o n d uct of t he st u d y, as s pecifie d 
i n t his pr ot oc ol, is c o nsi dere d j ustifia ble.
3
O bjecti ves a n d E n d p oi nts
T he o bjecti ves a n d e n d p oi nts are defi ne d i n  Ta ble 7 . E n d p oi nt assess me nts are i n Secti o n  8.
T a ble 7
St u d y O bjecti ves a n d E n d p oi nts
O bj e cti v e s
E n d p oi nt s ( O ut c o m e M e a s ur e s)
Pri m ar y
T o d e m o n str at e i m pr o v e m e nt i n P F S wit h 
M 7 8 2 4 c o m p ar e d wit h p e m br oli z u m a b
T o d e m o n str at e i m pr o v e m e nt i n O S wit h 
M 7 8 2 4 c o m p ar e d wit h p e m br oli z u m a b
P F S a c c or di n g t o R E CI S T 1. 1 a s s e s s e d b y I R C 
O S
S e c o n d ar y
S af et y
T o e v al u at e t h e s af et y a n d t ol er a bilit y of 
M 7 8 2 4 c o m p ar e d wit h p e m br oli z u m a b
O c c urr e n c e of T E A E s a n d tr e at m e nt -r el at e d A E s 
Effi c a c y
T o e v al u at e t h e effi c a c y i n o bj e cti v e 
r e s p o n s e of M 7 8 2 4 c o m p ar e d wit h 
p e m br oli z u m a b
O bj e cti v e r e s p o n s e a c c or di n g t o R E CI S T 1. 1 a s s e s s e d b y I R C
T o e v al u at e t h e d ur ati o n of r e s p o n s e 
( D O R) of M 7 8 2 4 c o m p ar e d wit h 
p e m br oli z u m a b
D O R a s s e s s e d fr o m C R or P R a c c or di n g t o R E CI S T 1. 1 a s s e s s e d b y 
I R C u ntil P D, d e at h, or l a st t u m or a s s e s s m e nt
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
L o n g -t er m f oll o w-u p of s ur vi v al f or 5 y e ar s aft er t h e l a st d o s e of M 7 8 2 4 or p e m br oli z u m a b i n a p arti ci p a nt u nl e s s 
r e p ort e d a s l o st t o f oll o w-u p, h a d di e d, or t h e st u d y i s t er mi n at e d.
A E = a d v er s e e v e n t; C R = c o m pl et e r e s p o n s e; D O R = d ur ati o n of r e s p o n s e; 
; 
; I R C = I n d e p e n d e nt R e vi e w C o m mitt e e; 
 
; 
O R R = o bj e cti v e r e s p o n s e r at e; O S = o v er all s ur vi v al; P D = pr o gr e s si v e di s e a s e; 
 1; P F S = pr o gr e s si o n -fr e e s ur vi v al; s ur vi v al; 
 
P R = p arti al r e s p o n s e; R E CI S T = R e s p o n s e E v al u ati o n Crit eri a i n S oli d T u m or s; T E A E = tr e at m e nt- e m er g e nt 
a d v er s e e v e nt; 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
4
St u d y Desi g n
4. 1
O ver all Desi g n
T he o verall st u d y desi g n is s h o w n i n Fi g ure 1 . Detaile d sc he d ules of st u d y pr oce d ures/assess me nts 
are pr o vi de d i n Secti o n  8 a n d in  Ta ble 1 a n d Ta ble 2 f or t he M 7 8 2 4 a n d pe m br oliz u ma b treat me nt 
ar ms, res pecti vel y. See Secti o n  6. 7 f or details of st u d y i nter ve nti o n after t he e n d of t he st u d y.
T his is a m ultice nter, a da pti ve P hase III, i nter nati o nal, ra n d o mize d, o pe n -la bel, c o ntr olle d st u d y 
of i ntra ve n o us (i v) M 7 8 2 4 m o n o t hera py vers us pe m br oliz u ma b as 1 L  treat me nt f or partici pa nts 
wit h a d va nce d N S C L C wit h hi g h P D -L 1 -t u m or e x pressi o n . T he st u d y will e nr oll partici pa nts w h o 
ha ve n ot recei ve d pre vi o us treat me nt f or t heir a d va nce d N S C L C f or e xa mi nati o n of t he efficac y 
a n d safet y of M 7 8 2 4 vers us pe m br oliz u ma b. Partici pa nts will be ra n d o ml y assi g ne d t o treat me nt 
ar m i n a 1: 1 rati o. P D -L 1 hi g h is defi ne d as ≥ 8 0 % P D -L 1 p ositi ve t u m or cells as deter mi ne d b y  
t he P D -L 1  I H C 7 3- 1 0 assa y. T hese partici pa nts m ust n ot ha ve E G F R se nsitizi n g m utati o n or A L K 
tra nsl ocati o n, R O S 1 m utati o n, or B R A F V 6 0 0 E m utati o n if tar gete d t hera p y is l ocall y ap pr o ve d. 
T he a da pti ve trial desi g n pr o vi des pres pecifie d decisi o n r ules, w hic h all o w t he I D M C t o
rec o m me n d a n e x pa nsi o n fr o m i nitial 3 0 0 partici pa nts i nt o a lar ger st u d y wit h a sa m ple size of 5 8 4 
partici pa nts i n t otal, i.e. a d di n g 2 8 4 partici pa nts. Refer t o Secti o n 4. 2. 6 f or f urt her details o n 
a da pti ve P hase III desi g n. Partici pa nts w h o meet t he st u d y criteria will be ra n d o ml y assi g ne d i n a 
1: 1 rati o t o recei ve eit her:

M 7 8 2 4 at a d ose of 1 2 0 0
m g per i nf usi o n o nce e ver y  2 wee ks ( q 2 w), or

Pe m br oliz u ma b at d ose of 2 0 0 m g per i nf usi o n o nce e ver y  3 wee ks ( q 3 w).
T he partici pa nts will be stratifie d acc or di n g t o t u m or hist ol o g y  (n o n s q ua m o us vers us s q ua m o us) 
a n d s m o ki n g hist or y as f oll o ws:

S q ua m o us hist ol o g y

N o ns q ua m o us hist ol o g y  a n d ne ver s m o ke d

N o ns q ua m o us hist ol o g y  a n d e ver s m o ker (i.e, f or mer or c urre nt).
T his st u d y  i ncl u des: 

2 8- d a y  Scree ni n g peri o d

Treat me nt u ntil c o nfir me d pr o gressi ve disease ( P D) per Res p o nse E val uati o n Criteria i n S oli d 
T u m ors V ersi o n 1. 1 ( R E CI S T 1. 1), u nacce pta ble t o xicit y, or f or u p t o 2 4 m o nt hs. I n the case 
of P D, treat me nt ma y  co nti n ue past t he i nitial deter mi nati o n of P D or c o nfir me d P D if t he 
partici pa nt's Easter n C o o perati ve O nc ol o g y  Gr o u p P erf or ma nce S tat us ( 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 I nvesti gat or, t he partici pa nt will be nefit fr o m 
c o nti n ue d treat me nt a n d if ot her criteria are f ulfille d as o utli ne d i n t his pr ot oc ol ( Secti o ns 5. 1
a n d 5) . Partici pa nts i n eit her c o h ort w h o e x perie nce sta ble disease (S D ), partial res p o nse ( P R ), 
or c o m plete res p o nse (C R ) s h o ul d c o nti n ue treat me nt u ntil t he e n d of 2 4 m o nt hs, alt h o u g h 
a d diti o nal treat me nt ma y be p ossi ble. If t he I n vesti gat or belie ves t hat a partici pa nt will be nefit 
fr o m treat me nt b e y o n d 2 4 m o nt hs, it ma y  be per missi ble after disc uss i o n wit h t he Me dical 
M o nit or a n d t he S p o ns or Me dical Res p o nsi ble. Of n ote, pe m br oliz u ma b is o nl y  all o we d f or 
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
2 4 m o nt hs per re g ulat or y (F D A, E M A) la bels; t heref ore, e xte n uati n g circ u msta nces a n d 
o utsta n di n g j ustificati o n m ust be d oc u me nte d t o s u p p ort treat m e nt be yo n d 2 4 m o nt hs i n eit her 
ar m.

Safet y  foll o w - u p Visit s u ntil 1 2 wee ks after t he last d ose of M 7 8 2 4 or pe m br oliz u ma b ( Safet y 
F oll o w - u p Visit at 1 2 wee ks is all o we d via tele p h o ne call) .

S ur vi val f oll o w-u p u p t o 5 years wit h visits (i n pers o n or b y  ph o ne call) e ver y 1 2 wee ks after 
t he last d ose of M 7 8 2 4 or pe m br oliz u ma b u nless re p orte d as l ost t o f oll o w- u p, dea d , or after 
st u d y ter mi nati o n (rec o m me n de d e ver y 6 wee ks o n 2 L treat me nt as bel o w).

Partici pa nts w h o start 2 L treat me nt s h o ul d be m o nit ore d f or res p o nse t o t hat treat me nt. 
I n vesti gat ors s h o ul d f oll o w l ocal cli nical practice f or m o nit ori n g disease stat us o n s u bse q ue nt 
li nes of t hera p y. T he st u d y tea m e nc o ura ges a n d re q uest s sca ns t o be perf or me d e very 6 wee ks, 
if feasi ble, i n a dditi o n t o a sca n wit hi n 2 8 da ys pri or t o starti n g 2 L treat me nt. T hese e val uati o ns 
s h o ul d be d oc u me nte d by t he I n vesti gat or a n d u pl oa de d t o t he i ma gi n g re p osit or y, if a vaila ble. 
Best o verall res p o nse acc or di n g t o R E CI S T 1. 1 t o t his 2 L  treat me nt f or metastat ic disease 
s h o ul d als o be re p orte d. A partici pa nt’s pr o gressi o n ma y  in v ol ve t he f oll o wi n g: o bjecti ve 
ra di ol o gical, s ym pt o matic pr o gressi o n, or deat h d ue t o a d va nci n g disease . T h is s h o ul d be 
d oc u me nte d e ver y 6 wee ks u ntil pr o gressi o n o n 2 L  treat me nt, i nitiati o n of s u bse q ue nt 
(t hir d-li ne) treat me nt, wit h dra wal of c o nse nt, or deat h.
See Secti o n  4. 4 f or t he e n d of st u d y defi niti o n.
4. 1. 1
Tre at me nt Be y o n d Pr o gr essi o n
Tre at me nt be y o n d i niti al pr o gressi o n
Partici pa nts will recei ve M 7 8 2 4 a n d pe m br oliz u ma b as o utli ne d i n Secti o n 1. 3 (Sc he d ule of 
Acti vities ) u ntil disease pr o gressi o n. M 7 8 2 4 or pe m br oliz u ma b 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 as l o n g as t he f oll o wi n g criteria are 
met:

Part ici pa nt is i n t he st u d y a n d treat me nt wit h M 7 8 2 4 or pe m br oliz u ma b is o n g oi n g

N o ne w u nacce pta ble treat me nt or disease -relate d t o xicit y

T olera nce of st u d y i nter ve nti o ns

Sta ble E C O G P S

Treat me nt b e y o n d pr o gressi o n will n ot dela y  an i m mi ne nt i nter ve nti o n t o pre ve nt seri o us 
c o m plicati o ns of disease pr o gressi o n ( e. g., ce ntral ner v o us sys te m [ C N S] metastases).
A ra di o gra p hic assess me nt s h o ul d be perf or me d wit hi n 4 t o 6 wee ks of ori gi nal P D t o deter mi ne 
w het her t here has bee n a decrease i n t he t u m or size, or c o nti n ue d P D. T he assess me nt of cli nical 
be nefit s h o ul d be bala nce d b y  cli nical j u d g me nt as t o w het her t he partici pa nt is cli nicall y 
deteri orati n g a n d u nli kel y  to recei ve a n y be nefit fr o m c o nti n ue d treat me nt wit h M 7 8 2 4 
a n d 
pe m br oliz u ma b.
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
Tre at me nt be y o n d c o nfir me d pr o gressi o n
After c o nfir me d P D, if t he I nvesti gat or feels t hat t he partici pa nt c o nti n ues t o ac hie ve cli nical 
be nefit b y  c o nti n ui n g treat me nt, t he partici pa nt s h o ul d re mai n o n t he st u d y an d c o nti n ue t o recei ve 
m o nit ori n g acc or di n g t o Secti o n  1. 3 (Sc he d ule of Acti vities ). T he decisi o n t o c o nti n ue treat me nt 
be y o n d c o nfir me d P D s h o ul d be disc usse d wit h t he Me dical M o nit or a n d d oc u me nte d i n t he st u d y 
rec or ds.
Partici pa nts w h o c o nti n ue be y o n d pr o gressi o n will be e val uate d f or f urt her t u m or res p o nse as per 
t he pr ot oc ol sc he d ule. Treat me nt s h o ul d be disc o nti n ue d per ma ne ntl y u p o n d oc u me ntati o n of 
f urt her, u ne q ui v ocal, disease pr o gr essi o n u nless t here are n o alter nati ve t hera pe utic o pti o ns a n d 
t he be nefit -ris k assess me nt is fa v ora ble i n c o ns ultati o n bet wee n t he I n vesti gat or a n d t he Me dical 
M o nit or . In case of c o nti n uati o n of treat me nt be y o n d P D, treat me nt will be disc o nti n ue d o nce a n y 
ot her criteri a f or wit h dra wal are met (see S ecti o n 7. 1 ).
4. 1. 2
C o nti n u ati o n of St u d y I nter ve nti o n After L oc al Tre at me nt of 
Dise ase Pr o gressi o n
If dise ase pr o gressi o n is d ue t o brai n metastasis, partici pa nts ma y  co nti n ue st u d y inter ve nti o ns 
after t he l ocal treat me nt of t he brai n lesi o ns pr o vi de d t hat t he a b o ve criteria are met i n a d diti o n t o 
t he f oll o wi n g:

T u m or assess me nt s h o wi n g disease pr o gressi o n has bee n perf or me d a n d was d oc u me nte d 
acc or di n g t o R E CIS T 1. 1 pri or t o t he pr oce d ure.

Brai n metastases ha ve bee n treate d l ocall y a n d are cli nicall y sta ble f or a t least 2 wee ks pri or t o 
rei nitiati o n of st u d y i nter ve nti o ns. 

T here are n o o n g oi n g ne ur ol o gical s ym pt o ms t hat are relate d t o t he brai n l ocalizati o n of t he 
disease (se q uelae t hat are a c o nse q ue nce of t he treat me nt of t he brai n metastases are acce pta ble).

Partici pa nts 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).  

Be nefit -ris k assess me nt t o c o nti n ue st u d y i nter ve nti o n is fa v ora ble u n der c o nsi derati o n of a n y 
alter nati ve treat me nt o pti o ns as assesse d b y t he I nvesti gat or 
I n a d diti o n, if disease pr o gressi o n is mai nl y d ue t o a metastatic lesi o n w hic h i n t he o pi ni o n of t he 
I n vesti gat or m a y  be s ur gicall y re m o ve d, partici pa nts ma y  co nti n ue st u d y inter ve nti o ns after t he 
l ocal treat me nt of s uc h a lesi o n pr o vi de d t hat:

T u m or assess me nt s h o wi n g disease pr o gressi o n has bee n perf or me d a n d was d oc u me nte d 
acc or di n g t o R E CIS T 1. 1 pri or t o t he pr oce d ure.

It has bee n at least 2 wee ks a n d t he partici pa nt has f ull y rec o vere d fr o m t he s ur ger y.

Be nefit -ris k assess me nt t o c o nti n ue st u d y i nter ve nti o n is fa v ora ble u n der c o nsi derati o n of a n y 
alter nati ve treat me nt o pti o ns as assesse d b y t he I nvesti gat or .
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
4. 2. 2
Pe m br oliz u m a b as C o m p ar at or
Pe m br oliz u ma b 
is t he o nl y  ap pr o ve d i m m u n o-o nc ol o g y  
mo n ot hera p y  in 1 L  
NS C L C. 
Pe m br oliz u ma b has bee n a p pr o ve d as :

M o n ot hera p y f or t he treat me nt of patie nts wit h metastatic
N S C L C w h ose t u m ors e x press
P D -L 1  (T P S ≥ 1 % as deter mi ne d b y  t he P D-L 1 I H C 2 2C 3 p har m D x assa y  assa y) wit h disease 
pr o gressi o n o n or f oll o wi n g plati n u m -c o ntai ni n g c he m ot hera p y. Patie nts
ha d disease 
pr o gressi o n o n a p pr o ve d tar gete d t hera py f or E G F R or A L K ge n o mic t u m or a berrati o ns 
(K E Y N O T E -0 1 0 st u d y ). 

M o n ot hera p y f or t he 1 L  treat me nt of partici pa nts wit h metastatic N S C L C w h ose t u m ors ha d 
hi g h P D -L 1 e x pressi o n as deter mi ne d b y  t he P D -L 1 I H C 2 2 C 3 p har m D x assa y ( T P S ≥5 0 %) 
a n d were ne gati ve f or E G F R a n d A L K ge n o mic t u m or a berrati o ns ( K E Y N O T E- 0 2 4 st u d y ).

M o n ot hera p y f or t he 1 L treat me nt of patie nts wit h Sta ge 3 NS C L C w h o are n ot ca n di dates f or 
s ur gical resecti o n or defi niti ve c he m ora diati o n, or metastatic N S C L C, w h ose t u m ors e x press 
P D -L 1  (T P S ≥ 1 %) wit h n o E G F R or A L K ge n o mic t u m or a berrati o ns. T he a p pr o val of 
pe m br oliz u ma b i n se veral c o u ntries was base d o n cli nical data fr o m t he K E Y N O T E- 0 4 2 trial .

I n co m bi nati o n wit h car b o plati n a n d pe metre xe d as 1 L  treat me nt of partici pa nts wit h metastatic 
n o ns q ua m o us N S C L C (K E Y N O T E -0 2 1 st u d y). T his i n dicati o n is a p pr o ved u n der accelerate d 
a p pr o val i n t he U S A a n d E U.
N ote, t he a p pr o ve d i n dicati o ns ma y  differ by c o u ntr y.
T he res p o nse rates of pe m br oliz u ma b are s u m marize d i n Secti o n 2. 2.  
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
4. 2. 3
O pe n- l a bel Desi g n
T his st u d y  will use a n o pe n-la bel desi g n.
D ue t o t he differe nt d osi n g sc he d ules, pe m br oliz u ma b d ose d q 3 w w hile M 7 8 2 4 q 2 w, a tr ue
bli n di n g w o ul d re q uire a c o nsi dera ble n u m ber of st u d y visits (i.e., a p pr o xi matel y 1 wee k off e ver y 
6 wee ks ) a n d b ur de n t he partici pa nt . F urt her, d osi n g of pe m br oliz u ma b is o ver 3 0 mi n ute s w hile 
f or M 7 8 2 4 it is o ver 6 0 mi n utes; t heref ore, partici pa nts w o ul d re q uire 2 i nf usi o ns per visit. 
A n o pe n -la bel desi g n is selecte d t o re d uce t he b u r de n t o partici pa nts a n d sites (i ncl u di n g 
p har macies) . T he pla n ne d I D M C a n d bli n de d I R C re vie w will miti gate ris k of bias b y n ot d o u ble-
bli n di n g t he st u d y. Access t o a g gre gate d a nal ys es per treat me nt ar m will be restricte d t o t he I D M C 
a n d a Fire wall Tea m a s per c orres p o n di n g c harters.
4. 2. 4
Str atific ati o n
Stratificati o n at ra n d o mizati o n is pla n ne d f or partici pa nts wit h s q ua m o us hist ol o g y , n o ns q ua m o us 
hist ol o g y a n d ne ver s m o ke d, a n d n o ns q ua m o us hist ol o g y  wit h a s m o ki n g hist or y. Ne ver s m o ki n g 
is defi ne d as s m o ki n g fe wer t ha n 1 0 0 ci garette-e q ui vale nts o ver lifeti me. T here is i ncreasi n g 
e vi de nce t hat hi g her t u m or m utati o nal b ur de n ( T M B) is pre dicti ve of i m pr o ve d res p o nse t o 
i m m u n ot hera p y, a n d t hat s m o ki n g m a y  increase t his T M B d ue to its carci n o ge nic c he micals. I n 
cli nical st u dies, e mer gi n g data s u g gest i m pr o ve d O R R i n s m o kers vers us n o n s m o kers; h o we ver, 
d ue t o l o w n u m bers of n o n s m o ki n g N S C L C partici pa nts i n pri or st u dies, t his has n ot bee n 
c o ncl usi vel y de m o nstrate d. I n E M R 2 0 0 6 4 7 - 0 0 1, a p pr o xi matel y 20 % of partici pa nts were ne ver 
s m o kers. If t his tre n d c o nti n ues, u p t o 6 0 partici pa nts are pre dicte d t o e nr oll wit h n o s m o ki n g 
hist or y . As o nl y  ap pr o xi matel y  30 % of n o n s m o kers are e x pecte d t o ha ve s q ua m o us hist ol o g y , 
t here are pre dicte d t o be a n i ns ufficie nt n u m ber of P F S e ve nts t o j ustif y stratif yi n g o n n o n s m o kers 
wit h s q ua m o us hist ol o g y; t heref ore, o nl y partici pa nts wit h n o n s q ua m o us hist ol o g y  will be f urt her 
stratifie d b y s m o ki n g stat us.
4. 2. 5
P F S a n d O S as t he Pri m ar y E n d p oi nts
T his st u d y is t he first direct c o m paris o n of 2 i m m u n ot hera pies. T heref ore , t o f urt her i n vesti gate 
t he o utc o mes, d ual pri mar y  en d p oi nts , P F S a n d O S , will be e x pl ore d. T he i nteri m a n d pri mar y 
a nal ys es of O S a n d P F S will be perf or me d as o utli ne d i n Secti o n  9. 4. 4.
In N S C L C , P F S a n d O S ca n be c o nsi dere d as pri mar y e n d p oi nt s f or de m o nstrati o n of efficac y f or 
dr u g a p pr o val base d o n ma g nit u de of effect a nd ris k be nefit pr ofile of t he dr u g , as p er t he F D A 
a n d E M A g ui da nce.
4. 2. 6
A d a pti ve P h ase III D esi g n
I n pr ot oc ol V ersi o n 3. 0, t he st u d y desi g n was m o difie d t o a n a da pti ve trial desi g n t o per mit sa m ple 
size a da ptati o n base d o n pres pecifie d a da ptati o n r ules e val uati n g t he o bjecti ve res p o nse at a 
pre pla n ne d I A. A da pti n g t he st u d y at a n earl y si g nal of efficac y foll o wi n g t he pre pla n ne d I A, 
mi ni mizes ris k t o patie nts b y  deferri n g e x pa nsi o n u ntil preli mi nar y efficac y is o bser ve d, w hile 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
mi ni mizi n g t he n u m ber of e x p ose d patie nts i n c o m paris o n wit h 2 se parate trials. T he a da pti ve 
desi g n is i nte n de d t o preser ve t he gl o bal re gistrati o nal i nte nt of t his trial.
W hile t he st u d y tea m will re mai n bli n de d t o t he a g gre gate res ults b y  treat me nt ar m, t he st u d y’s 
I D M C e val uates o bjecti ve res p o nse as assesse d b y  the I R C o n t he 7 3 -1 0 P D -L 1 hi g h a nal ys is set 
restricte d t o partici pa nts ra n d o mize d at least 6 m o nt hs bef ore t he data c ut off date. T hat i nteri m 
a nal ys is ( O R I A) c ut off date is 6 m o nt hs after e nr olli n g t he 1 0 0t h partici pa nt teste d 7 3-1 0 P D -L 1  
hi g h. Base d o n t he re vie w of t he data, t he I D M C will rec o m me n d o ne of t he f oll o wi n g p ossi ble 
o pti o ns base d u p o n pre -s pecifie d decisi o n r ules: ter mi nate t he trial f or f utilit y, c o nti n ue as i nitiall y 
pla n ne d wit h a t otal sa m ple size of N = 3 0 0 or i ncrease t he sa m ple size t o N = 5 8 4 . T he i nte grate d 
a nal ys is pla n (IA P ) will i ncl u de details a n d s pecificati o ns f or t he pla n ne d a nal ys es as well as a n 
a n ne x wit h si m ulati o n res ults re gar di n g t he a da pti ve trial desi g n . F urt her, t he I D M C c harter will 
pr o vi de details o n i m ple me ntati o n of t he a da pti ve desi g n al o n g wit h s pecific r ules t hat will be use d 
t o g ui de a da ptati o n decisi o n. A c o m pre he nsi ve res ults access pla n defi nes h o w trial i nte grit y will 
be mai ntai ne d i n t he prese nce of pla n ne d a da ptati o ns. 
4. 3
J ust ific ati o n f or D ose
T he R P 2 D f or M 7 8 2 4 is 1 2 0 0 m g a d mi nistere d as a n intra ve n o us i nf usi o n q 2 w. T he selecti o n of 
R P 2 D is base d o n t he a vaila ble cli nical data fr o m P hase I St u d y  EM R 2 0 0 6 4 7 - 0 0 1 a n d St u d y 
M S 2 0 0 6 4 7 - 0 0 0 8, i ncl u di n g safety/ t olera bilit y, p har mac o ki netics ( P K), a n d p har mac o d y n a mic 
(s uc h as P D -L 1 tar get occ u pa nc y  [ T O] i n peri p heral bl o o d m o n o n uclear cells (P B M C ) a n d T G F β 
tra p pi n g i n bl o o d ), as well as efficac y in 2 L  NS C L C c o h orts fr o m St u d y  EM R 2 0 0 6 4 7 - 0 0 1. T he 
selecti o n of R P 2 D is als o s u p p orte d b y p o p ulati o n P K (p o p P K) a n d e x p os ure -res p o nse m o deli n g 
a n d si m ulati o n. 
Safet y /t olera bilit y i n P hase I 
T he hi g hest d ose f or M 7 8 2 4 teste d i n E M R 2 0 0 6 4 7 - 0 0 1 was 3 0 m g/ k g, w hic h corres p o n ds t o 
2 1 0 0 m g f or a 7 0- k g partici pa nt (t he me dia n b o d y wei g ht i n t he c urre nt dataset) a n d t o 2 4 0 0 m g 
f or a n 8 0- k g partici pa nt (c orres p o n di n g t o a t ypical me dia n b o d y  wei g ht f or s oli d t u m or t ype 
partici pa nts) (Fres h water, 2 0 1 7 ; Bajaj, 2 0 1 7 ; Z ha o, 2 0 1 7 ). Base d o n cli nical o bser vati o ns, M 7 8 2 4 
is well t olerate d u p t o 3 0 m g/ k g a n d t he ma xi m u m t olerate d d ose was n ot reac he d. I n a d diti o n, f or 
t he 2 d ose le vels e val uate d i n 2 L N S C L C c o h orts of St u d y  E M R 2 0 0 6 4 7 -0 0 1 ( 5 0 0 a n d 1 2 0 0 m g  iv 
q 2 w), o verall safety fi n di n gs were c o m para ble a n d c o nsiste nt wit h o bser ve d safet y pr ofile i n 
St u dies E M R 2 0 0 6 4 7 - 0 0 1 a n d M S 2 0 0 6 4 7- 0 0 0 8.
 a n d P hase I d ose escalati o n P K a n d 
T he P K d ose -pr o p orti o nalit y , peri p heral P D -L 1 T O/ T G F β tra p pi n g fr o m t he d ose escalati o n p hase 
of St u d y  EM R 2 0 0 6 4 7 -0 0 1 (at d oses of 1, 3, 1 0, 2 0, a n d 3 0 m g/ k g q 2 w), a n d 
 
 
 
 
 I n partici pa nts wit h 
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
Flat d ose rati o nale 
T o ac hie ve less varia bilit y  in e x p os ure, miti gate t he ris k of d osi n g err ors, re d uce t he ti me necessar y 
f or d ose pre parati o n, a n d re d uce dr u g wasta ge c o m pare d wit h t he wei g ht -base d d osi n g, a flat d ose 
a p pr oac h was a d o pte d f or e x pa nsi o n p hases of P hase I cli nical st u dies. 
T he flat d osi n g a p pr oac h f or P hase II is s u p p orte d b y p o p P K m o deli n g a n d si m ulati o n usi n g data 
fr o m 3 5 0 partici pa nts fr o m t he 2 P hase I cli nical st u dies of M 7 8 2 4 i n m ulti ple s oli d t u m or t ypes, 
w hic h s h o we d t hat alt h o u g h b o d y  wei g ht was f o u n d t o be a c o variate f or cleara nce, t he esti mate d 
ma g nit u de of t he b o d y  wei g ht e x p o ne nt o n cleara nce is < 0. 5, pre dicti n g less e x p os ure varia bilit y  
fr o m flat d osi n g t ha n t hat fr o m b o d y  wei g ht-base d d osi n g (Wa n g , 2 0 0 9). Acc or di n gl y, si m ulati o ns 
of A U C a n d C tr o u g h s h o we d t hat varia bilit y  in e x p os ure was i n dee d sli g htl y lo wer f or flat d osi n g 
c o m pare d wit h wei g ht -base d d osi n g.
Preli mi nar y  efficac y a n d e x p os ure-res p o nse a nalysis
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
4. 4
E n d of St u d y Defi niti o n
A partici pa nt has c o m plete d t he st u d y if he/s he has c o m plete d all st u d y parts, i ncl u di n g t he last 
visit or t he last sc he d ule d pr oce d ure s h o w n i n Sectio n  1. 3 ( Sc he d ule of Acti vities).
T he e n d of t he st u d y is defi ne d as t he data c ut off date f or t he pri mar y  OS a nal ysis w he n t he pla n ne d 
n u m ber of deat hs ha d bee n re p orte d. After sti p ulate d e n d of st u d y, s ur vi val f oll o w- u p ma y  co nti n ue 
u ntil t he last partici pa nt has die d or at t he discreti o n of t he S p o ns or. T he S p o ns or ma y  ter mi nate 
t he st u d y at a n y ti me o nce access t o M 7 8 2 4 or pe m br oliz u ma b f or partici pa nts still be nefi ti n g is 
pr o visi o ne d via a r ollo ver st u d y, e x pa n de d access, mar ket e d pr o d uct or a n ot her mec ha nis m of 
access as a p pr o priate.
5
St u d y P o p ul ati o n
T he criteria i n Secti o n s 5. 1 (Incl usi o n Criteria) a n d 5. 2 ( E xcl usi o n Criteria) are desi g ne d t o e nr oll 
o nl y  partici pa nts, w h o are a p pr o priate f or t he st u d y; t here b y, e ns uri n g t he st u d y fulfills its 
o bjecti ves. All rele va nt me dical a n d n o n me dical c o n diti o ns s h o ul d be ta ke n i nt o c o nsi derati o n 
w he n deci di n g w het her a partici pa nt is s uita ble f or t his st u d y .
Pr os pecti ve a p pr o val of pr ot oc o l de viati o ns t o i ncl usi o n a n d e xcl usi o n criteria, als o k n o w n as 
pr ot oc ol wai vers or e xe m pti o ns, is n ot per mitte d.
Bef ore perf or mi n g a n y st u d y assess me nts t hat are n ot part of t he partici pa nt’s r o uti ne me dical care, 
t he I nvesti gat or will c o nfir m t hat t he pa rtici pa nt or t he partici pa nt’s le gal re prese ntati ve (w here 
all o we d b y  local la ws a n d re g ulati o ns) has pr o vi de d writte n i nf or me d c o nse nt, as i n dicate d i n 
A p pe n di x 2 ( St u d y G o ver na nce).
5. 1
I ncl usi o n Criteri a
Partici pa nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all t he f oll o wi n g criteria a p pl y:
A ge
1.
Are ≥ 1 8 years of a ge i ncl usi ve, at t he ti me of si g ni n g t he i nf or me d c o nse nt. I n Ja pa n, if a 
partici pa nt is < 2 0 years, t he writte n i nf or me d c o nse nt fr o m his/ her pare nt or g uar dia n will be 
re q uire d i n a d diti o n t o t he partici pa nt’s writte n c o nse nt as per c o u ntr y re q uire me nts.
T y pe of P artici p a nt a n d Dise ase C h ar acteristics
2.
Are partici pa nts w h o h a ve a hist ol o gicall y c o nfir me d dia g n osis of a d va nce d N S C L C a n d: 
a.
Ha ve n ot recei ve d pri or s yste mic t hera p y treat me nt f or t heir a d va nce d/Sta ge I V N S C L C. 
C o m pleti o n of treat me nt wit h c yt ot o xic c he m ot hera p y, bi ol o gical t hera p y, a n d/ or 
ra diati o n as part of ne oa dj u va nt/a dj u va nt t hera p y is all o we d as l o n g as t hera py was 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
c o m plete d at least 6 m o nt hs pri or t o t he dia g n osis of metastatic disease. C o nfir mati o n of 
res ol uti o n of t o xic effects of pre vi o us ne oa dj u va nt/a dj u va nt c he m ot hera p y  thera p y t o 
Gra de ≤1. F or ra diati o n t o xicit y or pri or maj or s ur geries, partici pa nts s h o ul d ha ve 
rec o vere d fr o m side effects a n d/ or c o m plicati o ns.
b.
Ha ve meas ura ble disease base d o n R E CI S T 1. 1 .
c.
Ha ve a life e x pecta nc y  of at least 3 m o nt hs
d.
A vaila bilit y  of t u m or tiss ue ( < 6 m o nt hs ol d e x cl u di n g b o ne bi o psies) bef ore t he first
d ose is ma n dat or y  to deter mi ne P D -L 1 e x pressi o n le vel pri or t o e nr oll me nt. If partici pa nt
recei ve d l ocal t hera p y (i. e., ra diati o n t hera p y [R T ] or c he m ora di ot hera p y [C R T ]) after 
t he arc hi val bi o ps y  was ta ke n, a fres h bi o ps y  will be re q uire d pri or t o st u d y e ntr y. 
Arc hi val material is f or mali n fi xe d t u m or tiss ue sa m ple fr o m a bi o ps y  of a t u m or lesi o n 
eit her at t he ti me of or after t he dia g n osis of metastatic disease has bee n ma de A N D fr o m 
a site n ot pre vi o usl y irra diate d. Bi o psies o btai ne d P RI O R t o t he a d mi nistrati o n of a n y 
s yste mic t hera py a d mi nistere d f or t he treat me nt of a partici pa nt ’s t u m or (s uc h as 
ne oa dj u va nt/a dj u va nt t hera p y) will n ot be per mitte d f or a nal ysis. E n d osc o pic bi o psies, 
c ore nee dle bi o psies, e xcisi o nal bi o psies, p u nc h bi o psies, or s ur gical s peci me ns are 
re q uire d. Fi ne nee dle as pirati o n bi o psies, cell bl oc ks , a n d ot her t ypes of c yt ol o gic 
s peci me ns are n ot acce pta ble.
e.
As of Versi o n 3. 0 of t his pr ot oc ol, P D -L 1 hi g h stat us b y  ce ntral testi n g is re q uire d. P D-
L 1 hi g h t u m ors are defi ne d as ha vi n g ≥8 0 % P D -L 1 p ositi ve t u m or cells b y t he P D -L 1  
I H C 7 3- 1 0 assa y. I n all cases, t u m or material m ust be pr o vi de d as s pecifie d a n d m ust 
ha ve be e n e val uate d fr o m tiss ue w hic h is < 6 m o nt hs ol d . T he tiss ue sa m ple m ust be 
e val uate d b y  the ce ntral ve n d or pri or t o ra n d o mizati o n ( vali dati o n of tiss ue t ypicall y 
occ urs wit hi n 5 b usi ness da y s). I n case a t u m or s peci me n is assesse d as n ot e val ua ble f or 
P D -L 1  ex pressi o n b y  the ce ntral la b orat or y, if a n a d diti o nal t u m or s peci me n is s u b mitte d 
A N D e val ua ble f or P D -L 1 e x press i o n, t he partici pa nt will be eli gi ble t o partici pate if 
P D -L 1  e x pressi o n is assesse d as “ hi g h” b y t he ce ntral la b orat or y. 
f.
See Secti o n  5 f or e xcl usio n criteria f or partici pa nts wit h E G F R A L K, R O S 1, or B R A F 
V 6 0 0 E m olec ular alterati o ns.
3.
E C O G P S of 0 t o 1 at st u d y  e ntr y a n d date of first d ose 
4.
Ha ve a de q uate or ga n f u ncti o n as i n dicate d b y t he f oll o wi n g la b orat or y val ues
a.
A de q uate 
he mat ol o gical f u ncti o n def i ne d b y a bs ol ute ne utr o p hil c o u nt ( A N C) 
≥1. 5 × 1 0 9/ L, platelet c o u nt ≥ 1 0 0 × 1 0 9/ L, a n d he m o gl o bi n ≥ 9 g/ d L
b.
A de q uate he patic f u ncti o n defi ne d b y  a total bilir u bi n le vel ≤ t he u p per li mit of n or mal 
( U L N), as partate a mi n otra nsferase ( A S T) a n d ala ni ne a mi n otra nsferase ( A LT) le vels 
≤1. 5 × U L N a n d al kali ne p h os p hatase ≤ 2. 5
× U L N .
For partici pa nts wit h li ver 
i n v ol ve me nt i n t heir t u m or, A S T ≤ 5. 0 × U L N, A L T ≤5. 0 × U L N, a n d bilir u bi n 
≤3. 0 × U L N is acce pta ble
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
c.
A de q uate re nal f u ncti o n defi ne d b y  creati ni ne ≤ 1. 5 × U L N or calc ulate d creati ni ne 
cleara nce ( Cr C L) ≥ 3 0 m L / mi nute f or partici pa nt wit h Cr eati ni ne > 1. 5
× U L N 
(gl o mer ular filtrati o n rate ca n als o be use d)
N ote: Cr C L s h o ul d be calc ulate d per i nstit uti o nal sta n dar d. If n o l ocal g ui deli ne is 
a vaila ble, Cr C L s ho ul d be calc ulate d usi n g t he C oc kcr oft -Ga ult Met h o d:
Cr C L = ([ 1 4 0-a ge] × wei g ht [ k g] × [ 0. 8 5 f or fe males o nl y ]) / ( 7 2 × creati ni ne)
d.
A de q uate c oa g ulati o n f u ncti o n defi ne d as i nter nati o nal n or malize d rati o or pr ot hr o m bi n 
ti me ≤1. 5 × U L N u nless t he partici p a nt is recei vi n g a ntic oa g ula nt t hera p y, a n d acti vate d 
partial t hr o m b o plasti n ti me ≤1. 5 × U L N u nless t he partici pa nt is recei vi n g a ntic oa g ula nt 
t hera py
Se x
5.
C o ntrace pti ve use b y  
males or fe males will 
be c o nsiste nt wit h 
l ocal re g ulati o ns o n 
c o ntrace pti o n met h o ds f or t h ose partici pati n g i n cli nical st u dies. 
Male partici pa nts are eli gi ble t o partici pate if t he y agree t o t he f oll o wi n g d uri n g t he i nter ve nti o n 
peri o d a n d f or at least 4 m o nt hs after t he last d ose of st u d y  i nter ve nti o n:

Refrai n fr o m d o nati n g s per m
P L U S, eit her:

A bstai n fr o m i nterc o urse wit h a fe male 
O R

Use a male c o n d o m
W he n ha vi n g se x ual i nterc o urse wit h a w o ma n of c hil d beari n g p ote ntial ( W O C B P), w h o is n ot 
c urre ntl y p re g na nt, a n d a d vise her t o use a hi g hly effecti ve c o ntrace pti ve met h o d wit h a fail ure 
rate of < 1 % per year, as descri be d i n  A p pe n di x 3 si nce a c o n d o m ma y brea k or lea k
Fe male partici pa nts:
Are n ot pre g na nt or breastfee di n g, a n d at least o ne of t he f oll o wi n g c o n diti o ns a p plies:

N ot a W O C B P
O R
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9

If a W O C B P, use a hi g hl y  effecti ve c o ntrace pti ve met h o d (i.e., wit h a fail ure rate of < 1 % 
per year), prefera bl y wit h l o w user de pe n de nc y , as descri be d i n A p pe n di x 3 f or t he f oll o wi n g 
ti me peri o ds:

Bef ore t he first d ose of t he st u d y  i nter ve nti o n(s), if usi n g h or m o nal c o ntrace pti o n: 

Has c o m plete d at least o ne 4- wee k c ycle of a n oral c o ntrace pti o n pill a n d eit her ha d 
or has be g u n her me nses
O R

Has use d a de p ot c o ntrace pti ve or e xte n de d-c ycle oral c o ntrace pti ve f or least 2 8 
da y s a n d has a d oc u me nte d ne gati ve pre g na nc y test usi n g a hi g hl y se nsiti ve assa y.

D uri n g t he i nter ve nti o n peri o d.

After t he st u d y inter ve nti o n peri o d (i.e, after t he last d ose of st u d y inter ve nti o n is 
a d mi nistere d) f or at least 4 m o nt hs after t he last d ose of st u d y  i nter ve nti o n.

Ha ve a ne gati ve pre g na nc y  test, as re q uire d b y l ocal re g ulati o ns, o n W 1 D 1 bef ore t he first 
d ose of st u d y  i nter ve nti o n. 
A d diti o nal re q uire me nts f or pre g na nc y  testi n g d uri n g a n d after st u d y inter ve nti o n are i n 
Sc he d ule of Acti vities.
T he I n vesti gat or re vie ws t he me dical hist or y , me nstr ual hist or y , a n d rece nt se x ual acti vit y to 
decrease t he ris k f or i ncl usi o n of a fe male wit h a n earl y u n detecte d pre g na nc y.
I nf or me d C o nse nt
6.
Ca pa ble of gi vi n g si g ne d i nf or me d c o nse nt, as i n dicate d i n A p pe n di x 2 ( St u d y Go ver na nce), 
w hic h i ncl u des c o m plia nce wit h t he re q uire me nts a n d restricti o ns liste d i n t he i nf or me d 
c o nse nt f or m (IC F) a n d t his pr ot oc ol.
5. 2
E xcl usi o n Criteri a
Partici pa nts are e xcl u de d fr o m t he st u d y  if a n y of t he f oll o wi n g criteria a p pl y:
Me dic al C o n diti o ns
1.
Partici pa nts wit h n o ns q ua m o us N S C L C hist ol o gies w h ose t u m or har b ors a n y of t he f oll o wi n g 
m olec ular alterati o ns a n d tar gete d t he ra py is l ocall y a p pr o ve d:
a.
E G F R se nsitizi n g (acti vati n g) m utati o n. E G F R se nsitizi n g m utati o ns are t h ose m utati o ns 
t hat are a me na ble t o treat me nt wit h t yr osi ne ki nase i n hi bit ors i ncl u di n g, b ut n ot li mite d t o, 
erl oti ni b, gefiti ni b, afati ni b, or osi merti ni b.
b.
A L K tra nsl ocati o n(s) ass ociate d wit h res p o nsi ve ness t o A L K t yr osi ne ki nase i n hi bit ors.
c.
R O S 1 rearra n ge me nt(s) ass ociate d wit h res p o nsi ve ness t o R O S 1 t yr osi ne ki nase i n hi bit ors.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
d.
B R A F V 6 0 0 E m utati o n
F or partici pa nts wit h n o ns q ua m o us N S C L C hist ol o gies testi n g is re q uire d f or a n y m olec ular 
alterati o n descri be d a b o ve i n w hic h tar gete d t hera py is l ocally a p pr o ve d. If u na ble t o test f or 
i n dicate d m olec ular c ha n ges, f or mali n fi xe d paraffi n e m be d de d t u m or tiss ue s h o ul d be s u b mitte d 
t o a ce ntral la b orat or y desi g nate d b y t he S p o ns or f or s uc h testi n g. A n y re q uire d testi n g f or 
partici pa nts wit h n o ns q ua m o us hist ol o gies m ust be k n o w n a n d a vaila ble i n s o urce d oc u me ntati o n 
at t he site pri or t o ra n d o mizati o n.
M olec ular 
testi n g is n ot re q uire d f or partici pa nts k n o w n t o ha ve a t um or of pre d o mi na ntl y 
s q ua m o us hist ol o g y
2.
Has recei ve d maj or s ur ger y wit hi n 4 wee ks pri or t o t he first d ose of st u d y inter ve nti o n; 
recei ve d t h oracic R T of > 3 0 G y wit hi n 6 m o nt hs pri or t o t he first d ose of st u d y i nter ve nti o n.
3.
Pre vi o us mali g na nt disease ( ot he r t ha n t he tar get mali g na nc y  t o be i n vesti gate d i n t his st u d y) 
wit hi n t he last 3 years. Partici pa nts wit h a hist or y of cer vical carci n o ma i n sit u, s u perficial or 
n o ni n vasi ve bla d der ca ncer, or basal cell or s q ua m o us cell carci n o ma i n sit u pre vi o usl y  treated 
wit h c urati ve i nte nt are N O T e xcl u de d. Partici pa nts wit h ot her l ocalize d mali g na ncies treate d 
wit h c urati ve i nte nt nee d t o be disc usse d wit h t he Me dical M o nit or.
4.
Has acti ve C N S metastases ca usi n g cli nical s ym pt o ms or metastases t hat re q uire t hera pe utic 
inter ve nti o n a n d/ or carci n o mat osis me ni n gitis (i ncl u di n g le pt o me ni n geal carci n o mat osis) 
i de ntifie d eit her o n Baseli ne brai n i ma gi n g d uri n g t he Scree ni n g peri o d O R i de ntifie d pri or t o 
si g ni n g t he I C F. Partici pa nts wit h a hist or y  of treate d C N S metastases ( b y s ur ger y or R T) are 
n ot eli gi ble u nless t he y ha ve f ull y rec o vere d fr o m treat me nt, de m o nstrate ra di o gra p hic sta bilit y 
defi ne d as 2 brai n i ma ges, b ot h of w hic h are o btai ne d after treat me nt t o t he brai n metastases. 
T hese i ma gi n g sca ns s h o ul d b ot h be o btai ne d at least 2 wee ks a part a n d s h o w n o e vi de nce of 
i ntracra nial press ure. I n a d diti o n, a n y ne ur ol o gic s y m pt o ms t hat de vel o pe d eit her as a res ult of 
t he brai n metastases or t heir treat me nt m ust ha ve ret ur ne d t o B aseli ne or res ol ve d. A n y ster oi ds 
a d mi nistere d as part of t his t hera py m ust be c o m plete d at least 3 da y s pri or t o st u d y 
i nter ve nti o n. Partici pa nts wit h C N S metastases i nci de ntall y detecte d d uri n g Scree ni n g w hic h 
d o n ot ca use cli nical s ym pt o ms a n d f or w hic h sta n dar d of care s u g gests n o t hera pe utic 
i nter venti o n is i n dicate d s h o ul d be disc usse d wit h t he S p o ns or Me dical Res p o nsi ble t o c o nfir m 
eli gi bilit y. 
5.
Acti ve a ut oi m m u ne disease t hat has re q uire d s yste mic treat me nt i n past 1 ye ar (i.e., wit h use 
of disease -m o dif y i n g a ge nts, c ortic oster oi ds, or i m m u n os u p pressi ve dr u gs), O R is recei vi n g 
s yste mic ster oi d t hera p y < 3 d a ys pri or t o t he first d ose of st u d y i nter ve nti o n or recei vi n g a n y 
ot her f or m of i m m u n os u p pressi ve me dicati o n. Partici pa nts re q uiri n g h or m o ne re place me nt 
wit h c ortic oster oi ds are eli gi ble if t he ster oi ds are a d mi nistere d o nl y f or t he p ur p ose of 
h or m o nal re place me nt a n d at l o w d oses (t ypicall y  ≤ 1 0 m g of pre d nis o ne or e q ui vale nt per 
da y ). E q ui vale nt h y dr oc ortis o ne d oses are als o per mitte d if a d mi nistere d as a re place me nt 
t hera py. C ortic oster oi d use o n st u d y as a pre me dicati o n f or i v c o ntrast aller gies/reacti o ns 
(relate d t o sca ns) is all o we d a n d m ust be d oc u me nte d. T his m ust be disc usse d wit h Me dical 
M o nit ors f or cli nical i n dicati o ns i n w hic h partici pa nts ma y  re q uire a hi g her d ose. Acti ve 
a ut oi m m u ne d isease t hat mi g ht deteri orate w he n recei vi n g a n i m m u n osti m ulat or y a ge nt:
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
a.
Partici pa nts wit h dia betes T y pe I, vitili g o, al o pecia, ps oriasis, h y p o- or h y pert h yr oi d 
disease n ot re q uiri n g i m m u n os u p pressi ve treat me nt are eli gi ble. C o ns ult Me dical M o nit or 
f or ot her a ut oi m m u ne diseases.
6.
A d mi nistrati o n of ster oi ds f or ot her c o n diti o ns t hr o u g h a r o ute k n o w n t o res ult i n a mi ni mal 
s yste mic e x p os ure (t o pical, i ntra nasal, i ntr o-oc ular, or i n halati o n) is acce pta ble
7.
K n o w n se vere h y perse nsiti vit y  (Gra de ≥ 3 Nati o nal Ca n cer I nstit ute [ N CI] C o m m o n 
Ter mi n ol o g y  Criteria f or A d verse E ve nts [ C T C A E] v 5. 0) t o i n vesti gati o nal pr o d uct ( M 7 8 2 4 
or pe m br oliz u ma b) or a n y co m p o ne nts i n t heir f or m ulati o ns, or u nc o ntr olle d ast h ma (ie, 3 or 
m ore feat ures of partiall y c o ntr olle d ast h ma)
8.
Rec ei pt of a n y or ga n tra ns pla ntati o n, i ncl u di n g all o ge neic ste m-cell tra ns pla ntati o n, b ut wit h 
t he e xce pti o n of tra ns pla nts t hat d o n ot re q uire i m m u n os u p pressi o n (e. g., c or neal tra ns pla nt, 
hair tra ns pla nt) 
9.
Has i nterstitial l u n g disease O R has ha d a hist or y of p ne u m o nitis t hat has re q uire d oral or i v
ster oi ds
1 0. Si g nifica nt ac ute or c hr o nic i nfecti o ns i ncl u di n g, a m o n g ot hers:
a.
K n o w n hist or y  of p ositi ve test f or h u ma n i m m u n o deficie nc y vir us ( HIV) or k n o w n 
ac q uire d i m m u n o deficie nc y sy n dr o me ( n o testi n g at Scree ni n g re q uire d). If a n I nvesti gat or 
has a str o n g s us pici o n of HI V i nfecti o n wit h o ut k n o w n hist or y  for a partici pa nt i n 
Scree ni n g, h o we ver partici pa nt ref uses testi n g, disc uss wit h Me dical M o nit or t o assess 
eli gi bilit y. ( N ote: HI V testi n g is n ot ma n date d f or st u d y incl usi o n; h o we ver, if it is 
perf or me d at a n y p oi nt i n Scree ni n g or w hile o n st u d y, a site m ust c o nse nt t he partici pa nt 
f or HI V testi n g as per l ocal sta n dar d g ui da nce.)
b.
Acti ve he patitis B vir us ( H B V) or he patitis C vir us ( H C V) i nfecti o n ( H B V s urface a nti ge n 
p ositi ve a n d H B V c ore a nti b o d y  p ositi ve wit h refle x t o p ositi ve H B V D N A, or H B V c ore 
a nti b o d y positi ve al o ne wit h refle x t o p ositi ve H B V de o x yri b o n ucleic aci d (D N A ), or 
p ositi ve H C V a nti b o d y wit h refle x t o p ositi ve H C V R N A) at Baseli ne. Disc uss wit h t he 
Me dical M o nit or if hist or y  of H B V or H C V i nfecti o n is k n o w n. If me dicall y  in dicate d, 
partici pa nts i nfecte d wit h H B V m ust be treate d a n d o n a sta ble d ose of a nti virals (e g, 
e nteca vir, te n of o vir, or la mi vu di ne; a def o vir or i nterfer o n are n ot all o we d) at st u d y entr y 
a n d wit h pla n ne d m o nit ori n g a n d ma na ge me nt acc or di n g t o a p pr o priate la beli n g g ui da nce. 
Partici pa nts o n acti ve H C V t hera py at st u d y entr y  must be o n a sta ble d ose wit h o ut 
d oc u me nte d cli nicall y sig nifica nt i m paire d li ver f u ncti o n test or he mat ol o gic a b n or malities 
( m ust meet criteria bel o w) a n d wit h pla n ne d m o nit ori n g a n d ma na ge me nt acc or di n g t o 
a p pr o priate la beli n g g ui da nce. H B V a n d/ or H C V viral titers m ust be m o nit ore d acc or di n g 
t o Secti o n 1. 3 ( Sc he d ule of Acti vities) i n t hese partici pa nts.
c.
Partici pa nts wit h acti ve t u berc ul osis ( hist or y of e x p os ure or hist or y  of p ositi ve t u berc ul osis 
test; plus prese nce of cli nical s y m pt o ms, p h ys ical, or ra di o gra p hic fi n di n gs)
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
1 1. Has a hist or y  or c urre nt e vi de nce of a n y c o n diti o n, t hera py, or la b orat or y ab n or malit y  that 
mi g ht c o nf o u n d t he res ults of t he st u d y , i nterfere wit h partici pati o n f or t he f ull d urati o n of t he 
st u d y, or is n ot i n t he best i nterest of t he partici pa nt, i n t he o pi ni o n of t he treati n g I n vesti gat or.
Partici pa nts wit h hist or y  of blee di n g diat hesis or rece nt maj or blee di n g e ve nts c o nsi dere d b y  
t he I nvesti gat or as hi g h ris k f or i n vesti gati o nal dr u g treat me nt s uc h as patie nts wit h cli nicall y  
rele va nt blee di n g e ve nts of he m o pt ysis Gra de ≥ 2 wit hi n t he last m o nt h are als o e xcl u de d .
Pri or/ C o nc o mit a nt T her a p y
1 2. Has recei ve d pri or t hera p y wit h a n a nti-P D -1, a nti-P D -L 1 , a nti-P D -L 2, a nti-C D 1 3 7, or a nti-
C y t ot oxic T- l ym p h oc y te-ass ociate d a nti ge n- 4 ( C T LA- 4) a nti b o d y (i ncl u di n g i pili m u ma b or 
a n y ot her a nti b o d y or dr u g s pecifically tar geti n g T- cell c o-sti m ulati o n or c hec k p oi nt pat h wa y s)
1 3. Is e x pecte d t o re q uire a n y ot her f or m of s yste mic or l ocalize d a nti ne o plastic t hera p y w hile o n 
st u d y (i ncl u di n g mai nte na nce t hera p y wit h a n ot her a ge nt f or N S C L C, R T , a n d/ or s ur gical 
resecti o n)
1 4. Use of a pr o hi bite d c o nc o mita nt dr u g, as defi ne d i n Secti o n  6. 5. 2
1 5. Has recei ve d or will recei ve a li ve vacci ne wit hi n 3 0 da y s pri or t o t he first a d mi nistrati o n of 
st u d y inter ve nti o n . Seas o nal fl u vacci nes t hat d o n ot c o ntai n a li ve vir us are per mitte d . C o ntact 
Me dical M o nit or if scree n i n g e xte nsi o n is nee de d f or partici pa nt vacci nate d wit hi n 3 0 da y s of 
pla n ne d first d ose
1 6. Has a n acti ve i nfecti o n re q uiri n g s yste mic t hera p y/a nti bi otics (e xce pt as i n dicate d, disc uss 
alter nati ve sce nari os wit h t he Me dical M o nit or)
Pri or/ C o nc urre nt Cli nic al St u d y E x perie nce
1 7. Is c urre ntl y partici pati n g a n d recei vi n g st u d y thera p y or has partici pate d i n a st u d y of a n 
i n vesti gati o nal a ge nt a n d recei ve d st u d y thera p y  or use d a n i n vesti gati o nal de vice wit hi n 
4 wee ks of t he first d ose of treat me nt
Ot her E xcl usi o ns
1 8. K n o w n acti ve alc o h ol or dr u g a b use
1 9. A n y  ps yc hiatric c o n diti o n t hat w o ul d pr o hi bit t he u n dersta n di n g or re n deri n g of i nf or me d 
c o nse nt or c o nsiste nt partici pati o n i n st u d y  pr oce d ures
2 0. Le gal i nca pacit y or li mite d le gal ca pacit y.
5. 3
Lifest yle C o nsi der ati o ns
N ot a p plica ble.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
5. 4
Scree n F ail ures
I n di vi d uals w h o d o n ot meet t he criteria f or partici pati o n i n t his st u d y (scree n fail ure) m a y  b e 
rescree ne d if t he i n dicati o n f or scree n-fail has res ol ve d a n d after disc ussi o n wit h t he M e dical 
M o nit or .
F or partici pa nts t hat ha ve a n a b n or mal la b orat or y val ue at Scree ni n g t hat ma y c orrect or are usi n g 
a pr o hi bite d c o nc o mita nt me dicati o n t hat will be disc o nti n ue d, or u n der g oi n g a pr o hi bite d 
pr oce d ure t hat will be c o m plete d, it is rec o m me n de d t o disc uss wit h t he Me dical M o nit or a b o ut 
w het her t he Scree ni n g wi n d o w ca n be e xte n de d, rat her t ha n scree n-fail t he partici pa nt . I n ot her 
sit uati o ns w he n a partici pa nt has bee n scree n-faile d, t he site s h o ul d c o ntact t he Me dical M o nit or 
t o disc uss w het her t he partici pa nt ma y  be rescree ne d.
6
St u d y I nter ve nti o n(s)
St u d y  inter ve nti o n is a n y i n vesti gati o nal i nter ve nti o n(s), mar kete d pr o d uct(s), place b o, or me dical 
de vice(s) i nte n de d t o be a d mi nistere d t o a st u d y  partici pa nt per t he st u d y pr ot oc ol.
6. 1
St u d y I nter ve nti o n(s) A d mi nist r ati o n
St u d y  I nt er v e nti o n 
N a m e:
M 7 8 2 4
P e m br oli z u m a b
D o s e F or m ul ati o n:
St eril e c o n c e ntr at e s ol uti o n f or i nf u si o n
R ef er t o p e m br oli z u m a b S m P C or 
P a c k a g e I n s ert f or m or e i nf or m ati o n
U nit D o s e 
Str e n gt h( s)/
D o s a g e L e v el( s):
1 0 m g/ m L i n si n gl e -u s e gl a s s vi al s.  
R ef er t o p e m br oli z u m a b S m P C or 
P a c k a g e I n s ert f or m or e i nf or m ati o n
R o ut e of 
A d mi ni str ati o n:
I ntr a v e n o u s i nf u si o n
I ntr a v e n o u s i nf u si o n
D o si n g I n str u cti o n s:
1 2 0 0 m g o v er 1 h o ur ( -1 0 mi n ut e s/ + 2 0 
mi n ut e s; i .e, o v er 5 0 t o 8 0 mi n ut e s) o n c e 
e v er y 2 w e e k s.
S e e S e cti o n  6. 9 f or s p e ci al pr e c a uti o n s.
2 0 0 m g o v er 3 0 mi n ut e s e v er y 3 w e e k s.
S e e S e cti o n  6. 9 f or s p e ci al pr e c a uti o n s.
P h E ur = E ur o p e a n P h ar m a c o p o ei a ; S m P C = S u m m ar y of pr o d u ct c h a r a ct eri sti c s; U S P = U nit e d St at e s 
P h ar m a c o p ei a .
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
6. 2
St u d y I nter ve nti o n(s) Pre p ar ati o n, H a n dli n g, St or a ge, a n d 
Acc o u nt a bilit y
F urt her g ui da nce a n d i nf or mati o n f or t he pre parati o n, ha n dli n g, a n d st ora ge of st u d y 
i nter ve nti o n(s) are pr o vi de d i n t he P har mac y Ma n ual.
T he In vesti gat or, i nstit uti o n, or t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) is res p o nsi ble 
f or st u d y inter ve nti o n acc o u nta bilit y, rec o nciliati o n, a n d rec or d mai nte na nce 
(i.e, recei pt, 
rec o nciliati o n, a n d fi nal dis p ositi o n rec or ds).

U p o n recei pt of t he st u d y inter ve nti o n(s), t he In vesti gat or or desi g nee m ust c o nfir m a p pr o priate 
te m perat ure c o n diti o ns ha ve bee n mai ntai ne d d uri n g tra nsit a n d a ny discre pa ncies are re p orte d 
a n d res ol ve d bef ore use. Als o, t he res p o nsi ble pers o n will c hec k f or acc urate deli ver y  an d 
ac k n o wle d ge recei pt b y  si g ni n g or i nitiali n g a n d dati n g t he a p pr o priate d oc u me nt a n d ret ur ni n g 
it t o t he l ocati o n s pecifie d. A c o py will be arc hi ve d f or t he I n vesti gat or Site File.

O nl y  partici pa nts e nr olle d i n t he st u d y ma y recei ve st u d y inter ve nti o n(s) a n d o nl y  aut h orize d 
site staff m a y  su p pl y or a d mi nister it. All st u d y i nter ve nti o n(s) m ust be st ore d i n a sec ure, 
e n vir o n me ntall y-c o ntr olle d, a n d m o nit ore d ( ma n ual or a ut o mate d) area, i n acc or da nce wit h t he 
la bele d st ora ge c o n diti o ns, a n d wit h access li mite d t o t he In vesti gat or a n d a ut h orize d site staff.

Dis pe nsi n g will be rec or de d o n t he a p pr o priate acc o u nta bilit y for ms s o t hat acc urate rec or ds 
will be a vaila ble f or verificati o n at eac h m o nit ori n g visit.

St u d y  i nter ve nti o n(s) acc o u nta bilit y rec or ds at t he st u d y site will i ncl u de t he f oll o wi n g:

C o nfir mati o n of recei pt, i n g o o d c o n diti o n a n d i n t he defi ne d te m perat ure ra n ge.

T he i n ve nt or y  pr o vi de d f or t he cli nical st u d y a n d pre pare d at t he site.

T he d ose(s) eac h partici pa nt use d d uri n g t he st u d y.

T he dis p ositi o n (i ncl u di n g ret ur n, if a p plica ble) of a n y  u n use d st u d y i nter ve nti o n(s).

Dates, q ua ntities, batc h n u m bers, c o ntai ner n u m bers, e x pir y dates, f or m ulati o n (f or st u d y 
i nter ve nti o ns pre pare d at t he site), a n d t he partici pa nt n u m bers.

T h e I n vesti gat or site will mai ntai n rec or ds, w hic h a de q uatel y d oc u me nts t hat partici pa nts were 
pr o vi de d t he d oses s pecifie d i n t his pr ot oc ol, a n d all st u d y i nter ve nti o n(s) pr o vi de d were f ully 
rec o ncile d.

U n use d st u d y inter ve nti o n(s) m ust n ot be discar de d or use d f or a n y p ur p ose ot her t ha n t he 
prese nt st u d y. N o st u d y i nter ve nti o n t hat is dis pe nse d t o a partici pa nt ma y be re -dis pe nse d t o a 
differe nt partici pa nt.

A St u d y  M o nit or will peri o dicall y c ollect t he st u d y i nter ve nti o n(s) acc o u nta bilit y f or ms.

Destr ucti o n of use d a n d u n use d st u d y  i nter ve nti o n(s) s h o ul d be perf or me d at site if all o we d b y 
l ocal la w o nl y after S p o ns or a ut h orizati o n. If t hat is n ot p ossi ble, t he S p o ns or/ desi g nee will be 
res p o nsi ble.

F urt her g ui da nce a n d i nf or mati o n f or t he fi nal dis p ositi o n o f u n use d st u d y inter ve nti o n(s) are 
pr o vi de d i n t he P har mac y Ma n ual.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
6. 2. 1
M 7 8 2 4
M 7 8 2 4 dr u g pr o d uct s h o ul d be 
 
 u ntil use. 
 
A d diti o nal i nstr ucti o ns f or t he pre parati o n, ha n dli n g, st ora ge, a n d dis p osal of M 7 8 2 4 will be 
pr o vi de d i n t he P har mac y Ma n ual.
6. 2. 2
Pe m br oliz u m a b
Pe m br o liz u ma b dr u g pr o d uct s h o ul d be
 
 
 
 
 
A d diti o nal i nstr ucti o ns f or t he pre parati o n, ha n dli n g, st ora ge, a n d dis p osal of pe m b r oliz u ma b will 
be pr o vi de d i n t he P har mac y  Ma n ual.
6. 3
Me as ures t o Mi ni mize Bi as: St u d y I nter ve nti o n Assi g n me nt 
a n d Bli n di n g
6. 3. 1
St u d y I nter ve nti o n Assi g n me nt
Partici pa nts will be ra n d o ml y assi g ne d t o treat me nt i n a 1: 1 rati o t o mi ni mize bias. T he 
ra n d o mizati o n will be stratifie d b y  s q ua m o us hist ol o g y , n o ns q ua m o us hist ol o g y  an d ne ver 
s m o ke d, a n d n o ns q ua m o us hist ol o g y  wit h a s m o ki n g hist or y . O nce a partici pa nt meets t he 
eli gi bilit y criteria, is c o nfir me d, a n d is e nr olle d, t he p artici pa nt will be ra n d o ml y assi g ne d t o a 
u ni q ue ra n d o mizati o n n u m ber t hat is ass ociate d wit h 
t he treat me nt assi g n me nt per t he 
ra n d o mizati o n sc he d ule.
Partici pa nt i de ntifiers will c o m prise 1 7 di gits, t he first 1 0 di gits re prese nti n g t he st u d y n u m ber, t he 
foll o wi n g 3 di gits re prese nti n g t he site n u m ber, a n d t he last 4 di gits re prese nti n g t he partici pa nt
n u m ber, w hic h is all ocate d se q ue ntiall y starti n g wit h 0 0 0 1.
After c o nfir mati o n of partici pa nt’s eli gi bilit y an d at t he last practical m o me nt pri or t o st u d y 
inter ve nti o n a d mi nistrati o n, partici pa nts will 
be ce ntrall y all ocate d t o eit her M 7 8 2 4 
or 
pe m br oliz u ma b i n a 1: 1 rati o usi n g a n I nteracti ve We b
Res p o nse S y ste m (IW R S) a n d per a 
c o m p uter-ge nerate d ra n d o mizati o n list.
T he IW R S will be use d t o assi g n u ni q ue par tici pa nt n u m bers, all ocate partici pa nts t o st u d y 
i nter ve nti o n gr o u p at t he ra n d o mizati o n visit, a n d st u d y i nter ve nti o n t o partici pa nts at eac h st u d y 
i nter ve nti o n visit.
Bef ore t he st u d y is i nitiate d, t he I WR S will be pr o vi de d t o eac h site. T he site will c o ntact t he IW R S
pri or t o starti n g st u d y i nter ve nti o n a d mi nistrati o n f or eac h partici pa nt.
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
6. 3. 2
Bli n di n g
T his is a n o pe n -la bel st u d y; t h us, st u d y i nter ve nti o n is n ot bli n de d t o partici pa nts or I n vesti gat ors.
T he I R C will be bli n de d t o a partici pa nt ’s st u d y i nter ve nti o n d uri n g t heir efficac y assess me nts.
T he st u d y tea m is bli n de d f or all a nal yses c o n d ucte d b y  treat me nt ar m u ntil t he I D M C rec o m me n ds 
u n bli n di n g.
6. 4
St u d y I nter ve nti o n C o m pli a nce
I n t his st u d y, partici pa nts will recei ve st u d y inter ve nti o n at t he i n vesti gati o nal site. Well -trai ne d 
me dical staff will m o nit or a n d perf or m t he st u d y i nter ve nti o n a d mi nistrati o n. T he i nf or mati o n of 
eac h a d mi nistrati o n i ncl u di n g t he date, ti me, a n d d ose of st u d y inter v e nti o n will be rec or de d o n 
t he electr o nic case re p ort f or m (e C R F). T he I nvesti gat or will ma ke s ure t hat t he i nf or mati o n 
e ntere d i nt o t he e C R F re gar di n g st u d y i nter ve nti o n a d mi nistrati o n is acc urate f or eac h partici pa nt. 
A n y  reas o n f or n o na d here nce s h o ul d be d oc u me nte d.
N o na d here nce is defi ne d as a partici pa nt missi n g st u d y i nter ve nti o n f or n o n me dical reas o ns a n d 
barri n g a n y e xte n uati n g circ u msta nces i n t he o pi ni o n of t he I nvesti gat or. E xte n uati n g 
circ u msta nces s h o ul d be d oc u me nte d, a n d w he n p ossi ble, disc usse d wit h t he S p o ns or i n a d va nce. 
If t he i nter val bet wee n t he s u bse q ue nt treat me nt c ycle a n d t he last a d mi nistere d treat me nt c ycle is 
l o n ger t ha n 6 wee ks f or n o n me dical reas o ns, t he criteri o n f or i ns ufficie nt a d here nce is met as well.
C o nse q ue nces of n o nc o m plia nce m a y lea d t o disc o nti n uati o n of st u d y inter ve nti o ns as descri be d 
i n Secti o n 7. 1 . In case of o ver d ose, see Secti o n  8. 4.
6. 5
C o nc o mit a nt T her a p y
Rec or d i n t he eC R F all c o nc o mita nt t hera pies (e. g., me dici nes or n o n dr u g i nter ve nti o ns) use d fr o m 
t he ti me t he partici pa nt si g ns t he mai n i nf or me d c o nse nt u ntil c o m pleti o n of t he st u d y, i ncl u di n g 
a n y cha n ges. F or prescri pti o n a n d o ver-t he-c o u nter me dici nes, vacci nes, vita mi ns, a n d her bal 
s u p ple me nts, rec or d t he na me, reas o n f or use, dates a d mi nistere d, a n d d osi n g i nf or mati o n.
C o ntact t he Me dical M o nit or f or a n y q uesti o ns o n c o nc o mita nt or pri or t hera p y.
6. 5. 1
Per mitte d Me dici nes
T he o nl y  per mitte d me dicati o ns are t he f oll o wi n g:
1.
A n y  me dicati o ns ( ot her t ha n t h ose e xcl u de d b y t he e xcl usi o n criteria or t he pr o hi bite d 
me dici nes) t hat are c o nsi dere d nec essar y for t he partici pa nts’ welfare a n d will n ot i nterfere 
wit h t he st u d y i nter ve nti o n ma y  be gi ve n at t he I n vesti gat or’s discreti o n.
2.
Ot her dr u gs t o be use d f or pr o p h yla xis, treat me nt of h yperse nsiti vit y  reacti o ns, a n d treat me nt 
of fe ver or fl u -li ke sy m pt o ms are descri be d i n Secti o n 6. 9 as part of preca uti o ns
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
A n y  me dici nes t hat are c o nsi dere d necessar y  to pr otect t he partici pa nt’s welfare i n e mer ge ncies
ma y  be gi ve n at t he I n vesti gat or’s discreti o n , re gar dless if it res ults i n a pr ot oc ol de viati o n . T he 
Me dical M o nit or m ust be c o ntacte d if a dr u g liste d u n der t he e xcl usi o n criteria was gi ve n, b ut t he 
I n vesti gat or w o ul d li ke t he partici pa nt t o be c o nsi dere d f or c o nti n uati o n o n st u d y.
6. 5. 2
Pr o hi bite d Me dici nes
As state d f or t he e xcl usi o n criteria i n Secti o n 5,  partici pa nts m ust n ot ha ve ha d pri or s yste mic 
c yt ot o xic c he m ot hera p y f or t heir metastatic N S C L C O R a n y a nti b o d y or dr u g tar geti n g T -cell 
c ore g ulat or y pr otei ns (im m u ne c hec k p oi nts) s uc h as a nti-P D - 1, a nti-P D -L 1 , or a nti-C T L A -4 
a nti b o d y O R c o nc urre nt a ntica ncer treat me nt i ncl u di n g:

C y t ore d ucti ve t hera p y

Ra di ot hera p y deli vere d f or n o n - palliati ve i n dicati o ns (see Secti o n 6. 5. 3)

Use of a n y i n vesti gati o nal dr u g as s pecifie d i n Secti o n 1. 3 ( Sc he d ule of Acti vities). 

I m m u n ot hera py, i m m u n os u p pressi ve dr u gs (i.e., c he m ot hera p y or s yste mic c ortic oster oi ds 
e xce pt f or s h ort-ter m treat me nt of aller gic reacti o ns or f or t he treat me nt of ir A Es), or ot her 
e x peri me ntal p har mace utical pr o d ucts. S h ort -ter m a d mi nistrati o n of s yste mic ster oi d (i.e., f or 
aller gic reacti o ns or the ma na ge me nt of ir A Es is all o we d).

Vacci ne a d mi nistrati o n wit hi n 3 0 d a y s bef ore M 7 8 2 4 
or pe m br oliz u ma b a d mi nistrati o n. 
Vacci nati o n wit h li ve vacci nes w hile o n st u d y is pr o hi bite d. A d mi nistrati o n of i nacti vate d 
vacci nes is all o we d ( e. g., i nacti vate d i nfl uenza vacci nes).

A n y  tra diti o nal C hi nese me dicati o n or her bal e q ui vale nt wit h a p pr o val f or use as a ntica ncer 
treat me nt (re gar dless of t he t ype of ca ncer) will n ot be per mitte d. Tra diti o nal C hi nese 
me dicati o n f or i n dicati o ns ot her t ha n a ntica ncer treat me nt, suc h as s u p p orti ve care, m a y  be 
a d mi nistere d at t he discreti o n of t he I n vesti gat or (see  A p pe n di x 4 ).
If t he a d mi nistrati o n of a n o n per mitte d c o nc o mita nt dr u g bec o mes necessar y d uri n g t he st u d y, t he 
partici pa nt will be wit h dra w n fr o m st u d y inter ve nti o n (t he S p o ns or ma y  be c o ntacte d t o disc uss 
w het her t here is a p ossi bilit y  for a partici pa nt t o c o nti n ue o n st u d y). T he partici pa nt s h o ul d 
c o m plete t he E n d - of-Treat me nt Visit a n d be f oll o we d f or s ur vi val.
6. 5. 3
Per mitte d/ Pr o hi bite d Pr oce d ures
Per mitte d Pr oce d ures
O r ga n-s pari n g ra di ot hera p y ma y be a d mi nistere d f or palliati ve a n d/ or s pecific cli nical i n dicati o ns 
d uri n g t he st u d y. T he assess me nt of P D will be ma de acc or di n g t o R E CIS T 1. 1 a n d n ot base d o n 
t he necessi t y for palliati ve ra di ot hera py. T he i n dicati o n f or palliati ve ra di ot hera py m ust be 
d oc u me nte d a n d disc usse d wit h Me dical M o nit or, i n a d va nce of pr oce d ure if cli nicall y feasi ble.
Pr o hi bite d Pr oce d ures
T he f oll o wi n g n o n dr u g t hera pies m ust n ot be a d mi nistere d d uri n g t he st u d y ( or wit hi n 2 8 da y s 
bef ore ra n d o mizati o n):
D oc u me nt N o.
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9

Maj or s ur ger y  (e xcl u di n g pri or dia g n ostic bi o psy) wit hi n 4 wee ks bef ore t he start of t he st u d y . 
Disc uss wit h Me dical M o nit or if u n pla n ne d maj or s ur ger y is re q uire d o n st u d y to pla n f or ti mi n g 
of n e xt d ose.
6. 5. 4
Ot her I nter ve nti o ns
T he f oll o wi n g n o n dr u g t hera pies m ust n ot be a d mi nistere d d uri n g t he st u d y:

Her bal re me dies wit h i m m u n osti m ulati n g pr o perties (e. g., mistlet oe e xtract) or k n o w n t o 
p ote ntiall y  i nterfere wit h maj or or ga n f u ncti o n (f or e xa m ple, hy perici n) .
6. 6
D ose Selecti o n a n d M o dific ati o n
See Secti o n  4. 3 f or t he j ustificati o n of d oses use d i n t his st u d y.
D oses ca n n ot be dela y e d be y o n d t he treat me nt wi n d o w. Partici pa nts m ust s ki p d ose if t he treat me nt 
wi n d o w is misse d. E ver y atte m pt s h o ul d be ma de t o perf or m a p plica ble assess me nts i n Ta ble 1
a nd Ta ble 2 f or a n y misse d visits. C o m plete t he ne xt visit f oll o wi n g t he sc he d ule of assess me nts.
6. 7
St u d y I nter ve nti o n A fter t he E n d of t he St u d y
After a partici pa nt has c om plete d t he st u d y or has wit h dra w n earl y,  partici pa nts ma y  recei ve t he 
care t he y an d t heir p h y sicia ns a gree u p o n. Partici pa nts will be f oll o we d f or s ur vi val a n d A Es as 
s pecifie d i n Secti o n 4. 1.
6. 8
S peci al Prec a uti o ns
6. 8. 1
S pecific Pl a n ne d Assess me nts 
6. 8. 1. 1
A d verse E ve nts of S peci al I nterest /I de ntifie d Ris ks
See Secti o n 6. 9 f or A E SIs a n d ris k ma na ge me nt.
6. 8. 1. 2
A d diti o n al P ote nti al Ris ks
Alterati o ns i n W o u n d Heali n g or Re pair of Tiss ue Da ma ge
D ue t o t he i n v ol ve me nt of T G F β i n tiss ue a n d s ki n re pair, alterati o ns i n w o u n d heali n g or re pair 
of tiss ue da ma ge is c o nsi dere d a n i m p orta nt p ote ntial ris k. N o rele va nt e ve nt is re p orte d i n t he 
o n g oi n g M 7 8 2 4 
cli nical st u dies. M o nit o ri n g of a n y s ur gical w o u n ds 
w hile 
o n st u d y is 
rec o m me n de d. I n ge neral, a 2 -wee k dela y  fr o m treat me nt is rec o m me n d f oll o wi n g mi n or s ur ger y 
a n d 4 wee k dela y f or maj or s ur ger y, b ut cases s h o ul d be disc usse d wit h t he Me dical M o nit or.
E m br y o- fetal T o xicities
E m br y o -fetal t o xicities are a k n o w n ris k of t he P D -1/ P D -L 1 tar geti n g class. A ni mal m o dels li n k 
t he P D-1/ P D -L 1 si g nali n g pat h wa y wit h mai nte na nce of pre g na nc y t hr o u g h i n d ucti o n of mater nal 
i m m u ne t olera nce t o fetal tiss ue (G uleria, 2 0 0 5 ; Le ber , 2 0 1 0 ; Waf ula, 2 0 0 9 ; Ze ncl usse n , 2 0 1 3). 
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
E m br y o -fetal a n d re pr o d ucti ve t o xicities ha ve als o bee n i n vesti gate d i n a ni mal m o dels f or a 
h u ma nize d m o n ocl o nal a nti b o d y tar geti n g T G F β 1. At d oses as hi g h as 3 0 m g/ k g, n o mater nal 
re pr o d ucti ve t o xicit y or e m br yo- fetal let halit y were o bser ve d i n ra b bits (Hil bis h, 2 0 1 6 ). T o 
miti gate 
t hese p ote ntial ris ks, pre g na nt partici pa nts are e xcl u de d fr o m t he st u d y, a n d all 
partici pa nts of c hil d beari n g/c o ncei vi n g p ote ntial m ust use hi g hl y effecti ve c o ntrace pti o n.
6. 8. 2
A d verse 
Dr u g
Re acti o ns 
Re q uiri n g 
Tre at me nt 
Disc o nti n u ati o n 
A d verse dr u g reacti o ns are de fi ne d i n t his st u d y as a n y A Es relate d t o st u d y i nter ve nti o n assesse d 
b y  the I n vesti gat or a n d/ or S p o ns or. Seri o us a d verse reacti o ns are A D Rs w hic h are assesse d as 
seri o us. A n y  q uesti o ns or c o ncer ns wit h re gar ds t o ma na ge me nt a n d/ or f oll o w -u p of A D Rs s h o ul d
be disc usse d wit h t he Me dical M o nit or.
I m m u ne-relate d A Es, I RRs i ncl u di n g h y perse nsiti vit y , a ne mia, T G F β -me diate d s ki n reacti o ns, 
a n d blee di n g e ve nts are ma na ge d a n d f oll o we d -u p i n t heir res pecti ve secti o ns as i n dicate d bel o w. 
Per ma ne nt Treat me nt disc o nti n uati o n ma y  be rec o m me n de d, s o t he rele va nt secti o n m ust be 
re vie we d:

F or ma na ge me nt a n d g ui da nce of s us pecte d ir A Es, see Secti o n  6. 9. 2. 

F or i nf usi o n -relate d reacti o ns a n d h yperse nsiti vit y reacti o ns g ui da nce , see Secti o n  6. 9. 1.

F or a ne mia g ui da nce , see Secti o n  6. 9. 4. 

F or g ui da nce a n d ma na ge me nt f or p ote ntiall y T G F β me diate d s ki n A Es, see Secti o n  6. 9. 3

F or g ui da nc e a n d ma na ge me nt of blee di n g e ve nts, see Secti o n  6. 9. 5.
Ge ner al g ui d a nce :

I n a ny case, if ≥2 d oses are misse d d ue t o A E, t he Me dical M o nit or s h o ul d be c o ns ulte d.

I na bilit y to re d uce c ortic oster oi d d ose t o 1 0 m g or less of pre d nis o ne or e q ui vale nt per d a y  
wit hi n 1 2 wee ks is a n i n dicati o n f or per ma ne nt treat me nt disc o nti n u ati o n (e xce pt f or use of 
ster oi ds as h or m o ne s u bstit uti o n).

Persiste nt Gra de 2 or 3 a d verse reacti o ns (e xcl u di n g e n d ocri n o pat hies c o ntr olle d wit h h or m o ne 
re place me nt t hera p y) t hat d o n ot rec o ver t o Gra de ≤1 wit hi n 1 2 wee ks after last d ose of st u d y  
i nter ve nti o n is a n i n dicati o n f or per ma ne nt treat me nt disc o nti n uati o n.
Gr a de 4 A D Rs:

Partici pa nts wit h A n y Gra de 4 A D Rs re q uire per ma ne nt treat me nt disc o nti n uati o n e xce pt:
a.
Is olate d la b orat or y val ues o ut of n or mal ra n ge t hat d o n ot ha ve a n y c li nical c orrelati o n. 
Disc uss 
wit h 
Me dical 
M o nit or 
re gar di n g w or k -u p, ma na ge me nt, 
a n d treat me nt 
c o nti n uati o n vers us h ol d vers us disc o nti n uati o n f or is olate d Gra de 4 la b orat or y 
a b n or malities. 
b.
E n d ocri n o pat hies c o ntr olle d wit h h or m o ne re place me nt t hera p y. 
c.
If alter nati ve e x pla nati o n is i de ntifie d f or Gra de 4 n o n-t u m or blee di n g.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
See Secti o n 6. 9. 2 f or ot her s us pecte d Gra de 4 ir A Es, as m ost re q uire per ma ne nt treat me nt 
disc o nti n uati o n.
Gr a de 3 A D Rs:
1.
Partici pa nts wit h a n y se vere or Gra de 3 treat me nt-relate d a d verse reacti o ns t hat rec ur s h o ul d 
be per ma ne ntl y disc o nti n ue d. E xce pti o ns ma y  be c o nsi dere d as f oll o ws after disc ussi o n wit h 
Me dical M o nit or :
a.
Tra nsie nt (≤ 6 h o urs) Gra de 3 fl u-li ke s ym pt o ms or fe ver, w hic h is c o ntr olle d wit h 
me dical ma na ge me nt .
b.
Tra nsie nt (≤ 2 4 h o urs) Gra de 3 fati g ue, l ocal reacti o ns, hea dac he, na usea, e mesis t hat 
res ol ves t o ≤ Gra de 1 or baseli ne. 
c.
T u m or flare p he n o me n o n defi ne d as l ocal pai n, irritati o n, or ras h l ocalize d at sites of 
k n o w n or s us pecte d t u m or.
d.  
G ra de 3 he m o gl o bi n decrease ( < 8. 0 g/ d L) t hat is cli nicall y ma na gea ble wit h bl o o d 
tra nsf usi o ns or er yt hr oi d gr o wt h fact or. 
e.
I ncreases i n E C O G P S ≥3 t hat res ol ves t o ≤ 2 b y  Da y 1 of t he ne xt i nf usi o n 
(i.e., i nf usi o ns s h o ul d n ot be gi ve n if t he E C O G P S is ≥ 3 o n t he da y  of treat me nt a n d 
s h o ul d be dela ye d u ntil E C O G P S ≤ 2).
f.
Kerat oaca nt h o mas a n d/ or c S C C (see Secti o n  6. 9. 3 f or ma na ge me nt).
g.
Gra de 3 n o n- t um or blee di n g re q uiri n g i nter ve nti o n or h os pitalizati o n if alter nati ve 
e x pla nati o n ca n be i de ntifie d (s uc h as c o nc o mita nt use of a ntit hr o m b otic a ge nts, 
tra u matic e ve nt, etc).
2. See Secti o n 6. 9. 2
f or s us pecte d Gra de 3 ir A Es as ma n y re q uire per ma ne nt treat me nt 
disc o nti n uati o n, i ncl u di n g p ne u m o nitis a n d ne p hritis.
a.
A S T or A L T > 5 ti mes U L N or t otal bilir u bi n greater t ha n 3 ti mes U L N m ust be 
per ma ne ntl y di sc o nti n ue d, e xce pt f or partici pa nts wit h li ver metastases (f or e xa m ple) w h o 
be gi n treat me nt wit h Gra de 2 A S T or A L T. T hese partici pa nts s h o ul d be disc o nti n ue d if 
A S T or A L T i ncreases b y ≥5 0 % relati ve t o baseli ne a n d lasts f or at least 1 wee k.
3. Persiste n t Gra de 3 a d verse reacti o ns (e xcl u di n g e n d ocri n o pat hies c o ntr olle d wit h h or m o ne 
re place me nt t hera py)  t hat d o n ot rec o ver t o Gra de ≤ 1 wit hi n 1 2 wee ks after d ose of treat me nt .
Gra de 2 A D Rs s h o ul d be ma na ge d as f oll o ws:

If a Gra de 2 A D R res ol ves t o Gra de ≤ 1 b y  the d a y  bef ore t he ne xt i nf usi o n, treat me nt m a y  
c o nti n ue.

If a Gra de 2 A D R d oes n ot resol ve t o Gra de ≤ 1 b y  the d a y  bef ore t he ne xt i nf usi o n, b ut it is 
ma na gea ble a n d/ or n ot cli nicall y  rele va nt, t he Me dical M o nit or s h o ul d be c o ns ulte d t o assess 
if cli nicall y reas o na ble t o a d mi nister t he f oll o wi n g i nf usi o n.
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
6. 9
M a n a ge me nt of A d verse E ve nts of S peci al I nterest
As a part of preca uti o nar y  safet y meas ures, a ris k ma na ge me nt g ui da nce is defi ne d f or b ot h 
treat me nt ar ms ( M 7 8 2 4 a n d pe m br oliz u ma b) f or I R Rs a n d ir A Es, w hic h ma y arise o n eit her ar m 
d ue t o t he c o m m o n m A b i n hi biti o n of P D -L 1 .
6. 9. 1
I nf usi o n-rel ate d 
Re acti o ns 
I nclu di n g 
I m me di ate 
H y perse nsiti vit y
I nf usi o n-relate d reacti o ns, i ncl u di n g hy p erse nsiti vit y, are defi ne d i n t his secti o n.  I nf usi o n-relate d 
reacti o ns are A E SIs a n d i de ntifie d ris ks f or M 7 8 2 4.
I nf usi o n-relate d reacti o ns are defi ne d as a n y si g ns or s ym pt o ms e x perie nce d b y  partici pa nts 
occ urri n g d uri n g or wit hi n 1 da y  of st u d y i nter ve nti o n a d mi nistrati o n. A n assess me nt f or p ossi ble 
I R R s h o ul d be tri g gere d base d u p o n t he de vel o p me nt of s pecific s ym pt o ms wit hi n 2 4 h o urs of a n 
i nf usi o n.
T hese p ossi ble I R Rs are i de n tifie d base d o n a list of Me dical Dicti o nar y f or Re g ulat or y Acti vities 
( Me d D R A) preferre d ter ms a n d criteria base d o n t he ti mel y relati o ns hi p t o a n i nf usi o n. E ve nts are 
di vi de d i nt o reacti o ns vers us si g ns a n d s y m pt o ms:

I nf usi o n-relate d reacti o ns s h o ul d be c o nsi dere d w he n o nset is o n t he da y of 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 i nf usi o n (irres pecti ve of res ol uti o n date) f or 
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 , a n d 
T y pe 1 h y p ersensiti vit y . 

Si g ns a n d s ym pt o ms of I R Rs a n d h y perse nsiti vit y/aller gic reacti o ns s h o ul d be c o nsi dere d w he n 
o nset is o n t he d a y  of 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 c o m pletel y wit h t he 
e n d date wit hi n 2 d a y s after o nset of ( b ut n ot li mite d t o) p yre xia, c hills, fl us hi n g, h yp ote nsi o n, 
d y s p nea, w heezi n g, bac k pai n, a b d o mi nal pai n, a n d urticaria.
M a n a ge me nt of I nf usi o n -Rel ate d Re acti o ns
C urre nt e x perie nce i n m ore t ha n 7 0 0 st u d y partici pa nts re veale d t hat I R Rs t o M 7 8 2 4 occ ur 
sel d o ml y an d are ge n erall y 
mil d t o m o derate 
i n se verit y. T heref ore, a d mi nistrati o n of a 
pre me dicati o n is ge nerall y  n ot re q uire d. 
If a n i n vesti gat or dee ms necessar y  to a d mi nister a pre me dicati o n t o a partic ular partici pa nt, a n 
a nti hista mi ne (e. g. 2 5 t o 5 0 m g di p he n h y dra mi ne) a n d paraceta m ol (aceta mi n o p he n, 5 0 0 t o 6 5 0 
m g i v or e q ui vale nt oral d ose) 3 0 t o 6 0 mi n utes pri or t o M 7 8 2 4 i nf usi o n is rec o m me n de d. 
Pre me dicati o n s h o ul d be a d mi nistere d f or s u bse q ue nt M 7 8 2 4 d oses base d u p o n cli nical j u d g me nt 
a n d prese nce/se verit y of pri or i nf usi o n reacti o ns. T his re gi me n m a y  be m o difie d base d o n l ocal 
D oc u me nt N o.
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
treat me nt sta n dar ds a n d g ui deli nes as a p pr o priate, pr o vi de d it d oes n ot i ncl u de s yste mic 
c ortic oster oi ds.
T a ble 8
Tre at me nt M o dific ati o n f or S y m pt o ms of I nf usi o n -rel ate d Re acti o ns
N CI - C T C A E v 5. 0 Gr a d e
Tr e at m e nt M o difi c ati o n 
Gr a d e 1 – mil d
Mil d tr a n si e nt r e a cti o n ; i nf u si o n i nt err u pti o n n ot 
i n di c at e d; i nt er v e nti o n n ot i n di c at e d.
I n cr e a s ed
m o nit ori n g of vit al si g n s a s m e di c all y 
i n di c at e d, pr e s u mi n g t h e s e p arti ci p a nt s ar e d e e m e d 
m e di c all y st a bl e.
Gr a d e 2 – m o d er at e
T h er a p y or i nf u si o n i nt err u pti o n i n di c at e d b ut if 
r e s p o n d s pr o m ptl y t o s y m pt o m ati c tr e at m e nt (f or 
e x a m pl e, a nti hi st a mi n e s, N S AI D s, n ar c oti c s, I V fl ui d s); 
pr o p h yl a cti c m e di c ati o n s i n di c at e d f or 2 4 h o ur s.
St o p M 7 8 2 4/ P e m br oli z u m a b
i nf u si o n.
I n cr e a s ed
m o nit ori n g of vit al si g n s a s m e di c all y 
i n di c at e d a s p arti ci p a nt s ar e d e e m e d m e di c all y st a bl e 
b y att e n di n g I n v e sti g at or. 
If s y m pt o m s r e s ol v e q ui c kl y or d e cr e a s e d t o Gr a d e 1 , 
r e s u m e i nf u si o n at 5 0 % of ori gi n al r at e wit h cl o s e 
m o nit ori n g of a n y w or s e ni n g ot h er wi s e d o si n g h el d u ntil 
r e s ol uti o n of s y m pt o m s wit h m a n d at e d pr e m e di c ati o n 
f or t h e n e xt s c h e d ul e . 
If w or s e n s t o Gr a d e 3 or 4, f oll o w tr e at m e nt m o difi c ati o n 
g ui d eli n e s a c c or di n gl y.
Gr a d e 3 or Gr a d e 4 – s e v er e or lif e- t hr e at e ni n g
Gr a d e 3: Pr ol o n g e d ( f or e x a m pl e, n ot r a pi dl y 
r e s p o n si v e t o s y m pt o m ati c m e di c ati o n a n d/ or bri ef 
i nt err u pti o n of i nf u si o n); r e c urr e n c e of s y m pt o m s 
f oll o wi n g i niti al i m pr o v e m e nt; h o s pit ali z ati o n i n di c at e d 
f or cli ni c al s e q u el a e.
Gr a d e 4: Lif e -t hr e at e ni n g c o n s e q u e n c e s; ur g e nt 
i nt er v e nti o n i n di c at e d.
St o p t h e M 7 8 2 4/ P e m br oli z u m a b i nf u si o n i m m e di at el y 
a n d di s c o n n e ct i nf u si o n t u bi n g fr o m t h e p arti ci p a nt wit h 
a d diti o n al a p pr o pri at e m e di c al m e a s ur e s a n d cl o s e 
m o nit ori n g u ntil d e e m e d m e di c all y st a bl e b y att e n di n g 
I n v e sti g at or. H o s pit ali z ati o n m a y b e i n di c at e d.
P arti ci p a nt s will b e p er m a n e ntl y wit h dr a w n i m m e di at el y 
fr o m M 7 8 2 4/ P e m br oli z u m a b tr e at m e nt a n d m u st n ot 
r e c ei v e a n y f urt h er M 7 8 2 4/ P e m br oli z u m a b tr e at m e nt
N CI -C T C A E = N ati o n al C a n c er I n stit ut e -C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt; N S AI D s = n o n st er oi d al 
a nti -i nfl a m m at or y dr u g s. 
F or Gr a d e 3 or 4 i nf u si o n -r el at e d r e a cti o n s, M 7 8 2 4/ P e m br oli z u m a b di s c o nti n u ati o n i s m a n d at e d.
F or all t y p e s a n d gr a d e s of i nf u si o n r e a cti o n s, d et ail s a b o ut dr u g p h y si c al c o n stit uti o n, m et h o d of pr e p ar ati o n a n d 
i nf u si o n m u st b e r e c or d e d.
I n t he e ve nt of a Gra de 2 I R R t hat d oes n ot i m pr o ve or w orse ns after i m ple me ntati o n of t he d ose 
m o dificati o ns i n dicate d i n Ta ble 8   (i ncl u di n g re d uci n g t he i nf usi o n rate b y 5 0 %), t he I n vesti gat or 
ma y  co nsi der treat me nt wit h c ortic oster oi ds a n d t he i nf usi o n s h o ul d be st o p pe d f or t hat da y . At 
t he ne xt i nf usi o n, t he I nvesti gat or m a y  co nsi der t he a d diti o n of H 2 bl oc ker a nti hista mi nes (f or 
e xa m ple, fa m oti di ne or ra niti di ne), i n a d diti o n t o pr o p ose d pre me dicati o n, f or select partici pa nts. 
H o we ver, pr o p h yl actic ster oi ds are N O T per mitte d. At ne xt d ose, if t he partici pa nt has a sec o n d 
I R R Gra de ≥ 2 o n t he sl o wer i nf usi o n rate, wit h t he a d diti o n of f urt her me dicati o n 
t o 
pre me dicati o n, t he i nf usi o n s h o ul d be st o p pe d, a n d t he partici pa nt re m o ve d fr o m treat me nt.
H y perse nsiti vit y  Reacti o n
If a h y perse nsiti vit y reacti o n occ urs, t he partici pa nt m ust be treate d acc or di n g t o t he best a vaila ble 
me dical practice. A c o m plete g ui deli ne f or t he e mer ge nc y treat me nt of a na p h ylactic reacti o ns 
acc or di n g t o t he W or ki n g 
Gr o u p of t he Res uscitati o n C o u ncil ( UK ) a n d ca n be f o u n d at 
htt ps:// w w w.res us. o r g. u k/ pa ges/reacti o n. p df. Partici pa nts s h o ul d be i nstr ucte d t o re p ort a n y 
dela y e d reacti o ns t o t he I n vesti gat or i m me diatel y .
S y m pt o ms m a y  i ncl u de, b ut are n ot li mite d t o: 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9

I m paire d air wa y

Decrease d o x y ge n sat urati o n ( < 9 2 %)

C o nf usi o n

Let har g y

H y p ote nsi o n

P ale/cla m m y s ki n

C y a n osis.
Ma na ge me nt of h y p erse nsiti vit y i ncl u des: 
1.
E pi ne p hri ne i njecti o n a n d i v de xa met has o ne
2.
Partici pa nt s h o ul d be place d o n car diac, bl o o d press ure, heart rate, a n d o x y ge n sat urati o n 
m o nit or i m me diatel y
3.
Alert i nte nsi ve care u nit f or p ossi ble tra nsfer if re q uire d.
Pr o p h y la xis of fl u-li ke s y m pt o ms
F or pr o p h yl a xis of fl u -li ke s ym pt o ms, a n o nster oi dal a nti-i nfla m mat or y dr u g ( N S AI D), f or 
e xa m ple, i b u pr ofe n 4 0 0 m g or c o m para ble N S AI D d ose, ma y  be a d mi nistere d 2 h o urs bef ore a n d 
8 h o urs aft er t he start of eac h I V i nf usi o n.
6. 9. 2
I m m u ne-rel ate d A d verse E ve nts
I m m u ne-relate d A Es are s pecific t o i m m u n ot hera pies a n d var y b y or ga n s yste m. I m m u ne-relate d 
A Es are c o nsi dere d A E SIs f or b ot h M 7 8 2 4 a n d pe m br oliz u ma b. 
I n ge neral, t he s pectr u m of ir A Es are similar f or b ot h M 7 8 2 4 a n d pe m br oliz u ma b.
T he f oll o wi n g ir A Es are i m p orta nt i de ntifie d ris ks f or M 7 8 2 4. 

Im m u ne -relate d p ne u m o nitis

I m m u ne-relate d he patitis

I m m u ne-relate d c olitis

I m m u ne-relate d ne p hritis a n d re nal dys f u ncti o n

I m m u ne-relate d e n d ocri n o pat hies (t h yr oi d dis or ders, a dre nal i ns ufficie nc y, t ype 1 dia betes 
mellit us, pit uitar y  dis or ders)

I m m u ne-relate d ras h

Ot her i m m u ne- relate d e ve nts ( m yositis, m y ocar ditis, e nce p halitis)
T he f oll o wi n g ir A Es are i m p orta nt p ote ntial ris ks f or M 7 8 2 4 :
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9

G uillai n -Barré s y n dr o me

U veitis

Pa ncreatitis

M y ast he nia gra vis/ m yast he nic s y n dr o me
T he Me dical M o nit or ma y  be i n v ol ve d as nee de d f or F oll o w - u p. Details of t he dia g n ostic w or k -
u p will be re q ueste d b y t he st u d y  tea m. 
T he rec o m me n dati o ns f or ir A E ma na ge me nt, are g ui de d b y t he j oi nt A merica n S ociet y of Cli nical 
O nc ol o g y  (A S C O) Cli nical Practice G ui deli nes (Bra h mer, 2 0 1 8 ) a n d Nati o nal C o m pre he nsi ve 
Ca ncer Net w or k ( N C C N) (N C C N G ui deli nes ® ), liste d i n A p pe n di x 5 . Of n ote, official g ui da nce 
is als o a vaila ble fr o m Merc k S har p & D o h me f or ma na ge me nt a n d dr u g disc o nti n uati o n f or certai n 
ir A Es i n t he pe m br oliz u ma b F D A la bel ( Ke ytr u da U S PI). T hese ir A Es i ncl u de: p ne u m o nitis, 
c olitis, he patitis, e n d ocri n o pat hies (i ncl u di n g h y p o p h y sitis, t h yr oi d dis or ders, t ype 1 dia betes 
mellit us), a n d ne p hritis. T his pe m br oliz u ma b -s pecific g ui da nce is c o vere d i n t he A S C O/ N C C N 
g ui deli nes; h o we ver, res o urces fr o m Merc k & C o m pa n y f or partici pa nts w h o de vel o p t hese ir A Es 
w hile o n t he pe m br oliz u ma b treat me nt ar m are t o be c o nsi dere d as well.
Ge neral ma na ge me nt b y  N CI- C T C A E v 5. 0 gra di n g, as per A S C O, is liste d bel o w:

Gra de 1: st u d y treat me nt s h o ul d be c o nti n ue d wit h cl ose m o nit ori n g, w it h t he e xce pti o n of s o me 
ne ur ol o gic, he mat ol o gic, a n d car diac t o xicities. 

Gra de 2: st u d y treat me nt ma y  b e sus pe n de d f or m ost Gra de 2 t o xicities, wit h c o nsi derati o n of 
res u mi n g w he n s ym pt o ms re vert t o Gra de 1 or less. C ortic oster oi ds ma y  be a d mi nistere d (i nitial 
d ose of 0. 5 t o 1 m g/ k g/ d of pre d nis o ne or e q ui vale nt). 

Gra de 3: st u d y  treat me nt is ge nerall y s us pe n de d a n d t he hi g h-d ose c ortic oster oi ds ( pre d nis o ne 
1 t o 2 m g/ k g/ d 
or met h y l pre d nis ol o ne 1 t o 2 m g/ k g/ d) 
treat me nt s h o ul d be i nitiate d. 
C ortic oster oi ds s h o ul d be ta pere d o ver t he c o urse of at least 4 t o 6 wee ks. S o me refract or y cases 
ma y  re q uire i nfli xi ma b or ot her i m m u n os u p pressi ve t hera py. 

Gra de 4: i n ge neral, per ma ne nt disc o nti n uati o n of st u d y treat me nt is rec o m me n de d, wit h t he 
e xce pti o n of e n d ocri n o pat hies t hat ha ve bee n c o ntr olle d b y  h or m o ne re place me nt.
Per ma ne nt 
treat me nt disc o nti n uati o n 
is re q uire d i n case of 
i m m u ne-relate d Gra de 4 
ras h/i nfla m mat or y der matitis, ne p hritis, a ut oi m m u ne he m ol y tic a ne mia, he m ol yt ic ure mic 
s yn dr o me, a plastic a ne mia, i m m u ne t hr o m b oc yt o pe nia a n d ac q uire d t hr o m b otic t hr o m b oc yt o pe nic 
p ur p ura ( T T P). 
F or Gra de 4 i m m u ne -relate d l ym p h o pe nia, per ma ne nt treat me nt disc o nti n uati o n will be re q uire d, 
if l ym p h o pe nia is c o nsi dere d i m m u ne -relate d i n nat ure, n o clear alter nati ve e x pla nati o n e xists f or 
t he e ve nt, a n d Gra de 4 l ym p h o pe nia d oes n ot resol ve wit hi n 1 4 da y s. Per ma ne nt treat me nt 
disc o nti n uati o n is n ot re q uire d w he n t he A E is ma nifest b y a si n gle la b orat or y val ue o ut of n or mal 
ra n ge wit h o ut a n y cli nical c orrelates. I n t his case, treat me nt s h o ul d be hel d u ntil t he eti ol o g y is 
deter mi ne d. If the e ve nt is n ot c o nsi dere d i m m u ne -relate d a n d res ol ves t o Gra de ≤ 1 restarti n g 
treat me nt ma y be c o nsi dere d.
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
F or a d diti o nal or ga n/s ys te m s pecific ma na ge me nt g ui deli nes, re vie w A S C O g ui deli ne ta bles i n 
A p pe n di x 5 .
Rec o m me n de d g ui da nce a n d ma na ge me nt f or s pecific ir A Es are pr o vi de d i n t he c urre nt N C C N 
g ui deli ne a vaila ble at  htt p:// w w w. ncc n. or g .
6. 9. 3
T G F β In hi biti o n M e di ate d S ki n R e acti o ns
T G F β i n hi biti o n me diate d 
s ki n reacti o ns, i ncl u di n g h y pe r kerat osis, K A 
a n d/ or c uta ne o us 
s q ua m o us cell carci n o mas (c S C C), are i m p orta nt i de ntifie d ris ks f or M 7 8 2 4
a n d c o nsi dere d as 
A E SI . Cases of K A a n d c S C C ha ve als o bee n re p orte d f or patie nts u n der treat me nt wit h ot her 
c hec k p oi nt i n hi bit ors as well (Freites - Marti nez, 2 0 1 7 ; Be d nare k, 2 0 1 8 ).T he distri b uti o n of lesi o ns 
te n ds t o be i n s u n-e x p ose d areas. S ki n assess me nts will be perf or me d f or all partici pa nts per t he 
S o A (see Ta ble 1 ).
Ma na ge me nt g ui deli nes f or p ote ntial T G F β i n hi biti o n me diate d s ki n reacti o ns are:
1.
Disc o nti n uati o n or i nterr u pti o n is n ot re q uire d i n m ost cases. C o nti n uati o n o f treat me nt s h o ul d 
be e val uate d b y t he I n vesti gat or. 
2.
E m ollie nts ma y  c o nti n ue t o be use d.
3.
Dia g n ostic a n d treat me nt pla n s h o ul d be de vel o pe d i n c olla b orati o n bet wee n I n vesti gat or a n d 
der mat ol o gist. I n ge neral, treat me nt of T G F β me diate d s ki n lesi o ns s uc h as h y per kerat osis, K A 
a n d c S C C s h o ul d be base d o n l ocal g ui deli nes/ S o C. Lesi o n e val uati o n s h o ul d i ncl u de e xcisi o n 
bi o ps y  of o ne re prese ntati ve lesi o n t o c o nfir m dia g n osis.
4.
Treat me nt a n d F oll o w -u p f or K A a n d c S C C will de pe n d o n n u m ber a n d l ocalizati o n of lesio ns.
F or si n gle lesi o ns: F ull e xcisi o n ma y  be rec o m me n de d.

I n case of m ulti ple lesi o ns or l ocati o n n ot s uita ble f or f ull e xcisi o n, ot her treat me nt o pti o ns 
ma y  be offere d by t he der mat ol o gist, s uc h as:

M o hs 
s ur ger y, cr y ot hera p y, or ot her sta n dar d treat me nt o pti o ns de pe n di n g o n t he 
pat h ol o g y . 

Use of reti n oi ds, if rec o m me n de d b y  der mat ol o gist, ma y  be c o nsi dere d after disc ussi o n 
wit h Me dical M o nit or. 
5.
Cl ose cli nical F oll o w -u p f or r e-e val uati o n, res ol uti o n, or p ote ntial rec urre nce s h o ul d b e 
i m ple me nte d.
6.
S p o nta n e o us res ol uti o n of K A lesi o ns wit h o ut s ur gical i nter ve nti o n has bee n o bser ve d, 
t ypicall y occ urri n g wit hi n wee ks after disc o nti n ui n g M 7 8 2 4.
7.
T he n u m ber a n d l ocalizati o n of lesi o ns, dia g n osis (i ncl u di n g hist o pat h ol o gical dia g n osis), 
treat me nt, a n d o utc o me s h o ul d be a p pr o priatel y d oc u me nte d i n t he e C R F.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
C o ns ult wit h st u d y 
Me dical M o nit or, 
as nee de d, f or ma na ge me nt of T G F β -me diate d s ki n 
reacti o ns.
6. 9. 4
A ne mi a
A ne mia is a n A E SI a n d a n i m p orta nt i de ntifie d ris k f or M 7 8 2 4. N ota bl y , t here are ma n y reas o ns 
f or a ne mia i n patie nts wit h a d va nce d ca ncer, t heref ore a t h or o u g h i n vesti gati o n of ne w a ne mia 
cases of u ns pecifie d eti ol o g y  is re q ueste d.
F or ne w a ne mia e ve nts ite ms q uerie d m a y  incl u de, b ut are n ot li mite d t o, detaile d rele va nt past 
me dical a n d treat me nt hist or y , br u isi n g te n de nc y, hist or y  of bl o o d tra nsf usi o ns a n d/ or de pe n de nc y , 
a n d a re q uest f or a n u p date d e C R F i ncl u di n g details s uc h as c o nc o mita nt me dicati o ns, all 
la b orat or y data, u p date d d osi n g i nf or mati o n a n d, rece nt t u m or e val uati o n sca ns. 
Ge neral g ui da nce f or a ne mia ma na ge me nt a n d e val uati o n:

Partici pa nts m ust e nter t he st u d y wit h he m o gl o bi n val ues at least 9 g/ d L ; R o uti ne bl o o d test 
para meters are s pecifie d i n Ta ble 1 6.

All rele va nt he mat ol o gic testi n g f or treat me nt-relate d a ne mias s h o ul d be d o ne pri or t o bl o o d 
tra nsf usi o n, if cli nically feasi ble.

If a partici pa nt e x perie nces si g nifica nt a ne mia ( e. g., < 8 g/ d L), t he n t he a m o u nt of bl o o d t o be 
dra w n m a y  be re d uce d b y  not ta ki n g bl o o d at selecte d ti me p oi nts f or p har mac o d y n a mic 
a n d  
. T he decisi o n t o re d uce t he ti me p oi nts f or t hese 
 will be ta ke n 
b y  t he I n vesti gat or i n c o ns ultati on wit h t he Me dical M o nit or. T his will be d oc u me nte d. Bl o o d 
will c o nti n ue t o be ta ke n as sc he d ule d f or safet y anal y ses, P K, a n d a nti-dr u g a nti b o dies ( A D As).

Tra nsf usi o n s h o ul d be perf or me d at t he discreti o n of t he I nvesti gat or, base d o n cli nical 
assess me nt a n d c o nsi dere d w he n partici pa nt e x perie nces si g nifica nt a ne mia. atte m pt s h o ul d be 
ma de t o i nitiate w or k -u p (as s pecifie d bel o w) f or ca use of a ne mia pri or t o tra nsf usi o n if 
cli nicall y feasi ble t o n ot c o nf o u n d t his w or k-u p. G ui da nce f or e val uati o n of s us pect e d a ne mias 
is pr o vi de d i n Ta ble 9.

Disc uss f urt her ma na ge me nt wit h Me dical M o nit or f or cli nicall y si g nifica nt treat me nt-relate d 
a ne mias.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
T a ble 9
E v al u ati o n G ui d a nce of S us pecte d A ne mi a A d verse E ve nts
B a s i c A n e mi a E v al u ati o n 
1.
C B C wit h e m p h a si s o n r e d c ell i n di c e s (e. g. , H g b, h e m at o crit, M C V, R D W , M C H, M C H C, r eti c ul o c yt e s c o u nt s).
2.
If i n di c at e d a n d at cli ni c al di s cr eti o n, t h e f oll o wi n g s h o ul d b e c o n si d er e d:
a.
Ir o n st u di e s ( TI B C, F erriti n, F e)
b.
S er u m F ol at e a n d Vit B 1 2 v al u e s
c.
C o a g ul ati o n f a ct or s ( P T, P T T, I N R)
d.
F e c al o c c ult bl o o d t e sti n g
e.
Uri n al y si s
f.
H or m o n e p a n el: T S H, Er yt hr o p oi eti n
g.
P eri p h er al bl o o d s m e ar f or c ell m or p h ol o gi c al a s s e s s m e nt
F urt h er R e c o m m e n d ati o n B a s e d o n S u s p e ct e d Eti ol o g y  (i n A d diti o n t o B a s eli n e A n e mi a T e sti n g)
S u s p e c t e d h e m ol y si s:
Bilir u bi n l e v el, L D H, C o o m b s t e st, fi bri n o g e n, h a pt o gl o bi n , d-Di m er
C o n si d er H e m at ol o g y c o n s ult ati o n.
S u s p e ct e d bl e e di n g :
C o n si d er i m a gi n g/i nt er v e nti o n al r a di ol o g y c o n s ult ati o n a s i n di c at e d
C o n si d er e n d o s c o p y , a s cli ni c all y i n di c at e d.
C o n si d er i m a gi n g, a s cli ni c all y i n di c at e d .
S u s p e ct e d a pl a sti c a n e mi a:  
H e m at ol o g y c o n s ult ati o n.
C o n si d er b o n e m arr o w a s pir ati o n/ m or p h ol o gi c e v al u ati o n.
C B C = c o m pl et e bl o o d c o u nt, F e =Ir o n, H g b = h e m o gl o bi n , I N R =i nt er n ati o n al n or m ali z e d r ati o, L D H =l a ct at e d e h y dr o g e n a s e, 
M C H = M e a n C or p u s c ul ar H a e m o gl o bi n,
M C H C = M e a n C or p u s c ul ar H a e m o gl o bi n C o n c e ntr ati o n,
M C V = m e a n c or p u s c ul ar 
v ol u m e, P T = pr ot hr o m bi n ti m e, P T T = p ar ti al t hr o m b o pl a sti n ti m e, R D W = R e d Bl o o d C ell Di stri b uti o n W i dt h, TI B C =t ot al 
ir o n bi n di n g c a p a cit y, a n d T S H =t h yr oi d -sti m ul ati n g h or m o n e.
6. 9. 5
Blee di n g E ve nts
Blee di n g A Es are A E SIs a n d c o nsi dere d i m p orta nt i de ntifie d ris k f or M 7 8 2 4 
(refer t o t he 
In vesti gat or’s Br oc h ure ).
6. 9. 5. 1
M uc os al/ N o n -t u m or Blee di n g
Partici pa nts treate d wit h M 7 8 2 4 were c o m m o nl y re p orte d wit h mil d t o m o derate m uc osal A Es 
s uc h as e pista xis, he m o pt ysis, gi n gi val blee di n g a n d he mat uria. I n ge neral, t hese reacti o ns res ol ve 
wit h o ut disc o nti n uati o n of t reat me nt.

If a Gra de 2 treat me nt-relate d T E A E i m pr o ves t o Gra de ≤ 1 or c o m pletel y  res ol ves b y t he da y 
bef ore t he ne xt i nf usi o n, M 7 8 2 4 ma y  be c o nti n ue d

If a Gra de 2 treat me nt-relate d n o n- t u m or blee di n g d oes n ot i m pr o ve t o Gra de ≤ 1 or c o m pletel y 
res ol ve b y t he da y bef ore t he ne xt i nf usi o n, b ut it is ma na gea ble a n d/ or n ot cli nicall y rele va nt, 
t he Me dical M o nit or s h o ul d be c o ns ulte d t o assess if it is cli nicall y reas o na ble t o a d mi nister t he 
f oll o wi n g i nf usi o n.

F or Gra de 3 n o n -t u m or blee di n g, st u d y treat me nt m u st be per ma ne ntl y disc o nti n ue d u nless a n 
alter nati ve e x pla nati o n ca n be i de ntifie d (s uc h as c o nc o mita nt use of a ntit hr o m b otic a ge nts, 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
tra u matic e ve nt, etc). I n case of alter nati ve e x pla nati o ns f or t he Gra de 3 blee di n g e ve nt, st u d y 
treat me nt s h o ul d be hel d u ntil t he e ve nt rec o vers t o Gra de ≤1.

F or Gra de 4 n o n -t u m or blee di n g, treat me nt m ust be per ma ne ntly disc o nti n ue d if n o alter nati ve 
e x pla nati o n is i de ntifie d.
6. 9. 5. 2
T u m or Blee di n g
Partici pa nts treate d wit h M 7 8 2 4 were re p orte d i n l o wer fre q ue ncies, wit h Gra de ≥3 he m orr ha ges 
i ncl u di n g t u m or blee di n g.
F or Gra de ≥ 2 t u m or blee di n g, st u d y  treat me nt m ust be hel d u ntil t he e ve nt rec o vers t o Gra de ≤1 
Treat me nt s h o ul d be per ma ne ntl y  disc o nti n ue d if t he I nvesti gat or c o nsi ders t he partici pa nt t o be 
at ris k f or a d diti o nal se vere blee di n g.
7
Disc o nti n u ati o n 
of 
St u d y 
I nter ve nti o n a n d 
P artici p a nt 
Disc o nti n u ati o n/ Wit h dr a w al
7. 1
Disc o nti n u ati o n of St u d y I nter ve nti o n
Partici pa nts will be wit h dra w n fr o m treat me nt f or a n y  of t he f oll o wi n g reas o ns:

A partici pa nt ma y wit h dra w fr o m t he st u d y at a n y ti me, at his/ her o w n re q uest (i.e, wit h dra wal 
of c o nse nt), a n d wit h o ut gi vi n g a reas o n.

Occ urre nce of a n e xcl usi o n criteri o n, w hic h is cli nicall y rele va nt a n d affects t he partici pa nt’s 
safety, if disc o nti n uati o n is c o nsi dere d necess ar y b y t he I n vesti gat or a n d/ or Sp o ns or .

T he partici pa nt m a y  be wit h dra w n at a n y ti me at t he discreti o n of t he I nvesti gat or f or safety,  
be ha vi oral, c o m plia nce, or a d mi nistrati ve reas o ns.

C o nfir me d P D per R E CI S T 1. 1 wit h t he e xce pti o n t hat partici pa nts recei vi n g treat me nt ma y 
c o nti n ue past P D if t he partici pa nt’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 
I n vesti gat or, t he partici pa nt will be nefit fr o m c o nti n ue d treat me nt. See Secti o n 4. 1.

S o me A D Rs re q uire wit h dra wal fr o m treat me nt. See Secti o n 6. 8. 2 f or a d diti o nal details.

Dr u g m ust n ot be gi ve n t o a k n o w n pre g na nt partici pa nt.

Use of a n o n per mitte d c o nc o mita nt dr u g ( wit h o ut a p pr o val b y  the S p o ns or a n d t he Me dical 
Res p o nsi ble), as defi ne d i n Secti o n  6. 5. 2, w here t he pre defi ne d c o nse q ue nce is wit h dra wal fr o m 
t he st u d y i nter ve nti o n.
Please n ote: o ne rei nitiati n g c o urse of treat me nt at t he sa me d ose a n d sc he d ule a n d treat me nt 
d urati o n u p t o 2 4 m o nt hs is all o we d at t he discreti o n of t he I nvesti gat or a n d a gree m e nt of t he St u d y  
Me dical Res p o ns i ble f or: 

Partici pa nts w h o are e x perie nci n g S D, a P R , or C R o n eit her st u d y ar m at t he ti me of 
disc o nti n uati o n, a n d t he n s u bse q ue ntl y  de vel o p disease pr o gressi o n after st o p pi n g t hera p y, b ut 
pri or t o t he e n d of t he st u d y .
O R
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9

Partici pa nts w h o are disc o nti n ue d d ue t o a n A E t hat are s u bse q ue ntl y well ma na ge d or res ol ve d 
after st o p pi n g t hera p y, b ut pri or t o t he e n d of t he st u d y.

Partici pa nts meeti n g t he defi niti o n of c o nfir me d P D w hile o n- treat me nt base d o n R E CIS T 1. 1 .
( Partici pa nts w h o e x perie nce P D m a y  co nti n ue treat me nt wit h st u d y dr u gs if t he I n vesti gat or 
belie ves t he partici pa nt will e x perie nce cli nical be nefit fr o m t he treat me nt a n d t here is n o 
u nacce pta ble t o xicit y res ulti n g fr o m t he treat me nt. S uc h partici pa nts will be wit h dra w n fr o m 
t he treat me nt if a n y ot her criteria f or wit h dra wal are met or if alter nati ve treat me nt o pti o ns are 
a vaila ble a n d i n d icate d).
A disc ussi o n bet wee n t he I n vesti gat or a n d S p o ns or ’s Me dical Res p o nsi ble s h o ul d ta ke place. T he 
I n vesti gat or will nee d t o c o nfir m t hat t he be nefit of rei nitiati n g treat me nt o ut wei g hs a n y ris k 
i n v ol ve d, s uc h as t hat w hic h le d t o i nitial treat me nt disc o nti n uati o n. F or partici pa nts wit h o nl y S D 
at ti me of disc o nti n uati o n, t he I n vesti gat or s h o ul d c o nfir m n o ot her reas o na ble treat me nt o pti o ns 
are a vaila ble. I n a d diti o n, t o be eli gi ble f or rei nitiati o n, t he partici pa nt m ust n ot wit h dra w c o nse nt, 
a n d s h o uld be f oll o we d wit h re g ular e val uati o n sca ns as s pecifie d i n Secti o n 1. 3 ( Sc he d ule of 
Acti vities) . N o cr oss-o ver is all o we d. Pri or t o rei nitiati o n o f t he st u d y inter ve nti o n , mali g na nt 
disease m ust be ra di ol o gicall y resta ge d wit hi n 2 8 da ys of d osi n g t o assess all k n o w n sites disease.
Rele va nt safety la b orat or y res ults m ust be a vaila ble a n d verifie d pri or t o rei nitiati n g treat me nt. 
Partici pa nts w h o rei nitiate treat me nt will sta y on st u d y an d will be treate d a n d m o nit ore d acc or di n g 
t o Secti o n  1. 3 ( Sc he d ule of Acti vities ). A disc ussi o n wit h t he st u d y tea m is warra nte d t o deter mi ne 
if re peati n g P K/ 
 testi n g is i n dicate d w he n restarti n g treat me nt. A r oll o ver pr ot oc ol ma y 
acc o m m o date M 7 8 2 4 partici pa nts if a vaila ble at t he ti me of rei nitiati o n.
Secti o n 1. 3
( Sc he d ule o f Acti vities)
s pecifies t he data t o c ollect at st u d y inter ve nti o n 
disc o nti n uati o n a n d f oll o w- u p, a n d a n y a d diti o nal e val uati o ns t hat nee d t o be c o m ple te d.
7. 2
P artici p a nt Disc o nti n u ati o n/ Wit h dr a w al fr o m t he St u d y
A partici pa nt m ust be wit h dra w n i n t he e ve nt of a n y of t he f oll o wi n g:

A partici pa nt m a y  wit h dra w fr o m t he st u d y at a n y ti me, at his/ her o w n re q uest or m a y  be 
wit h dra w n at a n y ti me at t he discreti o n of t he I n vesti gat or f or safety, be ha vi oral, c o m plia nce, 
or a d mi nistrati ve reas o ns.
Secti o n 1. 3 ( Sc he d ule o f Acti vities ) s pecifies t he data t o c ollect at st u d y disc o nti n uati o n a n d 
f oll o w-u p, a n d a n y a d diti o nal e val uati o ns t hat nee d t o be c o m plete d.
I n case of wit h dra wal fr o m treat me nt, t he da y  of E n d - of-Treat me nt will c orres p o n d t o t he d a y  of 
wit h dra wal ( or wit hi n 7 da y s). T he assess me nts sc he d ule d f or t his visit s h o ul d be perf or me d, if 
p ossi ble, wit h f oc us o n t he m ost rele va nt assess me nts. I n case partici pa nt gets e nr olle d i nt o ne w 
st u d y or a n y ne w t hera p y post wit h dra wal fr o m st u d y, t he Safet y F oll o w - u p Visit s h o ul d be 
sc hed ule d pri or t o start of t he ne w treat me nt irres pecti ve of t he 2 8 -d a y  safet y f oll o w-u p peri o d. I n 
eit her case, t he a p pr o priate e C R Fs f or t he E n d - of-Treat me nt Visit m ust be c o m plete d. I n case of 
wit h dra wal, partici pa nts will be as ke d t o c o nti n ue safety a n d sur vi val f oll o w- u p, w hic h i ncl u des 
t he c ollecti o n of data o n s ur vi val a n d s u bse q ue nt a ntica ncer t hera p y. After c o m pleti o n of t he 
F o ll o w- u p peri o d or after t he E n d - of-Treat me nt Visit , w hic he ver is a p plica ble, t he a p pr o priate 
e C R F secti o n f or St u d y Ter mi nati o n m ust be c o m plete d .
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
7. 3
L ost t o F oll o w -u p
A partici pa nt will be c o nsi dere d l ost t o f oll o w- u p if he or s he re peate dl y fails t o ret ur n f or 
sc he d ule d visits a n d is u na ble t o be c o ntacte d by t he st u d y  site.
T he f oll o wi n g acti o ns m ust be ta ke n if a partici pa nt fai ls t o ret ur n t o t he cli nic f or a re q uire d st u dy 
visit:

T he site m ust atte m pt t o c o ntact t he partici pa nt a n d resc he d ule t he misse d visit as s o o n as 
p ossi ble, c o u nsel t he partici pa nt o n t he i m p orta nce of mai ntai ni n g t he assi g ne d visit sc he d ule 
a n d ascertai n if t he partici pa nt wa nts t o or s h o ul d c o nti n ue i n t he st u d y.

Bef ore a partici pa nt is dee me d “l ost t o f oll o w- u p”, t he In vesti gat or or desi g nee m ust ma ke e ver y 
eff ort t o re gai n c o ntact wit h t he partici pa nt: 1) w here p ossi ble, ma ke 3 tele p h o ne calls; 2) if 
ne cessar y, se n d a certifie d letter ( or a n e q ui vale nt l ocal met h o d) t o t he partici pa nt’s last k n o w n 
maili n g a d dress, a n d 3) if a partici pa nt has gi ve n t he a p pr o priate c o nse nt, c o ntact t he 
partici pa nt’s ge neral practiti o ner f or i nf or mati o n. T hese c o ntact atte mpts s h o ul d be d oc u me nte d 
i n t he partici pa nt’s me dical rec or d.

S h o ul d t he partici pa nt c o nti n ue t o be u nreac ha ble, he/s he will be c o nsi dere d t o ha ve wit h dra w n 
fr o m t he st u d y.
8
St u d y Assess me nts a n d Pr oce d ures

St u d y  assess me nts a n d pr oce d ures a n d t heir ti mi n g are s u m marize d i n Secti o n 1. 3 ( Sc he d ule of 
Acti vities) .

N o pr ot oc ol wai vers or e xe m pti o ns are all o we d.

I m me diate safety c o n cer ns s h o ul d be disc usse d wit h t he S p o ns or i m me diatel y u p o n occ urre nce 
or a ware ness t o deter mi ne i f t he partici pa nt s h o ul d c o nti n ue or disc o nti n ue st u d y i nter ve nti o n.

A d here nce t o t he st u d y  desi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n Secti o n 1. 3 ( Sc he d ule 
of Acti vities) , is esse ntial a n d re q uire d f or st u d y c o n d uct.

All 
Scree ni n g
e val uati o ns m ust 
be c o m plete d a n d re vie we d t o c o nfir m t hat p ote ntial 
partici pa nts meet all eli gi bilit y  criteria. T he In vesti gat or will mai ntai n a scree ni n g l o g t o r ec or d 
details of all partici pa nts scree ne d, t o c o nfir m eli gi bilit y, a n d if a p plica ble, rec or d reas o ns f or 
scree ni n g fail ure.

Pri or t o perf or mi n g a n y s t u d y assess me nts t hat are n ot part of t he partici pa nt’s r o uti ne me dical 
care, t he I n vesti gat or will o btai n writte n i nf or me d c o nse nt as s pecifie d i n A p pe n di x 2 ( St u d y 
G o ver na nce).

Pr oce d ures c o n d ucte d as part of t he partici pa nt’s r o uti ne me dical care (e. g., bl o o d c o u nt) a n d 
o btai ne d bef ore si g ni n g of t he I C F m a y  be use d f or scree ni n g or baseli ne p ur p oses pr o vi de d t he 
pr oce d ures met t he pr ot oc ol -s pecifie d criteria a n d were perf or me d wit hi n t he ti me fra me 
defi ne d i n Secti o n  1. 3 ( Sc he d ule of Acti vities).
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
8. 1
Effic ac y Assess me nts a n d Pr oce d ures
C o ntrast -e n ha nce d c o m p ute d t o m o gra p hy ( C T) of c hest/a b d o me n a n d pel vis c o veri n g t he area 
fr o m t he s u peri or e xte nt of t he t h oracic i nlet t o t he s ym p h y sis p u bis is t he first c h oice of i ma gi n g 
m o dalit y . T he C T of t he pel vis ma y  be o mitte d if it is n ot part of t he sta n dar d of care a n d C T of 
t he a b d o me n i ncl u des t he e ntirety of t he li ver a n d all ot her k n o w n sites of disease . If a partici pa nt 
ca n n ot recei ve i o di nate d c o ntrast, or if re gi o nal ra diati o n re g ulati o ns pre ve nt f ull C T sca n, 
ma g netic res o na nce i ma gi n g (M RI) of t he sa me area, usi n g ga d oli ni u m e n ha nce me nt (acc or di n g 
t o l ocal pr ot oc ol) is per mitte d i n c o nj u ncti o n wit h u ne n ha nce d C T of t he c hest fr o m t he t h oracic 
i nlet t o t he i nferi or c ost o p hre nic recess. T he sa me m o dalit y , a n d prefera bl y  the sa me sca n ner, 
sh o ul d be use d per partici pa nt t hr o u g h o ut t he st u d y . 
A brai n C T/ M RI  sca n s h o ul d be perf or me d at Baseli ne, a n d s u bse q ue ntl y if cli nicall y in dicate d b y 
de vel o p me nt of ne w s pecific s ym pt o ms. I n t his st u d y, we m o dif y  RE CI S T 1. 1 s o t hat ski n 
metastasis ca nn ot b e use d as tar get lesi o ns usi n g meas ure me nts b y  cali per b ut ma y  be selecte d if 
t he y fulfill R E CI S T 1. 1 re q uire me nts f or tar get lesi o ns usi n g C T/ M RI sca n (refer t o R E CI S T 1. 1 
criteria).
A ce ntral i ma gi n g la b orat or y will be use d t o rea d a n d i nter pret all C T /M RI  data; h o we ver, 
treat me nt decisi o ns will be ma de b y  the treati n g I n vesti gat or. Res p o nse will be e val uate d acc or di n g 
t o R E CI S T 1. 1 a n d i m m u ne-relate d R E CI S T (ir R E CIS T ) 1. 1 b y  I RC bli n de d f or treat me nt
 
 
 
Baseli ne sca ns are ta ke n wit hi n 2 8 da y s, a n d prefera bl y wit hi n 1 4 da y s, pri or t o ran d o mizati o n. 
All t he sca ns perf or me d at Baseli ne nee d t o be re peate d at s u bse q ue nt visits f or t u m or assess me nt. 
I n ge neral, lesi o ns detecte d at Baseli ne nee d t o be f oll o we d usi n g t he sa me i ma gi n g met h o d ol o g y 
a n d prefera bl y t he sa me i ma gi n g e q ui p me nt at s u b se q ue nt t u m or e val uati o n visits. 
All d uri n g treat me nt sca ns are t o be re peate d usi n g t he sa me met h o d at t he s u bse q ue nt assess me nt 
ti me p oi nts. 
Partici pa nts will be e val uate d e ver y 6 wee ks wit h ra di o gra p hic i ma gi n g t o assess res p o nse t o 
treat me nt wit hi n 1 8 m o nt hs
of t he partici pa nt’s first d ose, t he n e ver y 12 wee ks as sc he d ule d i n 
Secti o n 1. 3 . 
I n t he case of P D wit h disc o nti n uati o n of treat me nt, a n y su bse q ue nt l ocal t u m or assess me nts 
(i ncl u di n g sca ns u n der first s u bse q ue nt treat me nt f or O R as assesse d b y  In vesti gat or) s h o ul d be 
d oc u me nte d i n t he e C R F. C o nfir mati o n after at least 4 wee ks f oll o wi n g first assess me nt is 
rec o m me n de d f or P D if t he partici pa nt is n ot disc o nti n ue d earlier. A n y s u bse q ue nt a ntica ncer 
t hera pies a n d t he date of a n y res p o nse a n d s u bse q ue nt pr o gressi o n s h o ul d b e ca pt ure d i n t he e C R F.
Partici pa nts w h o start 2 L  treat me nt s h o ul d be m o nit ore d f or res p o nse t o t hat treat me nt as descri be d 
i n Secti o n  4. 1. Ra di ol o g ic sca ns perf or me d per l ocal cli nical practice use d f or m o nit ori n g res p o nse 
s h o ul d be u pl oa de d t o t he i ma gi n g re p osit or y.
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
8. 2
S afet y Assess me nts a n d Pr oce d ures
T he safet y profile of t he st u d y inter ve nti o n will be assesse d t hr o u g h t he rec or di n g, re p orti n g a n d 
anal ys is of baseli ne me dical c o n diti o ns, A Es, p h y sical e xa mi nati o n fi n di n gs, i ncl u di n g vital si g ns, 
E C O G P S , a n d la b orat or y tests.
C o m pre he nsi ve assess me nt of a n y pote ntial t o xicit y ex perie nce d b y  eac h partici pa nt will be 
c o n d ucte d starti n g w he n t he partici pa nts gi ve t he prescree ni n g i nf or me d c o nse nt a n d t hr o u g h o ut 
t he st u d y. T he In vesti gat or will re p ort a n y  AEs , w het her o bser ve d b y t he I nvesti gat or or re p orte d 
b y  t he partici pa nt; t he re p orti n g peri o d is s pecifie d i n Secti o n 8. 3. 1.
T he A E re p orti n g peri o d f or safet y s ur veilla nce be gi ns w he n t he partici pa nt is i nitiall y incl u de d i n 
t he st u d y ( date of first si g nat ure of prescree ni n g i nf or me d c o nse nt) a n d c o nti n ues u ntil last Safet y 
F oll o w -u p Visit or bef ore start of a n y  a ntica ncer t hera p y, w hic he ver c o mes first. 
T he safety assess me nts will be perf or me d acc or di n g t o Secti o n 1. 3 ( Sc he d ule of Acti vities ). 
E val uati o ns of t he st u d y data will be c o n d ucte d b y  a n I D M C t o e ns ure safet y a n d t he vali dit y a n d 
scie ntific merit of t he st u d y.
8. 2. 1
Cli nic al S afet y L a b or at or y Assess me nts

Bl o o d a n d uri ne sa m ples will be c o llecte d f or t he cli nical la b orat or y tests liste d i n A p pe n di x 7 , 
at t he ti me p oi nts liste d i n Secti o n 1. 3 ( Sc he d ule of Acti vities ). All sa m ples s h o ul d be clearl y 
i de ntifie d. 

A d diti o nal tests ma y  be perf or me d at a n y t i me d uri n g t he st u d y, as deter mi ne d necessar y  by t h e 
In vesti gat or or re q uire d b y l ocal re g ulati o ns.

T he tests will be perf or me d b y  t he l ocal la b orat or y.

T he S p o ns or m ust recei ve a list of t he l ocal la b orat or y n or mal ra n ges bef ore s hi p me nt of st u d y 
i nter ve nti o n(s). A n y c ha n ges t o t he ra n ges d uri n g t he st u d y m ust be f or war de d t o t he C o n tract 
Researc h Or ga nizati o n ( C R O ) a n d t he S p o ns or.

T he In vesti gat or m ust re vie w eac h la b orat or y re p ort, d oc u me nt t heir re vie w, a n d rec or d a n y 
cli nicall y rele va nt c ha n ges occ urri n g d uri n g t he st u d y in t he A E secti o n of t he e C R F. T he 
la b orat or y re p orts m ust be file d wit h t he s o urce d oc u me nts.
If a partici pa nt has a cli nicall y si gnifica nt a b n or mal la b orat or y test val ue t hat is n ot prese nt at 
Baseli ne, t he test s h o ul d be cl osel y m o nit ore d u ntil t he test val ue has ret ur ne d t o t he n or mal ra n ge 
or t he I n vesti gat or has deter mi ne d t hat t he a b n or malit y  is c hr o nic or sta ble. 
T he re p ort of t he res ults m ust be retai ne d as a part of t he partici pa nt ’s me dical rec or d or s o urce 
d oc u me nts. 
A b n or mal la b orat or y fi n di n gs a n d ot her a b n or mal i n vesti gati o nal fi n di n gs (f or e xa m ple, o n a n 
E C G trace) s h o ul d n ot be re p orte d as A Es u nless t he y are ass ociate d wit h cli nical si g ns a n d 
s ym pt o ms, lea d t o treat me nt disc o nti n uati o n, or are c o nsi dere d ot her wise me dicall y i m p orta nt by 
t he I n vesti gat or. If a la b orat or y a b n or malit y f ulfills t hese criteria, t he i de ntifie d me dical c o n diti o n 
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
(f or e xa m ple, a ne mia, i ncrease d A L T) m ust be re p orte d as t he A E rat her t ha n t he a b n or mal val ue 
itself.
See Secti o n  1. 3 f or t he Sc he d ule of Acti vities .
F or fe male partici pa nts of c hil d beari n g p ote ntial, uri ne or ser u m beta -h u ma n c h ori o nic 
g o na d otr o pi n ( β-h C G) test will be perf or me d acc or di n g t o Secti o n 1. 3 (Sc he d ule of Acti vities) . 
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 st u d y 
i nter ve nti o n. Partici pa nts w h o are n ot W O C B P (as defi ne d i n Secti o n 5. 1 ) are e xe m pte d fr o m 
pre g na nc y  testi n g, b ut reas o n m ust be d oc u me nte d.
8. 2. 2
Vit al Si g ns, P h ysic al E x a mi n ati o ns, a n d Ot her Assess me nts
Vital si g ns, p h y sical e xa mi nati o ns, a n d E C O G P S will be c o n d ucte d at Scree ni n g a n d at 
s u bse q ue nt visits as i n dicate d i n Secti o n 1. 3 (Sc he d ule of Acti vities . T hese s h o ul d be d oc u me nte d 
i n t he e C R F. 
Vital si g ns will be meas ure d i n a se mi-s u pi ne p ositi o n after 5 mi n utes rest a n d will i ncl u de 
te m perat ure, s yst olic a n d diast olic bl o o d press ure, a n d p ulse.
Bl o o d press ure a n d p ulse meas ure me nts will be assesse d wi t h a c o m pletel y aut o mate d de vice. 
Ma n ual tec h ni q ues will be use d o nl y if a n a ut o mate d de vice is n ot a vaila ble .

A 
c o m plete p h y sical e xa mi nati o n will 
i ncl u de, at a mi ni m u m, 
assess me nts of t he 
Car di o vasc ular, Res pirat or y , Gastr oi ntesti nal , S ki n,
a n d Ne ur ol o gi c s yste ms. Hei g ht (at 
Scree n i n g) a n d wei g ht will als o be meas ure d a n d rec or de d.

A brief p h y sical e xa mi nati o n will i ncl u de, at a mi ni m u m, assess me nts of pre -e xisti n g s ym pt o ms 
of u n derl yi n g c o n diti o ns a n d/ or si g ns of i nfecti o n a n d s h o ul d be i n vesti gate d as cli nicall y 
i n dicate d. S ki n assess me nts s h o ul d be perf or me d as per Secti o n 1. 3 ( Sc he d ule of Acti vities)
a n d as cli nicall y i n dicate d.

I n vesti gat ors s h oul d pa y  s pecial atte nti o n t o cli nical si g ns relate d t o pre vi o us seri o us ill nesses.

A b n or mal fi n di n gs are t o be reassesse d at s u bse q ue nt visits.
A si n gle 1 2 -lea d E C G will be o btai ne d as o utli ne d i n Secti o n  1. 3 ( Sc he d ule of Acti vities) usi n g a n 
E C G mac hi ne t hat a ut o maticall y calc ulates t he heart rate a n d meas ures P R, Q R S, Q T, a n d Q Tc 
i nter vals. 
D oc u me nt N o.
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
8. 3
A d verse E ve nts a n d Seri o us A d verse E ve nts
T he defi niti o ns of a n A d verse E ve nt ( A E) a n d a Seri o us A d verse E ve nt ( S A E) are i n  A p pe n di x 6.
8. 3. 1
Ti me Peri o d a n d Fre q ue nc y f or C ollecti n g A d verse E ve nt a n d 
Seri o us A d verse E ve nt I nf or m ati o n
T he A E re p orti n g peri o d f or safet y s ur veilla nce be gi ns w he n t he partici pa nt is i nitiall y  incl u de d i n 
t he st u d y ( date of first si g nat ure of prescree ni n g i nf or me d c o nse nt) a n d c o nti n ues u ntil t he st u d y’s 
2 8- d a y  Safet y F oll o w -u p Visit, defi ne d as 2 8 da y s ( ± 5 d a y s) after t he last st u d y inter ve nti o n 
a d mi nistrati o n. After t he E n d - of-Treat me nt Visit , relate d A Es s h o ul d be d oc u me nte d u ntil t he last 
Safet y  F oll o w- u p Visit, defi ne d as 1 2 wee ks ( ± 2 wee ks) after t he last st u d y inter ve nti o n. O n g oi n g 
e ve nts at t he 1 2- w ee k Safet y  Foll o w -u p Visit s h o ul d c o nti n ue t o be m o nit ore d a n d d oc u me nte d 
u ntil res ol uti o n or res ol uti o n wit h se q uelae. 
A n y S A E assesse d as relate d t o st u d y  i nter ve nti o n m ust be rec or de d a n d re p orte d, as i n dicate d i n 
A p pe n di x 6,  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 i nter ve nti o n.
T he met h o d of rec or di n g, e val uati n g, a n d assessi n g ca usalit y of A Es (i ncl u di n g S A Es) a n d t he 
pr oce d ures f or c o m pleti n g a n d tra ns mitti n g S A E re p orts are i n  A p pe n di x 6 .
8. 3. 2
Met h o d 
of Detecti n g A d verse E ve nts a n d Seri o us A d verse 
E ve nts
At eac h st u d y visit, t he partici pa nt will be q uerie d o n c ha n ges i n his or her c o n diti o n. D uri n g t he 
re p orti n g peri o d, a n y u nfa v ora ble c ha n ges i n t he partici pa nt’s c o n diti o n will be rec or de d as A Es, 
re gar dless if re p orte d by t he partici pa nt or o bser ve d b y the In vesti gat or.
C o m plete, acc urate a n d c o nsiste nt data o n all A Es e x perie nce d f or t he d urati o n of t he re p orti n g 
peri o d ( defi ne d bel o w) will be re p orte d o n a n o n g oi n g basis i n t he a p pr o priate secti o n of t he eC R F. 
All S A Es m ust be a d diti o nall y doc u me nte d a nd re p orte d usi n g t he a p pr o priate Re p ort F or m as 
s pecifie d i n A p pe n di x 6 .
8. 3. 3
F oll o w -u p of A d verse E ve nts a n d Seri o us A d verse E ve nts
A Es are rec or de d a n d assesse d c o nti n u o usl y thr o u g h o ut t he st u d y, as s pecifie d i n Secti o n 8. 3. 1
( Ti me Peri o d a n d Fre q ue nc y  for C ollecti n g A d verse 
E ve nt a n d Seri o us A d verse 
E ve nt 
I nf or mati o n) a n d are assesse d f or t heir o utc o me at t he E n d- of-Treat me nt Visit . All S A Es o n g oi n g 
at t he E n d - of-Treat me nt Visit
m ust be m o nit ore d a n d f oll o we d- u p b y  the I nvesti gat or u ntil 
sta bilizati o n or u ntil t he o utc o me is k n o w n, u nless t he partici pa nt is d oc u me nte d as “l ost t o f oll o w-
u p”. Reas o na ble atte m pts t o o btai n t his i nf or mati o n m ust be ma de a n d d oc u me nte d. It is als o t he 
res p o nsi bilit y of t he I n vesti gat or t o e ns ure t hat a n y necessar y a d diti o nal t hera pe utic meas ures a n d 
f oll o w- u p pr oce d ures are perf or me d. F urt her i nf or mati o n o n f oll o w- u p pr oce d ures is gi ve n i n 
A p pe n di x 6 ( A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, E val uati n g, F oll o w -u p, 
a n d Re p ort i n g).
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
See Secti o n  8. 3. 1 f or t he ti me peri o ds f or t he c ollecti o n of A Es a n d S A Es.
M o nit ori n g of S pecific A d verse E ve nts
If m o nit ori n g is warra nte d f or certai n A D Rs f or safet y iss ues, t he treati n g p h y sicia n or I n vesti gat or 
is re q ueste d t o f oll o w t he partici pa nt d uri n g t he p ost -treat me nt l o n g-ter m f oll o w- u p p hase u ntil t he 
e n d of st u d y peri o d or t he partici pa nt is “l ost t o f oll o w- u p” a n d re p ort t he ma na ge me nt a n d 
o utc o me of A E s t o t he S p o ns or. See S ecti o n 6. 9 (as a p plica ble).
8. 3. 4
Re g ul at or y 
Re p orti n g 
Re q uire me nts 
f or Seri o us A d verse 
E ve nts
T he S p o ns or will se n d a p pr o priate safety n otificati o ns t o Healt h A ut h orities i n acc or da nce wit h 
a p plica ble la ws a n d re g ulati o ns.
T he I n vesti gat or m ust re p ort S A Es ( partic ularly deat hs) i n acc or da nce wit h a p plica ble site-s pecific 
re q uire me nts t o t he I R B t hat a p pr o ve d t he st u dy.
I n acc or da nce wit h inter nati o nal co u ncil f or h ar m o nisati o n a n d g o o d cli nical practice ( I C H G C P)
a n d t he Ja pa nese mi nisterial or di na nce o n G C P, t he S p o ns or/ desi g nee will i m me diatel y i nf or m all 
t he st u d y In vesti gat ors a n d Hea ds of t he st u d y sites of fi n di n gs t hat c o ul d a d versel y affect t he 
safety of partici pa nts, i m pact t he c o n d uct of t he st u d y or alter t he I R B’s a p pr o val/fa v ora ble o pi ni o n 
t o c o nti n ue t he st u d y. I n li ne wit h res pecti ve a p plica ble re g ulati o ns, t he S p o ns or/ desi g nee will 
i m me diatel y inf or m all t he st u d y In vesti gat ors a n d t he Hea ds of t he st u d y sites of A Es t hat are 
b ot h seri o us a n d u ne x pecte d a n d c o n si dere d t o be relate d t o t he a d mi nistere d pr o d uct (“s us pecte d 
u ne x pecte d seri o us a d verse reacti o ns” or S U S A Rs). I n ad diti o n, per a p plica ble re g ulati o ns, t he 
S p o ns or/ desi g nee will i nf or m t he st u d y  In vesti gat ors a n d t he Hea ds of t he st u d y  sites of all S A Es 
w hic h were re p orte d t o t he healt h a ut h orities. I n acc or da nce wit h t he Ja pa nese re g ulat ory 
re q uire me nts c o ncer ni n g safety re p orti n g, t he I nvesti gat or s h o ul d place c o pies of t he Safet y 
Re p orts i n t he I n vesti gat or Site File. T he Hea d of t he st u d y site s h o ul d als o mai ntai n c o pies of 
safety re p orts a p pr o priatel y .
W he n 
s pecificall y re q uire d b y  re g ulati o ns a n d g ui deli nes, t he S p o ns or/ desi g nee will pr o vi de 
a p pr o priate Safet y Re p orts directl y  to t he c o ncer ne d lea d I R B a n d will mai ntai n rec or ds of t hese 
n otificati o ns. W he n direct re p orti n g is n ot clearl y  defi ne d b y  nati o nal or site-s pecific re g ulati o ns, 
t he I nvesti gat or will be res p o nsi ble f or pr o m ptl y  notif y i n g t he c o ncer ne d I nde pe n de nt Et hics 
C o m mittee (I EC) /IR B of a n y Safet y R e p orts pr o vi de d b y  the S p o ns or/ desi g nee a n d of fili n g c o pies 
of all relate d c orres p o n de nce i n t he I n vesti gat or Site File.
F or st u dies c o vere d b y  the E ur o pea n Directi ve 2 0 0 1/ 2 0/ E C, t he S p o ns or’s res p o nsi bilities 
re gar di n g t he re p orti n g of S A Es/ S U S A Rs/ Safet y  Iss ues will be carrie d o ut i n acc or da nce wit h t hat 
Directi ve a n d wit h t he relate d Detaile d G ui da nce d oc u me nts.
D oc u me nt N o.
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
8. 3. 5
Pre g n a nc y
O nl y  pre g na ncies t he I n vesti gat or c o nsi ders t o be relate d t o t he st u d y inter ve nti o n (e. g, res ulti n g 
fr o m a dr u g i nteracti o n wit h a c o ntrace pti ve met h o d) are A Es. H o we ver, all pre g na ncies wit h a n 
esti mate d c o nce pti o n date d uri n g t he peri o d defi ne d i n Secti o n 8. 3. 1 ( Ti me Peri o d a n d Fre q ue ncy 
f or C ollecti n g A d verse E ve nt a n d Seri o us A d verse E ve nt I nf or mati o n) m ust be rec or de d i n t he A E 
pa ge/secti o n of t he e C R F f or b ot h pre g na ncies i n fe male partici pa nts a n d pre g na ncies i n fe male 
part ners of male partici pa nts. T he I nv esti gat or m ust n otif y  the S p o ns or/ desi g nee i n a n e x pe dite d 
ma n ner of a n y pre g na nc y  usi n g t he Pre g na nc y  Re p ort F or m, w hic h m ust be tra ns mitte d b y  th e 
sa me pr ocess s pecifie d f or S A E re p orti n g i n A p pe n di x 6,  secti o n o n R e p orti n g Seri o us A d verse 
E ve nts.
I n vesti gat ors m ust 
acti vel y f oll o w- u p, d oc u me nt a n d re p ort o n t he o utc o me of all t hese 
pre g na ncies, e ve n if t he partici pa nts are wit h dra w n fr o m t he st u d y .
T he I n vesti gat or m ust n otif y  t he S p o ns or/ desi g nee of t hese o utc o mes usi n g t he Pre g na nc y  Re p ort 
F or m. If a n a b n or mal o utc o me occ urs, t he S A E Re p ort F or m will be use d if t he partici pa nt s ustai ns 
a n e ve nt a n d t he Pare nt -C hil d/ Fet us A d verse E ve nt Re p ort F or m if t he c hil d/fet us s ustai ns a n 
e ve nt. A n y a b n or mal o utc o me (e. g., s p onta ne o us a b orti o n, fetal deat h, still birt h, c o n ge nital 
a n o malies, ect o pic pre g na nc y ) m ust 
be re p orte d i n a n e x pe dite d ma n ner, 
as s pecifie d i n 
Secti o n 8. 3. 1,  w hile n or mal o utc o mes m ust be re p orte d wit hi n 4 5 da ys after deli ver y.
A pre g na nt partici pa nt is n ot all o we d t o recei ve st u d y i nter ve nti o n. T he S p o ns or/ desi g nee m ust be 
n otifie d wit h o ut dela y  if a partici pa nt bec o mes pre g na nt or i m pre g nates w hile
o n st u d y. T he 
pre g na nc y  m ust be f oll o we d as i n dicate d a b o ve.
8. 4
Tre at me nt of O ver d ose
F or t his st u d y, a n y d ose of M 7 8 2 4 greater t ha n 2 ti mes m ore (i.e., > 2 4 0 0 m g) t ha n t he pla n ne d 
d ose a d mi nistere d wit hi n a 2 4- h o ur ti me peri o d will be c o nsi dere d a n o ver d ose. T his is base d o n 
d ose escalati o n st u d y data i n w hic h partici pa nts safely recei ve d u p t o 3 0 m g/ k g M 7 8 2 4 e ver y 2 
wee ks (i ncl u di n g wit h d oses > 2 4 0 0 m g) wit h n o o bser ve d M T Ds (refer t o t he I n vesti gat ors’ 
Br oc h ure). Safet y a t si g nifica ntl y hi g her d os es has n ot bee n cli nicall y eval uate d. N o o ver d ose li mit 
is defi ne d b y  Merc k S har p & D o h me, a s u bsi diar y of Merc k 
& C o., i n t he pe m br oliz u ma b 
re g ulat or y la bel. F or t he p ur p ose of t his st u d y, as i n K E Y N O T E-0 2 4, pe m br oliz u ma b o ver d ose is 
defi ne d as recei vi n g greater t ha n 5 ti mes t he pla n ne d d ose.
I n case of o ver d ose wit h cli nical c orrelati o n, s ym pt o matic treat me nt m ust be use d ; t here are n o 
k n o w n a nti d otes f or t he c o m p o u n d. N o s pecific i nf or mati o n is a vaila ble f or t he treat me nt of 
o ver d ose f or pe m br oliz u ma b.
I n eve nt of o ver d ose, i nf usi o n s h o ul d be disc o nti n ue d , a n d partici pa nts s h o ul d be o bser ve d cl osel y 
f or a ny si g ns of t o xicit y. Su p p orti ve treat me nt s h o ul d be pr o vi de d if cli nicall y  i n dicate d. If a n A E 
occ urs res ulti n g fr o m o ver d ose, it s h o ul d f oll o w S A E re porti n g criteria as i n dicate d i n A p pe n di x 6 .
If a n i nci de nce of o ver d ose occ urs meeti n g t he pr ot oc ol -defi ne d defi niti o n wit h o ut a n y ass ociati o n 
of s ym pt o ms or la b orat or y a b n or malities, t he n it m ust be tra ns mitte d b y  th e sa me pr ocess s pecifie d 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
f or S A E re p orti n g i n A p pe n di x 6 , secti o n o n Re p orti n g Seri o us A d verse E ve nts , usi n g t he 
ter mi n ol o g y ”acci de ntal or i nte nti o nal o ver d ose” wit h o ut a d verse effects.
E ve n if it is n ot ass ociate d wit h a n A E or a S A E, a n y o ver d ose is rec or de d i n t he e C R F a n d re p orte d 
t o dr u g safet y i n a n e x pe dite d ma n ner. O ver d oses are re p orte d o n a n S A E Re p ort F or m, f oll o wi n g 
t he pr oce d ure i n A p pe n di x 6 , secti o n o n Re p orti n g Seri o us A d verse E ve nts.
8. 5
P h ar m ac o k i netics
P K sa m ples are n o l o n ger c ollecte d i n t his a me n d me nt.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
D oc u me nt N o.
O bject N o.
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
8. 1 0
P atie nt -re p orte d O utc o mes
Assess me nts are n o l o n ger perf or me d i n t his a me n d me nt.
D oc u me nt N o. 
O bject N o.
C CI
C CIC CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
D oc u me nt N o.
O bject N o.
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
9. 3
P o p ul ati o ns f or A n al yses
T he a nal ys is p o p ulati o ns are s pecifie d bel o w. T he fi nal decisi o n t o e xcl u de partici pa nts fr o m a ny 
a nal ys is p o p ulati o n will be ma de d uri n g a data re vie w meeti n g pri or t o data base l oc k.
F or p ur p oses of a nal ysis, t he a nal ys is p o p ulati o ns are defi ne d i n Ta ble 1 3.
D oc u me nt N o.
O bject N o. 
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
T a ble 1 3
A n al ysis P o p ul ati o ns
A n al y s i s P o p ul ati o n
D e s cri pti o n
S C R 
All p arti ci p a nt s, w h o si g n e d m ai n
i nf or m e d c o n s e nt, r e g ar dl e s s of t h e p arti ci p a nt’ s 
r a n d o mi z ati o n a n d st u d y i nt er v e nti o n st at u s i n t h e st u d y .
F A S
All p arti ci p a nt s, w h o w er e r a n d o mi z e d t o st u d y i nt er v e nti o n. A n al y s e s p erf or m e d o n 
t h e F A S p o p ul ati o n will c o n si d er p arti ci p a nt s’ all o c ati o n t o st u d y i nt er v e nti o n gr o u p s 
a s r a n d o mi z e d (I nt e nti o n-t o-tr e at pri n ci pl e). T h e F A S i s t h e pri m ar y a n al y si s 
p o p ul ati o n f or effi c a c y .
S A F
All p arti ci p a nt s, w h o w er e a d mi ni st er e d a n y d o s e of a n y st u d y i nt er v e nti o n. 
A n al y s e s will c o n si d er p arti ci p a nt s a s tr e at e d.
F A S = F ull A n al y si s S et; S A F = s af et y; S C R = s cr e e ni n g .
9. 4
St atistic al A n al yses
I n or der t o pr o vi de o verall esti mates of treat me nt effects, data will be p o ole d acr oss st u d y ce nters. 
T he fact or ‘ce nter’ will n ot be c o nsi dere d i n statistical m o dels or f or s u b gr o u p a nal ys es d ue t o t he 
hi g h n u m ber of partici pati n g ce nters i n c o ntrast t o t he a ntici pate d s mall n u m ber of partici pa nts 
ra n d o mize d at eac h ce nter.
I n ge neral, c o nti n u o us varia bles will be s u m marize d usi n g n u m ber ( n), mea n, me dia n, sta n dar d 
de viati o n, mi ni m u m, a n d ma xi m u m . Cate g orical varia bles will be s u m marize d usi n g fre q ue nc y 
c o u nts a n d perce nta ges. Pr o p orti o ns are calc ulate d base d o n t he n u m ber of partici pa nts i n t he 
a nal ys is set of i nterest, u nless ot her wise s pecifie d i n t he I A P. All safet y an d efficac y en d p oi nts 
will be s u m marize d b y  treat me nt ar m.
Data c ollecte d after rei nitiati o n of treat me nt will be i ncl u de d f or safet y an d efficac y  acc or di n g t o 
t he s pecificati o ns i n t he I A P.
9. 4. 1
Effic ac y A n al yses
Pri mar y efficac y anal ys es will be perf or me d o n F A S . T he 2 pri mar y  en d p oi n ts of t his st u d y are 
P F S acc or di n g t o R E CI S T 1. 1 assesse d b y  IR C a n d O S . T he st u d y will be c o nsi dere d p ositi ve if 
eit her t he O S a nal ys is res ults a n d/ or t he P F S a nalysis res ults are statisticall y si g nifica nt.
T he fa mily- wise err or rate f or testi n g t he o ne-s i de d h y p ot heses liste d i n Secti o n 9. 1 is strictl y 
c o ntr olle d at a le vel of 2. 5 % o ne- si de d f oll o wi n g t he 2- i n-1 a da pti ve P hase II/ III desi g n base d o n 
w or k b y  Che n et al. (C he n 2 0 1 8) as descri be d i n Secti o n  9. 2. B o nferr o ni met h o d is use d t o s plit 
t he al p ha of 2. 5 % a n d use 0.5 % f or testi n g     a n d 2 .0 % f or testi n g    (all o ne-si de d). If o nly 
o ne of t he b ot h h y p ot heses ca n be rejecte d t he c orres p o n di n g al p ha will be re-all ocate d a n d t he 
ot her h y p ot hesis will be teste d at t he 2. 5 % al p ha ( o ne-si de d) as s h o w n i n Fi g ure 2 ( Yi ni n g 2 0 1 2) . 
 Details o n t he 
a p plie d testi n g pr oce d ures are gi ve n i n t he f oll o wi n g secti o n.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7 -0 0 3 7
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 5 9
T he gr o u p se q ue ntial a p pr oac h f or testi n g t he P F S a n d O S e n d p oi nts will use al p ha s pe n di n g 
acc or di n g t o La n -De Mets wit h O’ Bria n -Fle mi n g -li ke b o u n daries acc or di n g t o t he act ual n u m ber 
of o bser ve d e ve nts at I A re gar di n g t he t otal e ve nt n u m ber pla n ne d f or t he res pecti ve pri mar y 
a nal ys is (see Ta ble 1 2 ).
Fi g ure 2
Al p h a re -all oc ati o n i n t he c o nfir m at or y h y p ot hesis testi n g ( d as he d li nes 
i n dic ate t h at all oc ati o n is d o ne o nl y w he n t he ori gi n ati n g h y p ot hesis w as 
rejecte d)
      = 2 .0 %
 = 0 .5 %
 = 2 .5 % ( o ne-si de d)
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
T a ble 1 4 
Effic ac y E n d p oi nts a n d St atistic al A n al ysis Met h o ds
E n d p oi nt
St ati sti c al A n al y si s M et h o d s
Pri m ar y
P F S a c c or di n g t o R E CI S T 1. 1 
a s s e s s e d b y I R C

P F S I A a n d P A wit h c ut off w h e n pl a n n e d n u m b er of P F S e v e nt s i s 
r e a c h e d a s pl a n n e d i n T a bl e 1 2 , w hil e t h e al p h a s p e n di n g i s a dj u st e d 
c orr e s p o n di n g t o t h e a ct u al n u m b er of e v e nt s at c ut off a c c or di n g t o 
L a n -D e M et s wit h O’ Bri a n - Fl e mi n g-li k e b o u n d ari e s c o n si d eri n g t h e 
t ot al n u m b er of e v e nt s pl a n n e d f or t h e pri m ar y a n al y s e s.

P F S i s d efi n e d a s t h e ti m e fr o m r a n d o mi z ati o n t o t h e d at e of t h e fir st 
d o c u m e nt ati o n of o bj e cti v e P D a s a s s e s s e d b y t h e I R C a c c or di n g t o 
R E CI S T 1. 1 or d e at h d u e t o a n y c a u s e i n t h e a b s e n c e of d o c u m e nt e d 
P D, w hi c h e v er o c c ur s fir st .

Pr o gr e s si o n or d e at h, w hi c h o c c urr e d l at er t h a n 2 s c h e d ul e d t u m or 
a s s e s s m e nt i nt er v al s aft er t h e l a st e v al u a bl e r e s p o n s e a s s e s s m e nt 
will b e c e n s or e d at t h e d at e of t h e l a st e v al u a bl e r e s p o n s e 
a s s e s s m e nt f or P F S a n al y s e s .

P F S ti m e will b e c e n s or e d t h e l a st e v al u a bl e a s s e s s m e nt d at e b ef or e 
t h e st art of a n e w a nti c a n c er tr e at m e nt if n o e v e nt o c c urr e d s o f ar; I n 
c a s e of n ot e v al u a bl e b a s eli n e a s s e s s m e nt o r all p o st-b a s eli n e 
a s s e s s m e nt s ar e n o n - e v al u a bl e t h e p arti ci p a nt will b e c e n s or e d at t h e 
r a n d o mi z ati o n d at e.

E sti m ati o n of t h e tr e at m e nt eff e ct ( H R  ) b y a C o x pr o p orti o n al 
h a z ar d s m o d el ( str atifi e d b y r a n d o mi z ati o n str at a, e a c h str at u m 
d efi n e s s e p ar at e b a s eli n e h a z ar d f u n cti o n); ti e s h a n dl e d b y r e pl a ci n g 
t h e pr o p orti o n al h a z ar d s m o d el b y t h e di s cr et e l o gi sti c m o d el; 9 5 % 
CI s f or t h e H R will b e c al c ul at e d.

Gr a p hi c al c h e c k of t h e pr o p orti o n al h a z ar d s a s s u m pti o n.

K a pl a n -M ei er e sti m at e s a n d a s s o ci at e d st ati st i c s ( P F S r at e s at 3, 6, 9, 
1 2, a n d 2 4 m o nt h s; m e di a n P F S) a n d c orr e s p o n di n g 9 5 % CI s will b e 
pr e s e nt e d b y tr e at m e nt gr o u p.

T e st st ati sti c s of str atifi e d l o g -r a n k t e st ( s a m e str at a a s u s e d f or 
r a n d o mi z ati o n) will b e pr e s e nt e d.

S e n siti vit y a n al y s e s of P F S wil l b e d o n e i n cl u di n g b ut n ot li mit e d t o:

A lt er n ati v e c e n s ori n g r ul e s, i n cl u di n g a n a n al y si s t h at c o u nt s 
d e at h a n d pr o gr e s si o n a c c or di n g t o R E CI S T 1. 1 a s a P F S e v e nt 
r e g ar dl e s s of t h e st art of a n e w a ntic a n c er t h er a p y a n d i g n ori n g 
t h e n u m b er of mi s si n g e v al u a bl e t u m or a s s e s s m e nt s b ef or e 
pr o gr e s si o n or d e at h

P F S a s a s s e s s e d b y t h e I n v e sti g at or .

S u b gr o u p a n al y s e s a s s p e cifi e d i n t h e I A P i n cl u di n g b ut n ot li mit e d t o :

Hi st ol o g y

S m o ki n g st at u s

A si a n v er s u s n o n -A si a n .
O S

O S I A a n d P A wit h c ut off w h e n pl a n n e d n u m b er of d e at h s i s r e a c h e d 
a s pl a n n e d i n T a bl e 1 2 , w hil e t h e al p h a s p e n di n g i s a dj u st e d 
a c c or di n g t o L a n -D e M et s wit h O’ Bri a n - Fl e mi n g-li k e b o u n d ari e s 
c o n si d eri n g t h e t ot al n u m b er of e v e nt s pl a n n e d f or t h e pri m ar y 
a n al y s e s

O S a n al y s e s u s e a si mil ar b ut r e d u c e d s et of m et h o d s a s a p pli e d f or 
P F S .

O S i s d efi n e d a s t h e ti m e fr o m r a n d o mi z ati o n t o t h e d at e of d e at h d u e 
t o a n y c a u s e.

F or p arti ci p a nt s ali v e, t h e O S will b e c e n s or e d at t h e l a st d at e k n o w n 
t o b e ali v e.
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
E n d p oi nt
St ati sti c al A n al y si s M et h o d s

S e n siti vit y a n al y si s of O S will b e d o n e

S u b gr o u p a n al y s e s a s s p e cifi e d i n t h e I A P i n cl u di n g b ut n ot li mit e d t o :

Hi st ol o g y

S m o ki n g st at u s

A si a n v er s u s n o n -A si a n .
S e c o n d ar y
O bj e cti v e r e s p o n s e a c c or di n g t o 
R E CI S T 1. 1 a s s e s s e d b y I R C

O R i nt eri m a n al y si s i s u s e d f or f utilit y or r e s p e cti v el y s a m pl e si z e 
a d a pt ati o n d e ci si o n – c orr e s p o n di n g effi c a c y a n al y s e s ar e c o n d u ct e d 
o n c o m pl et e I R C r e a d u n c o nfir m e d b e st o v er all r e s p o n s e d at a of t h e 
fir st 1 0 0 r a n d o mi z e d p arti ci p a nt s wit h c ut off 6 m o nt h s aft er 1 0 0t h
p arti ci p a nt r a n d o mi z ati o n d at e ( 7 3-1 0 P D - L 1 hi g h p o p ul ati o n).
I D M C will b a s e d e ci si o n t o e x p a n d s a m pl e si z e on t h e cr u d e O R R 
diff er e n c e b et w e e n tr e at m e nt ar m s (i g n ori n g r a n d o mi z ati o n str at a)

O R R – t h e r at e of p arti ci p a nts h a vi n g a n o bj e cti v e r e s p o n s e , i. e. at 
l e a st o n e o v er all a s s e s s m e nt of CR or P R ( b ef or e pr o gr e s si o n a n d 
b ef or e t h e st art of a n e w a nti c a n c er tr e at m e nt) will b e c al c ul at e d al o n g 
wit h t h e c orr e s p o n di n g 2 -si d e d e x a ct Cl o p p er -P e ar s o n 9 5 % CI p er 
tr e at m e nt gr o u p.

Diff er e n c e i n O R R i s e sti m at e d b a s e d o n C o c hr a n -M a nt el -H a e n s z el 
m et h o d (t a ki n g i nt o a c c o u nt t h e r a n d o mi z ati o n str at a)
a n d t e st 
st ati sti c s will b e pr e s e nt e d . O d d s r ati o i s e sti m at e d b a s e d o n lo gi sti c 
m o d el s f or o bj e cti v e r e s p o n s e . L o gi sti c m o d el s wil l b e fitt e d wit h t h e 
e n d p oi nt a s d e p e n d e nt v ari a bl e, s u b gr o u p, tr e at m e nt, a n d wit h a n d 
wit h o ut t h e tr e at m e nt b y s u b gr o u p i nt er a cti o n a s e x pl a n at or y 
v ari a bl e s. 

S e n siti vit y a n al y s e s i n cl u di n g b ut n ot li mit e d t o:

In v e sti g at or r e a d d at a .

C o nfir m e d o bj e cti v e r e s p o n s e
D O R a c c or di n g t o R E CI S T 1. 1 
a s s e s s e d b y I R C

D ur ati o n of r e s p o n s e a c c or di n g t o R E CI S T 1. 1 a s a dj u di c at e d b y t h e 
I R C will b e d efi n e d f or p arti ci p a nt s wit h o bj e cti v e r e s p o n s e a s t h e ti m e 
fr o m fir st r e s p o n s e u ntil t h e fir st d o c u m e nt e d di s e a s e pr o gr e s si o n. 

K- M e sti m at e s a n d a s s o ci at e d st ati sti c s (r e s p o n s e r at e s at 3, 6, 9, 1 2, 
a n d 2 4 m o nt h s; m e di a n D O R) a n d c orr e s p o n di n g 9 5 % CI s will b e 
pr e s e nt e d b y tr e at m e nt gr o u p. S u bj e ct s wit h o ut a n e v e nt at t h e 
a n al y si s c ut off d at e will b e c e n s or e d o n t h e d at e of t h e l a st t u m or 
a s s e s s m e nt.

S e n siti vit y a n al y s e s i n cl u di n g b ut n ot li mit e d t o:

In v e sti g at or r e a d d at a .

C o nfir m e d o bj e cti v e r e s p o n s e
CI = c o nfi d e n c e i nt er v al; C R = c o m pl et e r e s p o n s e; D O R = d ur ati o n of r e s p o n s e; H R = h a z ar d r ati o, I A = i nt eri m
a n al y si s ; I A P= i nt e gr at e d a n al y si s 
pl a n ; I D M C
=
I n d e p e n d e nt D at a 
M o nit ori n g 
C o m mitt e e ; 
 
; I R C = I n d e p e n d e nt R e vi e w C o m mitt e e ; O R R = o bj e cti v e r e s p o n s e r at e; O R = o v er all 
r e s p o n s e; O S
= o v er all s ur vi v al ; P A = pri m ar y a n al y si s ; P D = pr o gr e s si v e di s e a s e; 
 
P F S = pr o gr e s si o n -fr e e s ur vi v al ; P R = p arti al r e s p o n s e; R E CI S T 1. 1 = R e s p o n s e E v al u ati o n 
Crit eri a i n S oli d T u m or s V er si o n 1. 1.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
9. 4. 2
S a fet y A n al yses
All safet y a nal ys es will be perf or me d o n t he S A F p o p ulati o n .
Safet y  en d p oi nts i ncl u de A Es, cli nical la b orat or y assess me nts, vital si g ns, p h y sical e xa mi nati o n, 
a n d E C O G P S as descri be d i n Secti o n  8. 2 . 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 (as s pecifie d i n t he I A P). A n y A Es 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 A Es will be c o de d acc or di n g t o Me d D R A. T he se verit y  of A Es a n d la b orat or y res ults will be 
gra de d usi n g t he N CI -C T C A E Versi o n 5. 0 t o xicit y  gra di n g scale as assesse d b y t he I n vesti gat or. 
I m m u ne-relate d A Es are i de ntifie d acc or di n g t o a pres pecifie d searc h list of Me d D R A Preferre d 
Ter ms, d oc u me nte d i n a versi o n-c o ntr olle d re p osit or y mai ntai ne d b y  the S p o ns or a n d fi nalize d f or 
a nal ys is pri or t o data base l oc k.
T a ble 1 5
S afet y E n d p oi nts a n d St atistic al A n al ysis Met h o ds
E n d p oi nt
St ati sti c al A n al y si s M et h o d s
Pri m ar y
N ot a p pli c a bl e
S e c o n d ar y
O c c urr e n c e of T E A E s 
a n d tr e at m e nt -r el at e d 
A E s
T h e S af et y A n al y si s S et will i n cl u d e all p arti ci p a nt s w h o r e c ei v e at l e a st o n e d o s e of 
st u d y i nt er v e nti o n a n d will b e b a s e d o n all s af et y a n al y si s r e p orti n g o ut c o m e s li k e 
a d v er s e e v e nt s, cli ni c all y r el e v a nt bi o s ci e n c e ( A E SI s) a n d l a b or at or y t e st s o ut c o m e s.
P arti ci p a nt s will b e a n al y z e d a c c or di n g t o t h e a ct u al tr e at m e nt t h e y r e c ei v e. 
T h e s af et y e n d p oi nt s will b e t a b ul at e d u si n g d e s cri pti v e st ati sti c s.

P arti ci p a nt s will b e a n al y z e d a c c or di n g t o t h e a ct u al tr e at m e nt t h e y r e c ei v e.

T h e s af et y e n d p oi nt s will b e a n al y z e d u si n g d e s cri pti v e st ati sti c s.

T h e i n ci d e n c e of T E A E s, S A E s, tr e at m e nt -r el at e d A E s, a n d A E SI s, ir A E s will b e 
s u m m ari z e d b y Pr ef err e d T er m a n d S y st e m Or g a n Cl a s s f or e a c h tr e at m e nt ar m
a n d d e s cri b e d i n t er m s of s e v erit y a n d r el ati o n s hi p t o tr e at m e nt .

T h e w or st o n -tr e at m e nt gr a d e s f or c h e mi str y a n d h e m at ol o g y l a b or at or y r e s ult s 
will b e s u m m ari z e d.

S hift s i n t o xi cit y gr a di n g fr o m B a s eli n e t o hi g h e st gr a d e d uri n g t h e o n -tr e at m e nt 
p eri o d will b e di s pl a y e d. 

F or l a b or at or y t e st s wit h o ut a n N CI- C T C A E gr a d e d efi niti o n r e s ult s will b e 
pr e s e nt e d c at e g ori c all y ( e. g., b el o w, wit hi n, or a b o v e n or m al li mit s). 

S u m m ar y a n d a n al y si s of A E s will b e p erf or m e d b a s e d o n t h e 3- ti er a p pr o a c h 
(Cr o w e, 2 0 0 9 ) a s f urt h er d et ail e d i n t h e st u d y I A P. 
F urt h er d et ail s of s af et y a n al y s e s (i n cl u di n g A E s, cli ni c al l a b or at or y a s s e s s m e nt s, 
vit al si g n s, p h y si c al e x a mi n ati o n, E C G p ar a m et er s, a n d E C O G P S) will b e pr o vi d e d i n 
t h e I A P.
A E = a d v er s e e v e nt; A E SI = a d v er s e e v e nt of s p e ci al i nt er e st; 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 ; I A P = I nt e gr at e d A n al y si s Pl a n; 
 
; N CI -C T C A E = N ati o n al C a n c er I n stit ut e - C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt s; S A E = s eri o u s 
a d v er s e e v e nt ; T E A E = tr e at m e nt- e m er g e nt a d v er s e e v e nt.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
9. 4. 3
Ot her A n al yses
P K a nal yses will be perf or me d o n sa m ples c ollecte d i n t his st u d y as descri be d i n t he pre vi o us 
versi o ns of t he pr ot oc ol.
-
I D M C e val uates t he P F S i nteri m a nal ysis w he n t he n u m ber of e ve nts as gi ve n i n Ta ble 1 2
is reac he d.
-
I D M C e val uates (i n a bse nce of u n bli n di n g decisi o n at P F S I A) t he P F S pri mar y  anal ys is 
w he n t he n u m ber of e ve nts as gi ve n i n  Ta ble 1 2 is reac he d or is wit hi n a ra n ge of ± 5 % of 
t hat pla n ne d n u m ber at t he P F S pri mar y a nal ysis c ut off date.
-
I D M C e val uates (i n a bse nce of u n bli n di n g decisi o n) t he O S i nteri m a nal ysis w he n t he 
n u m ber of e ve nts as gi ve n i n Ta ble 1 2 is reac he d or is wit hi n a ra n ge of ± 5 % of t he pla n ne d 
n u m ber at t he P F S pri mar y  a nalys is c ut-off date .
-
T he fi nal pla n ne d a nal ys is is t he pri mar y  an al y sis f or O S, c o n d ucte d b y  the st u d y tea m 
w he n t he n u m ber of e ve nts as gi ve n i n  Ta ble 1 2 is reac he d.
1 0
Refere nces 
Bajaj G, Wa n g 
X, A gra wal S, et al. M o del -Base d P o p ulati o n P har mac o ki netic A nal ys is of 
Ni v ol u ma b 
i n Patie nts 
Wit h 
S oli d 
T u m ors. 
C P T 
P har mac o metrics 
S y st P har mac ol. 
2 0 1 7; 6( 1): 5 8 - 6 6. 
Be d nare k
R, 
Mar ks 
K, 
Li n 
G. 
Er u pti ve 
kerat oaca nt h o mas 
sec o n dar y to 
ni v ol u ma b 
i m m u n ot hera p y. I nt J Der mat ol. 2 0 1 8 Mar; 5 7( 3):e 2 8-e 2 9.
Bra h mer J, Rec ka m p K L, Baas P, et al. Ni v ol u ma b vers us D oceta xel i n A d va nce d S q ua m o us -Cell 
N o n -S mall -Cell L u n g Ca ncer. N E n gl J Me d 2 0 1 5; 3 7 3( 2): 1 2 3 - 3 5.
Bra h mer J, La cc hetti C, Sc h nei der B, et al. Ma na ge me nt of I m m u ne-Relate d A d verse E ve nts i n 
Patie nts Treate d Wit h 
I m m u ne C hec k p oi nt I nhi bit or T hera p y:  America n S ociet y  of Cli nical 
O nc ol o g y  Cli nical Practice G ui deli ne. J Cli n O nc ol. 2 0 1 8 Fe b 1 4:J C O 2 0 1 7 7 7 6 3 8 5.
B or g haei H, Paz -Ares L,  Hor n L, et al. Ni v ol u ma b vers us D oceta xel i n A d va nce d N o ns q ua m o us 
N o n -S mall -Cell L u n g Ca ncer. N E n gl J Me d . 2 0 1 5; 3 7 3( 1 7): 1 6 2 7 - 3 9.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
Car b o ne D P, Rec k M, 
Paz- Ares L,  et al. First -Li ne Ni v ol u ma b
i n Sta ge I V or Rec urre nt 
N o n -S mall -Cell L u n g Ca ncer. N E n gl J Me d . 2 0 1 7;3 7 6: 2 4 1 5 - 2 6.
Cr o we BJ, Xia H A,
Berli n J, et al. Rec o m me n dati o ns f or safety pla n ni n g, data c ollecti o n, 
e val uati o n a n d re p orti n g d uri n g dr u g, bi ol o gic a n d vacci ne de vel o p me nt: a re p ort of t he safet y 
pla n ni n g, e val uati o n, a n d re p orti n g tea m; Cli n Trials. 2 0 0 9 Oct; 6( 5): 4 3 0 -4 0.
Fe hre n bac her L, S pira A, Balli n ger M, et al. Atez oliz u ma b vers us d oceta xel f or patie nts wit h 
pre vi o usl y  treate d n o n- s mall-cell l u n g ca ncer ( P O P LA R): a m ultice ntre, o pe n -la bel, P hase 2 
ra n d o mise d c o ntr olle d trial. La ncet. 2 0 1 6; 3 8 7: 1 8 3 7 -4 6.
Ferla y  J, S oerj o matara m I, Ervi k M, 
et al. G L O B O C A N 2 0 1 2 v 1. 0, Ca ncer I nci de nce a n d 
M ortalit y  Worl d wi de: I AR C Ca ncer Base N o. 1 1 [Inter net]. L y o n, Fra nce: I nter nati o nal A ge nc y 
f or Researc h o n Ca ncer; 2 0 1 3. A vaila ble fr o m: htt p:// gl o b oca n.iarc.fr.
Freites -Marti nez
A, K w o n g B Y, Rie ger K E, et al. Er u pti ve Kerat oaca nt h o mas Ass ociate d Wit h 
Pe m br oliz u ma b T hera p y . J A M A Der mat ol. 2 0 1 7 J ul 1; 1 5 3( 7): 6 9 4- 7. 
Fres h water T, K o n dic A A ha ma di M, et al. E val uati o n of d osi n g strate g y for pe m br oliz u ma b f or 
o nc ol o g y  i n dicati o ns. J I m m u n ot her Ca ncer. 2 0 1 7; 5: 4 3.
G o u die D R, D’ Alessa n dr o M, Merri ma n B, et al. M ulti ple self-heali n g s q ua m o us e pit heli o ma is 
ca use d b y a disease -s pecific s pectr u m of m utati o ns i n T G F B R 1. Nat Ge net 2 0 1 1; 4 3( 4): 3 6 5- 9.
G uleria I, K h osr os ha hi A, A nsari MJ, et al. A critical r ole f or t he pr o gra m me d deat h li ga n d 1 i n 
fet o mater nal t olera nce. J E x p Me d. 2 0 0 5; 2 0 2( 2): 2 3 1 -7.
Hil bis h K G, Marti n 
J A, Sta u ber AJ, et al. T G F -β 1 m o n ocl o nal
a nti b o d y: Assess me nt of 
e m br yo- fetal t o xicit y in rats a n d ra b bits. Birt h 
Defects 
Res 
B 
De v 
Re pr o d 
T o xic ol . 
2 0 1 6; 1 0 7( 4 -5): 1 7 4 - 8 4.
Her bst R S, Baas P, Ki m D W, et al. Pe m br oliz u ma b vers us d ocet a xel f or pre vi o usl y  treate d, 
P D -L 1 -p ositi ve, a d va nce d n o n -s mall-cell l u n g ca ncer ( K E Y N O T E -0 1 0): a ra n d o mise d c o ntr olle d 
trial. La ncet. 2 0 1 6; 3 8 7( 1 0 0 2 7): 1 5 4 0 - 5 0. 
Le ber A, Tele s A, Ze ncl usse n A C. Re g ulat or y  T cells a n d t heir r ole i n pre g na nc y . A m J Re pr o d 
I m m u n ol. 2 0 1 0; 6 3( 6): 4 4 5 - 5 9.
Mal vezzi M, Cari oli G, Bert ucci o P, et al. E ur o pea n ca ncer m ortalit y  pre dicti o ns f or t he year 2 0 1 7, 
wit h f oc us o n l u n g ca ncer. A n n O nc ol . 2 0 1 7; 2 8( 5) : 1 1 1 7- 2 3. 
Merc k 
K E Y T R U D A ® 
( pe m br oliz u ma b) M o n ot hera p y  
Met Pri mar y  En d p oi nt i n P hase 3 
K E Y N O T E - 0 4 2 St u d y , Si g nifica ntl y I m pr o vi n g O S as First -Li ne T hera p y  in L ocall y  Ad va nce d 
or Metastatic 
N S C L C Patie nts E x pressi n g P D -L 1  in at Least 1 Perce nt of T u m or Cell s. 
0 9 A pr 2 0 1 8. 
( A vaila ble 
fro m : 
htt p://i n vest ors. merc k.c o m/ ne ws/ press -release-details/ 2 0 1 8/ 
K E Y T R U D A -pe m br oliz u ma b -M o n ot hera p y- Met -Pri mar y -E n d p oi nt -i n-P hase - 3- K E Y N O T E-
0 4 2 -St u d y -Si g nifica ntl y- I m pr o vi n g-O S -as-First -Li ne -T hera p y- i n-L o call y- A d va nce d - or-
Metast atic-N S C L C- Patie nts -E x pressi n g -P D -L 1 -i n-at-Least - 1-Perce nt -of- T u m or -
Cells/ defa ult.as p x ).
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
N C C N Cli nical Practice G ui deli nes i n O nc ol o g y ( N C C N G ui deli nes ®) i n part ners hi p wit h t he 
A merica n 
S ociet y of Cli nical O nc ol o g y  (A S C O) Ma na ge me nt 
of I m m u n ot hera p y-Relat e d 
T o xicities 
(Im m u ne 
C hec k p oi nt 
I nhi bit or -Rela te d 
T o xicities) 
Versi o n 
1. 2 0 1 8 
–
Fe br uar y 1 4, 2 0 1 8.
M orris J C, Ta n A R, Ole n cki T E, et al. P hase I st u d y of G C 1 0 0 8 (fres oli m u ma b): a h u ma n a nti-
tra nsf or mi n g gr o wt h fact or-beta ( T G F β) m o n ocl o nal a nti b o d y in pati e nts wit h a d va nce d mali g na nt 
mela n o ma or re nal carci n o ma. P L o S O ne 2 0 1 4; 9( 3):e 9 0 3 5 3.
Peters S, Getti n ger S, J o h ns o n M L , et al. P hase II Trial of Atez oliz u ma b As First -Li ne or 
S u bse q ue nt T hera p y f or Patie nts Wit h 
Pr o gra m me d Deat h -Li ga n d 1- Selecte d A d va nce d 
N o n -S mall -Cell L u n g Ca ncer ( BI R C H). J Cli n O nc ol. 2 0 1 7 A u g 2 0; 3 5( 2 4): 2 7 8 1 - 8 9. 
Rec k M, R o drí g uez -A bre u D, R o bi ns o n A G, et al. Pe m br oliz u ma b vers us C he m ot hera p y  for 
P D -L 1 – P ositi ve N o n – S mall -Cell L u n g Ca ncer. N E n gl J Me d . 2 0 1 6 ( 1 9);3 7 5: 1 8 2 3 - 3 3.
Ritc hie G, Gas per H, Ma n J, et al. Defi ni n g t he m ost a p pr o priate pri mar y  en d p oi nt i n p hase 2 
trials of i m m u ne c hec k p oi nt i n hi bit ors f or a d va nce d s oli d ca ncers. J A M A O nc ol. 2 0 1 8; 4( 4): 5 2 2- 8.
Sie gel R L, Miller K D, Je mal A. Ca ncer Statistics, 2 0 1 8. C A Ca ncer J Cli n. 2 0 1 8; 6 8: 7-3 0.
Waf ula P O, Teles A, Sc h u mac her A, et al. P D - 1 b ut n ot C T L A- 4 bl oc ka ge a br o gates t he pr otecti ve 
effect of re g ulat or y T cells i n a pre g na nc y  muri ne m o del. A m J Re pr o d I mm u n ol . 2 0 0 9; 6 2( 5): 2 8 3 -
9 2.
Wa n g D D , Z ha n g S, Z ha o H, et al. Fi xe d D osi n g Vers us B o dy S ize– Base d D osi n g of M o n ocl o nal 
A nti b o dies i n A d ult Cli nical Trials. J Cli n P har mac ol, 2 0 0 9; 4 9: 1 0 1 2 -1 0 2 4.
Yi ni n g Ye, Ai Li , Li n g y u n Li u a n d Bi n Ya o . A gr o u p se q ue ntial H ol m pr oce d ure wit h m ulti ple 
pri mar y  e n d p oi nts. Statistics i n Me dici ne, 2 0 1 2. 1 0. 1 0 0 2/si m. 5 7 0 0 .
Ze ncl usse n A C. A da pti ve 
I m m u ne res p o nses d uri n g pre g na nc y . A m J Re pr o d I mm u n ol .
2 0 1 3; 6 0: 2 9 1 -3 0 3.
Z ha o X, S ur va wa ns hi S, Hr us ka M, et al. Assess me nt of ni v ol u ma b be nefit -ris k pr ofile of a 
2 4 0- m g flat d ose relati ve t o a 3 -m g/ k g d osi n g re gi me n i n patie nts wit h a d va nce d t u m ors. A n n 
O nc ol. 2 0 1 7; 2 8( 8): 2 0 0 2 - 8.
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
1 1
A p pe n dices
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
A p pe n di x 1
A b bre vi ati o ns
A D A
A nti- dr u g a nti b o d y
A D R
A d verse dr u g reacti o n
A E
A d verse e ve nt
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 ns ferase
A S C O
A merica n S ociet y of Cli nical O nc ol o g y
A S T
As partate a mi n otra nsferase
C R
C o m plete res p o nse
Cr C L
Creati ni ne cleara nce
C N S
Ce ntral ner v o us s ys te m
c S C C
C uta ne o us s q ua m o us cell carci n o mas
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 
D N A
De o x yri b o n ucleic aci d
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 nce Stat us
e C R F
Electr o nic case re p ort f or m
E G F R
E pi der mal gr o wt h fact or rece pt or
1 L
First -li ne
G C P
G o o d Cli nical Practice
H B V
He patitis B vir us
H C V
He patitis C vir us
HI V
H u ma n i m m u n o deficie nc y vir us
H R T
H or m o nal re place me nt t hera p y
I A
I nteri m a nalys is
I A P
I nte grate d A nalys is Pla n
I CF
I nf or me d c o nse nt f or m
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n
I D M C
I n de pe n de nt Data M o nit ori n g C o m mittee
I E C
I n de pe n de nt Et hics C o m mittee
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
I g
I m m u n o gl o b uli n
I L D
I nterstitial l u n g disease 
I RB
I nstit uti o nal Re vie w B oar d
I R C
I n de pe n de nt Re vie w C o m mittee
I R R
I nf usi o n-relate d reacti o ns 
I T T
I nte nti o n-t o-Treat
i v
I ntra ve n o us 
I W R S
I nteracti ve We b
Res p o nse S y ste m
K A
Kerat oaca nt h o mas
m A b
M o n ocl o nal a nti b o d y
Me d D R A
Me dical Dicti o nar y  f or Re g ulat or y Acti vities
mI T T
M o difie d I nte nti o n -t o-Treat
M RI
Ma g netic res o na nce i ma gi n g
N C C N
Nati o nal C o m pre he nsi ve Ca ncer Net w or k
N CI
Nati o nal Ca ncer I nstit ute 
N S C L C
N o n -s mall cell l u n g ca ncer 
O R
O bjecti ve res p o nse
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 F S
Pr o gressi o n -free s ur vi val 
P K
P har mac o ki netics
p o p P K
P o p ulati o n p har mac o ki netic
P R
Partial res p o nse
q 2 w
E ver y  2 wee ks
q 3 w
E ver y  3 wee ks
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 P 2 D
Rec o m me n de d P hase II D ose
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
R T
Ra diati o n t hera p y
S A E
Seri o us a d verse e ve nt
S A F
Safet y  (a nal ysis p o p ulati o n)
S C R
Scree ni n g (a nal ys is p o p ulati o n)
S D
Sta ble disease 
2 L
Sec o n d -li ne 
T G F β
Tra nsf or mi n g gr o wt h fact or β
T P S
T u m or pr o p orti o n sc ore 
U L N
U p per li mit of n or mal
W O C B P  
W o ma n of c hil d beari n g p ote ntial
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
A p pe n di x 2
St u d y G o ver n a nce
Fi n a nci al Discl os ure
I n vesti gat ors a n d S u b -I nvesti gat ors will pr o vi de t he S p o ns or wit h s ufficie nt, acc urate fi na ncial 
i nf or mati o n, as re q ueste d, f or t he S p o ns or t o s u b mit c o m plete a n d acc urate fi na ncial certificati o n 
or discl os ure state me nts t o t he a p pr o priate re g ulat or y aut h orities. T his i nf or mati o n is re q uire d 
d uri n g t he st u d y a n d f or 1 year after c o m pleti o n o f t he st u d y.
I nf or me d C o nse nt Pr ocess

T he I n vesti gat or or his/ her re prese ntati ve will e x plai n t he nat ure of t he st u d y t o t he partici pa nt 
or his/ her le gall y- a ut h orize d re prese ntati ve a n d a ns wer all q uesti o ns o n t he st u d y .

Partici pa nts m ust be i nf or me d t hat t heir partici pati o n is v ol u ntar y.

Partici pa nts or t heir le gall y- a ut h orize d re prese ntati ve ( w here all o we d b y  local la ws a n d 
re g ulati o ns) will be re q uire d t o si g n a state me nt of i nf or med c o nse nt t hat meets t he re q uire me nts 
of 2 1 C F R 5 0; t he Ja pa nese mi nister ial or di na nce o n G C P; l ocal re g ulati o ns; I CH g ui deli nes; 
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y  Act ( HI P A A) re q uire me nts, w here a p plica ble; 
a n d t he I R B/I E C or st u d y ce nter.

T he me dical rec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o nse nt was o btai ne d bef ore 
t he partici pa nt was e nr olle d i n t he st u d y an d t he date t he writte n c o nse nt was o btai ne d. T he 
a ut h orize d pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n t he I C F.

If t he I C F is u p date d d uri n g t heir partici pati o n i n t he st u d y, participa nts m ust be re-c o nse nte d 
t o t he m ost c urre nt, a p pr o ve d versi o n.

Partici pa nts w h o are rescree ne d are re q uire d t o si g n a ne w I C F.
D at a Pr otecti o n

T he S p o ns or will assi g n a u ni q ue i de ntifier t o partici pa nts after o btai ni n g t heir i nf or me d 
c o nse nt. All partici pa nt rec or ds or datasets tra nsferre d t o t he S p o ns or will c o ntai n t he i de ntifier 
o nl y ; partici pa nt na mes or a n y i de ntifia ble i nf or mati o n will n ot be tra nsferre d.

T he S p o ns or m ust i nf or m partici pa nts t hat t heir pers o nal st u d y-relate d data will be use d per 
local data pr otecti o n a n d pri vac y  la ws. T he le vel of discl os ure m ust als o be e x plai ne d t o t he 
partici pa nt.

T he partici pa nt m ust be i nf or me d t hat his/ her me dical rec or ds ma y  be e xa mi ne d b y  Cli nical 
Q ualit y  Ass ura nce a u dit ors or ot her S p o ns or -a p p oi nte d, a ut h orize d pers o n nel, b y  ap pr o priate 
I RB/I E C me m bers, a n d b y  re g ulat or y aut h orit y i ns pect ors. All s uc h pers o ns will strictl y 
mai ntai n partici pa nts’ c o nfi de ntialit y .

T he I n vesti gat or will c o m plete t he partici pa nt re gistrati o n f or m a n d fa x it t o t he re gistrati o n 
ce nter. If t he partici pa nt meets all i ncl usi o n criteria a n d d oes n ot meet a n y of t he e xcl usi o n 
criteria, t he partici pa nt re gistrati o n ce nter will recei ve c o nfir mati o n, re gister t he partici pa nt a n d 
i nf or m t he I nvesti gat or a n d t he S p o ns or of t he re gistrati o n n u m ber b y  fa x. If t he partici pa nt is 
i neli gi ble f or t he st u d y, a partici pa nt n u m ber will be all ocate d a n d d oc u me nte d.
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
St u d y A d mi nistr ati ve
T he S p o ns or of t his cli nical st u d y  is E M D Ser o n o Researc h & De vel o p me nt Instit 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); Merc k Bi o p har ma C o., Lt d., Me g ur o -
k u, T o k y o, Ja pa n, i n Ja pa n; a n d Merc k K Ga A, Dar msta dt, Ger ma n y, f or sites o utsi de t he U S A a n d 
Ja pa n.
T he st u d y will be c o n d ucte d at a p pr o xi matel y 1 3 0 ce nters i n N ort h a n d S o ut h A merica , E U, a n d
Asia -Pacific. A p pr o xi matel y  3 0 sites will be i n t he U S A.
T he C o or di nati n g I n vesti gat or liste d o n t he title pa ge re prese nts all I n vesti gat ors f or decisi o ns a n d 
disc ussi o ns o n t his st u d y, per I C H G C P. T he C o or di nati n g I n vesti gat or will pr o vi de e x pert me dical 
i n p ut a n d a d vice o n t he st u d y desi g n a n d e xec uti o n a n d is res p o nsi ble f or t he re vie w a n d si g n off 
of t he cli nical st u d y re p ort.
T he st u d y  will a p pear i n t he f oll o wi n g cli nical st u dies re gistries: cli nicaltrials. g o v a n d E u dra C T .
Details of 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 , w hic h will be pre pare d u n der t he s u per visi o n of t he Cli nical St u d y Lea der.
F or st u d y sites i n Ja pa n, r efer t o t he St u d y Or ga nizati o n a n d t he St u d y Sites i n Ja pa n i n s u p p orti n g 
d oc u me nt.
A n I D M C will be f or me d i n t his st u d y (see Secti o n 8. 2 ).
Re g ul at or y a n d Et hic al C o nsi der ati o ns

T his st u d y  will be c o n d ucte d i n acc or da nce wit h t he pr ot oc ol a n d t he f oll o wi n g:

C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes, i ncl u di n g t he Declarati o n 
of Helsi n ki a n d C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical Scie nces ( CI O M S) 
I nter nati o nal Et hical G ui delines

A p plica ble I C H G o o d Cli nical Practice ( G C P) G ui deli nes

T he Ja pa nese mi nisterial or di na nce o n G C P 

A p plica ble la ws a n d re g ulati o ns
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9

T he I n vesti gat or m ust 
s u b mit t he pr ot oc ol, pr ot oc ol a me n d me nts (if a p plica ble), I CF, 
I n vesti gat or Br oc h ure, a n d ot her rele va nt d oc u me nts ( e. g., a d vertise me nts) t o a n I RB/I E C a n d 
t he IR B/I E C m ust re vie w a n d a p pr o ve t he m bef ore t he st u d y  is i nitiate d.

F or sites i n Ja pa n, t he S p o ns or i nitiates t he st u d y at a site after o btai ni n g writte n a p pr o val fr o m 
t he Hea d of t he st u d y site, base d o n fa v ora ble o pi ni o n/a p pr o val fr o m t he c o ncer ne d I RB.

A n y  pr ot oc ol a me n d me nts (i.e., c ha n ges t o t he pr ot oc ol) will be d oc u me nte d i n writi n g a n d 
re q uire I RB/I E C a p pr o val bef ore i m ple me ntati o n of c ha n ges, e xce pt f or c ha n ges necessar y  to 
eli mi nate a n i m me diate hazar d t o st u d y partici pa nts. W he n a p plica ble, a me n d me nts will be 
s u b mitte d t o t he a p pr o priate Healt h A ut h orities.

T he I n vesti gat or will be res p o nsi ble f or t he f oll o wi n g:

Pr o vi di n g writte n s u m maries of t he stat us of t he st u d y to t he I RB/I E C a n nuall y  or m ore 
fre q ue ntly per t he I R B’s/I E C’s re q uire me nts, p olicies, a n d pr oce d ures.

N otif y i n g t he I R B/I E C of S A Es or ot her si g nifica nt safet y fi n di n gs, as re q uire d b y I R B/I E C 
pr oce d ures

Pr o vi di n g o versi g ht of t he st u d y co n d uct at t he site a n d a d here nce t o re q uire me nts of 2 1 
C F R, I CH g ui deli nes, t he I R B/I E C, E ur o pea n re g ulati o n 5 3 6/ 2 0 1 4 f or cli nical st u dies (if 
a p plica ble), a n d all ot her a p plica ble l ocal re g ulati o ns

T he pr ot oc ol a n d a n y a p plica ble d oc u me ntati o n will be s u b mitte d or n otifie d t o t he Healt h 
A u t h orities i n acc or da nce wit h all l ocal a n d nati o nal re g ulati o ns f or eac h site.
E mer ge nc y Me dic al S u p p ort

T he S p o ns or or desi g nee will pr o vi de E mer ge nc y Me dical S u p p ort car ds t o partici pa nts f or use 
d uri n g t he st u d y. T hese pr o vi de t he mea ns 
f or partici pa nts
t o i de ntif y the msel ves as 
partici pati n g i n a cli nical st u d y. Als o, t hese gi ve healt h care pr o vi ders access t o a n y inf or mati o n 
a b o ut t his partici pati o n t hat m a y  be nee de d t o deter mi ne t he c o urse of me dical treat me nt f or t he 
partici pa nt. T he i nf or mati o n o n t he E mer ge nc y Me dical S u p p ort car d ma y  incl u de t he pr ocess 
f or e mer ge nc y u n bli n di n g (if a p plica ble).

T he first p oi nt of c o ntact f or all e mer ge ncies will be t he cli nical st u d y In vesti gat or cari n g f or 
t he partici pa nt. C o nse q ue ntl y , t he I n vesti gat or a grees t o pr o vi de his or her e mer ge nc y co ntact 
i nf or mati o n o n t he car d. If t he I n vesti gat or is a vaila ble w he n a n e ve nt occ urs, t he y will a ns wer 
a n y questi o ns. A n y  su bse q ue nt acti o n (e. g., u n bli n di n g) will f oll o w t he sta n dar d pr ocess 
esta blis he d f or I n vesti gat ors.
W he n t he I nvesti gat or is n ot a vaila ble, t he S p o ns or pr o vi des t he a p pr o priate mea ns t o c o ntact a 
S p o ns or p h y sicia n. T his i ncl u des pr o visi o n of a 2 4-h o ur c o ntact n u m ber at a call ce nter, w here b y  
t he healt h care pr o vi ders will be gi ve n access t o t he a p pr o priat e S p o ns or p h y sicia n t o assist wit h 
t he me dical e mer ge nc y an d t o pr o vi de s u p p ort f or t he p ote ntial u n bli n di n g of t he partici pa nt 
c o ncer ne d.
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
Cli nic al St u d y I ns ur a nce a n d C o m pe ns ati o n t o P artici p a nts
F or sites i n Ja pa n, the S p o ns or is e ntirel y res p o nsi ble f or A Es t hat are ass ociate d wit h t his st u d y 
a n d da ma ge t he healt h of t he partici pa nts, e xce pt f or A Es ca use d b y  an i nte nti o nal a n d/ or 
si g nifica nt de viati o n o n t he part of t he I n vesti gat or, t he st u d y site, a n d/ or t he partici pa nt. T he 
S p o ns or will pr o vi de i ns ur a nce t o f ulfill t his res p o nsi bilit y.
I ns ura nce c o vera ge will be pr o vi de d f or eac h c o u ntr y partici pati n g i n t he st u d y. I ns ura nce 
c o n diti o ns s hall meet g o o d l ocal sta n dar ds, as a p plica ble.
Cli nic al St u d y Re p ort
After st u d y co m pleti o n, t he S p o ns or will write a cli nical st u d y re p ort i n c o ns ultati o n wit h t he 
C o or di nati n g I n vesti gat or.
P u blic ati o n

T he res ults of t his st u d y ma y be p u blis he d or prese nte d at scie ntific meeti n gs. If t his is f oresee n, 
t he I n vesti gat or a grees t o s u b mit all ma n uscri pts or a bstracts t o the S p o ns or bef ore s u b missi o n. 
T his all o ws Merc k t o pr otect pr o prietar y  i nf or mati o n a n d t o pr o vi de c o m me nts. 

T he S p o ns or will c o m pl y wit h t he re q uire me nts f or p u blicati o n of st u d y res ults. Per sta n dar d 
e dit orial a n d et hical practice, t he S p o ns or will ge ner all y s u p p ort p u blicati o n of m ultice nter 
st u dies o nl y  in t heir e ntiret y an d n ot as i n di vi dual site data. I n this case, a C o or di nati n g 
I n vesti gat or will be desi g nate d by a gree me nt.

A ut h ors hi p will be deter mi ne d b y  agree me nt a n d i n li ne wit h I nter nati o nal C o m mittee of 
Me dical J o ur nal E dit ors a ut h ors hi p re q uire me nts.
Disse mi n ati o n of Cli nic al St u d y D at a
P osti n g of data o n Cli ntrials. g o v, E u dra C T, a n d all ot her re q uire d re gistries is pla n ne d a n d will 
occ ur 1 2 m o nt hs after t he last cli nic visit of t he fi nal stu d y  su bject or a n ot her a p pr o priate date t o 
meet a p plica ble re q uire me nts.
D at a Q u alit y Ass ur a nce

All partici pa nt st u d y data will be rec or de d o n pri nte d or electr o nic e C R Fs or tra ns mitte d t o t he 
S p o ns or or desi g nee electr o nicall y (e. g., la b orat or y data). T he I n vesti gat or is res p o nsi ble f or 
verif y i n g t hat data e ntries are c o m plete, acc urate, le gi ble, a n d ti mel y b y  ph y sically or 
electr o nicall y si g ni n g t he eC R F. Details f or ma na gi n g eC R Fs are i n t he Ma n ual of O perati o ns .

F or P R O data (e. g., Q o L a n d pai n assess ments), electr o nic patie nt -re p orte d o utc o me will b e 
use d.

T he I n vesti gat or m ust 
mai ntai n 
acc urate d oc u me ntati o n (s o urce data) t hat s u p p orts t he 
i nf or mati o n i n t he e C R F.

T he I n vesti gat or m ust per mit st u d y-relate d m o nit ori n g, q ualit y ass ura nce a u dits, I RB/I E C 
re vie w, a n d re g ulat or y age nc y  ins pecti o ns a n d pr o vi de direct access t o t he st u d y file a n d s o urce 
data.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9

T he S p o ns or or desi g nee is res p o nsi ble f or data ma na ge me nt of t his st u d y, i ncl u di n g q ualit y  
c hec ki n g of t he data a n d mai ntai ni n g a vali date d data base. D a ta base l oc k will occ ur o nce q ualit y 
c o ntr ol a n d q ualit y ass ura nce pr oce d ures ha ve bee n c o m plete d. P D F files of t he eC R Fs will be 
pr o vi de d t o t he I n vesti gat ors at st u d y  c o m pleti o n.

St u d y  m o nit ors will perf or m o n g oi n g s o urce data verificati o n t o c o nfir m t hat data i n t he eC R F 
are acc urate, c o m plete, a n d verifia ble; t hat t he safety a n d ri g hts of partici pa nts are bei n g 
pr otecte d; a n d t hat t he st u d y is bei n g c o n d ucte d per t he c urre ntl y ap pr o ve d pr ot oc ol a n d a n y 
ot her st u d y agree me nts, I CH G C P, t he Ja pa nese mi nist erial or di na nce o n G C P, a n d all 
a p plica ble re g ulat or y re q uire me nts.

Rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C Fs, pertai ni n g t o t he c o n d uct of t his st u d y m ust be 
retai ne d b y  the I n vesti gat or f or 1 5 ye ars after st u d y co m pleti o n, u nless l ocal re g ulati o ns, 
i nstit uti o nal p olicies, or t he S p o ns or re q uires a l o n ger rete nti o n. N o rec or ds ma y  be destr o ye d 
d uri n g t he rete nti o n peri o d wit h o ut t he S p o ns or’s writte n a p pr o val. N o rec or ds m a y  be 
tra nsferre d t o a n ot her l ocati o n or part y wit h o ut t he S p o ns or’s writte n n otificati o n.
S o urce D oc u me nts

S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he partici pa nt a n d s u bsta ntiate t he 
i nte grity of t he data c ollecte d.

T he I n vesti gat or m ust kee p a pa per or electr o nic file ( me dical file a n d ori gi nal me dical rec or ds) 
at t he site f or eac h st u d y partici pa nt. T he file m ust i de ntif y eac h partici pa nt, c o ntai n t he 
f oll o wi n g de m o gra p hic a n d me dical i nf or mati o n f or t he partici pa nt, a n d s h o ul d be as c o m plete 
as p ossi ble:

Partici pa nt’s f ull na me, date of birt h, se x, hei g ht, wei g ht , a n d race, as all o we d b y  local 
re g ulati o ns.

Me dical hist or y  a n d c o nc o mita nt diseases

Pri or a n d c o nc o mita nt t hera pies (i ncl u di n g c ha n ges d uri n g t he st u d y )

St u d y  i de ntifier (i.e., t he S p o ns or’s st u d y n u m ber) a n d partici pa nt’s st u d y n u m ber.

Dates of e ntr y i nt o t he st u d y (i.e., si g nat ure date o n t he i nf or me d c o nse nt) a n d eac h visit t o 
t he site

A n y  me dical e xa mi nati o ns a n d cli nical fi n di n gs pre defi ne d i n t he pr ot oc ol

All A Es

Date t hat t he partici pa nt left t he st u d y, i ncl u di n g a n y reas o n f or earl y wit h dra wal fr o m t he
st u d y or st u d y i nter ve nti o n, if a p plica ble.

All s o urce data m ust be file d (e. g., C T or M RI sca n i ma ges, E C G rec or di n gs, a n d la b orat or y 
res ults). Eac h d oc u me nt m ust ha ve t he partici pa nt n u m ber a n d t he pr oce d ure date; i deall y, 
pri nte d b y  the i nstr u me nt use d f or t he pr oce d ure. As necessar y , me dical e val uati o n of t hese 
rec or ds s h o ul d be perf or me d, d oc u me nte d, si g ne d a n d date d by t he I n vesti gat or. 
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9

Data rec or de d o n pri nte d or electr o nic C R Fs t hat are tra nscri be d fr o m s o urce d oc u me nts m ust 
be c o nsiste nt wit h t he s o urce d oc u me nts or t he discre pa ncies m ust 
be e x plai ne d. T he 
I n vesti gat or m a y  nee d t o re q uest pre vi o us me dical rec or ds or tra nsfer rec or ds, de pe n di n g o n t he 
st u d y. Als o, c urre nt me dical rec or ds m ust be a vaila ble.

T he st u d y mo nit ors will use pri nt o uts of electr o nic files f or s o urce data verificati o n. T hese 
pri nt o uts m ust be si g ne d a n d date d b y t he I n vesti gat or a n d ke pt i n t he st u d y file.

S o urce d oc u me nts are st ore d at t he site f or t he l o n gest p ossi ble ti me per mitte d b y  the a p plica ble 
re g ulati o ns, a n d/ or as per I C H G C P g ui deli nes, w hic he ver is l o n ger. T he I n vesti gat or (Hea d of 
t he st u d y site f or sites i n Ja pa n) e ns ures t hat n o destr ucti o n of me dical rec or ds is perf or me d 
wit h o ut t he S p o ns or’s writte n a p pr o val.

Defi niti o n of w hat c o nstit utes s o urce data is fo u n d i n t he e C R F g ui deli nes.
St u d y a n d Site Cl os ure

T he S p o ns or reser ves t he ri g ht t o cl ose t he st u d y  site or ter mi nate t he st u d y at a n y ti me a n d f or 
a n y reas o n. St u d y sites will be cl ose d u p o n st u d y c o m pleti o n. A st u d y site is c o nsi dere d cl ose d 
w he n all re q uire d d oc u me nts a n d st u dy s u p plies ha ve bee n c ollecte d a n d a site cl os ure visit has 
bee n c o m plete d.

T he I n vesti gat or m a y  initiate site cl os ure at a n y ti me, pr o vi de d t here is reas o na ble ca use a n d 
s ufficie nt n otice is gi ve n i n a d va nce of t he i nte n de d ter mi nati o n.

Reas o ns f or t he earl y cl os ure of a st u d y site b y t he S p o ns or or I n vesti gat or ma y  i ncl u de:

Fail ure of t he I n vesti gat or t o c o m pl y wit h t he pr ot oc ol, t he re q uire me nts of t he I R B/I E C or 
l ocal Healt h A ut h orities , t he S p o ns or’s pr oce d ures, or G C P g ui deli nes

I na de q uate recr uit me nt of partici pa nts b y  t he I n vesti gat or

Disc o nti n uati o n of f urt her de vel o p me nt of t he S p o ns or’s c o m p o u n d .
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
A p pe n di x 3
C o ntr ace pti o n
Defi niti o ns:
W o m a n of C hil d be ari n g P ote nti al ( W O C B P)
A w o ma n is c o nsi dered fertile f oll o wi n g me narc he a n d u ntil bec o mi n g p ost me n o pa usal u nless 
per ma ne ntl y sterile, as s pecifie d bel o w.
If fertilit y is u nclear (e. g., a me n orr hea i n a d olesce nts or at hletes) a n d a me nstr ual c ycle ca n n ot be 
c o nfir me d bef ore t he first d ose of st u d y  i nter ve nti o n, c o nsi der a d diti o nal e val uati o n.
A W O C B P is n ot :
1.
Pre me narc hal
2.
A pre me n o pa usal fe male wit h 1 of t he f oll o wi n g:
D oc u me nte d h ys terect o m y
D oc u me nte d bilateral sal pi n gect o m y / bilateral t u bal li gati o n
D oc u me nte d bilateral o o p h orect o m y
D oc u me ntati o n ca n c o me fr o m t he site pers o n nel’s re vie w of t he fe male’s me dical rec or ds, 
me di cal e xa mi nati o n, or me dical hist or y i nter vie w.
F or a fe male wit h per ma ne nt i nfertilit y due t o a n alter nate me dical ca use ot her t ha n t he 
a b o ve, (e. g., M ulleria n a genesis, a n dr o ge n i nse nsiti vit y), In vesti gat or discreti o n a p plies t o 
deter mi ne st u d y e ntr y.
3.
A p ost me n o pa usal fe male
A p ost me n o pa usal state is defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut a n alter nati ve 
me dical ca use.
A hi g h f ollicle-sti m ulati n g h or m o ne ( F S H) le vel i n t he p ost me n o pa usal ra n ge m a y  be use d 
t o c o nfir m a p ost me n o pa usal state i n a fe male n ot usi n g h or m o nal c o ntrace pti o n or 
h or m o nal re place me nt t hera p y (H R T). H o we ver, i n t he a bse nce of 1 2 m o nt hs 
of 
a me n orr hea , m ore t ha n 1 F S H meas ure me nt is re q uire d i n t he p ost me n o pa usal ra n ge.
A fe male o n H R T a n d w h ose me n o pa usal stat us is i n d o u bt will be re q uire d t o use o ne of t he n o n -
estr o ge n h or m o nal hi g hl y  effecti ve c o ntrace pti o n met h o ds if s he wis hes t o c o nti n ue her H R T
d uri n g t he st u d y . Ot her wise, s he m ust disc o nti n ue H R T t o all o w c o nfir mati o n of p ost me n o pa usal 
stat us bef ore st u dy e nr oll me nt.
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
C o ntr ace pti o n G ui d a nce:
C O N T R A C E P TI V E S A L L O W E D D U RI N G T H E S T U D Y I N C L U D E:
Hi g hl y  Eff e cti v e M et h o d s T h at H a v e L o w U s er D e p e n d e n c y
I m pl a nt a bl e pr o g e st o g e n-o nl y h or m o n e c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of o v ul ati o n ( n ot a p pr o v e d i n 
J a p a n)
I ntr a ut eri n e d e vi c e (I U D)
I ntr a ut eri n e h or m o n e-r el e a si n g s y st e m (I U S)
Bil at er al t u b al o c cl u si o n
V a s e ct o mi z e d p art n er: a hi g hl y eff e cti v e c o ntr a c e pti v e m et h o d pr o vi d e d t h at t h e p art n er i s t h e s ol e s e x u al 
p art n er of a W O C B P a n d t h e a b s e n c e of s p er m h a s b e e n c o nfir m e d. Ot h er wi s e, u s e a n a d diti o n al hi g hl y 
eff e cti v e m et h o d of c o ntr a c e pti o n. T h e s p er m at o g e n e si s c y cl e i s a p pr o xi m at el y 9 0 d a y s.
Hi g hl y  Eff e cti v e M et h o d s T h at Ar e U s er D e p e n d e nt
C o m bi n e d ( e str o g e n - a n d pr o g e st o g e n -c o nt ai ni n g) h or m o n al c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of 
o v ul ati o n
Or al
I ntr a v a gi n al ( n ot a p pr o v e d i n J a p a n)
Tr a n s d er m al ( n ot a p pr o v e d i n J a p a n)
I nj e ct a bl e ( n ot a ppr o v e d i n J a p a n)
Pr o g e st o g e n -o nl y h or m o n e c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of o v ul ati o n
Or al
I nj e ct a bl e
S e x u al a b sti n e n c e: a hi g hl y eff e cti v e m et h o d o nl y if d efi n e d a s r efr ai ni n g fr o m i nt er c o ur s e d uri n g t h e e ntir e 
p eri o d of ri s k a s s o ci at e d wit h t h e st u d y i nt er v e nti o n. T h e r eli a bilit y of s e x u al a b sti n e n c e n e e d s t o b e e v al u at e d 
i n r el ati o n t o t h e d ur ati o n of t h e st u d y.
N ot e s:
C o ntr a c e pti v e u s e b y m e n or w o m e n i s c o n si st e nt wit h l o c al r e g ul ati o n s o n t h e u s e of c o ntr a c e pti v e m et h o d s 
f or cli ni c al st u d y p arti ci p a nt s.
Hi g hl y eff e cti v e m et h o d s ar e t h o s e wit h a f ail ur e r at e of < 1 % p er y e ar w h e n u s e d c o n si st e ntl y a n d c orr e ctl y. 
T y pi c al u s e f ail ur e r at e s diff er fr o m t h o s e w h e n u s e d c o n si st e ntl y a n d c orr e ctl y.
If l o c all y r e q uir e d, i n a c c or d a n c e wit h Cli ni c al Tri al F a cilit ati o n Gr o u p ( C T F G) g ui d eli n e s, a c c e pt a bl e 
c o ntr a c e pti v e m et h o d s ar e li mit e d t o t h o s e w hi c h i n hi bit o v ul ati o n a s t h e pri m ar y m o d e of a cti o n.
P eri o di c a b sti n e n c e ( c al e n d ar, s y m pt ot h er m al, p o st - o v ul ati o n m et h o d s), wit h dr a w al ( c oit u s i nt err u pt u s), 
s p er mi ci d e s o nl y, a n d l a ct ati o n al a m e n orr h e a m et h o d ( L A M) ar e n ot a c c e pt a bl e m et h o d s of c o ntr a c e pti o n f or 
t hi s st u d y. M al e c o n d o m a n d f e m al e c o n d o m c a n n ot b e u s e d t o g et h er ( d u e t o ri s k of f ail ur e wit h fri cti o n).
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 9
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 3 /1 5 9
A p pe n di x 5 T he Rec o m me n d ati o ns f or ir A E M a n a ge me nt, i n Acc or d a nce wi t h 
t he J oi nt A meric a n S ociet y of Cli nic al O nc ol o g y Cli nic al Pr actice 
G ui deli nes a n d N ati o n al C o m pre he nsi ve C a ncer Net w or k
T his a p pe n di x pr o vi des rec o m me n dati o ns t o t he I n vesti gat ors f or t he ma na ge me nt of ir A Es. T he 
c o nte nts are base d o n t he N C C N ir A E ma na ge me nt g ui deli nes (i n Acc or da nce wit h t he J oi nt 
A merica n S ociet y o f Cli nical O nc ol o g y  Cli nical Practice G ui deli nes a n d Nati o nal C o m pre he nsi ve 
Ca ncer Net w or k, Bra h mer J R, 2 0 1 8) a n d F D A rec o m me n dati o ns t o re q uire per ma ne nt treat ment 
disc o nti n uati o n f or G 4 ir A Es ( u nless ot her wise i n dicate d i n t he ta bles bel o w). Differe nces wit h 
A S C O/ N C C N ir A E ma na ge me nt g ui deli nes as rec o m me n de d b y t he F D A are s h o w n i n b ol d a n d 
u n derli ne d te xt i n t he ta bles bel o w. Critical i nstr ucti o ns i ncl u de t he re q uire me nt t hat treat me nt 
m ust be per ma ne ntl y disc o nti n ue d f or t he f oll o wi n g Gra de 4 ir A E t o xicities: Ras h/i nfla m mat or y 
der matitis, ne p hritis, a ut oi m m u ne he m ol y tic a ne mia, he m ol y tic ure mic s yn dr o me, a plastic a ne mia, 
i m m u ne t hr o m b oc yt o pe nia, ac q uire d T T P, an d i n certai n circ u msta nces, l y m p h o pe nia.
A da pte d fr o m:
-Relate d A d verse E ve nts i n Patie nts Treate d Wit h I m m u ne C hec k p oi nt 
I n hi bit or T hera py:  A merica n S ociety of Cli nical O nc ol o g y Cli nical Practice G ui deli ne
D oc u me nt N o. 
O bject N o. 
C CI
C CI
P P D


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 4 /1 5 9
T a ble of T a bles
Ta ble A 1
Ma na ge me nt of S ki n ir A Es i n Patie nts Treate d Wit h I C Pis ............. 1 0 5
Ta ble A 2 
Ma na ge me nt of GI ir A Es i n Patie nts Treate d Wit h I C Pis ................ 1 1 0
Ta ble A 3
Ma na ge me nt of L u n g ir A Es i n Patie nts Treate d Wit h I C Pis ........... 1 1 4
Ta ble A 4
Ma na ge me nt of E n d ocri ne
ir A Es i n Patie nts Treate d Wit h IC Pis ... 1 1 5
Ta ble A 5
Ma na ge me nt of M usc ul os keletal ir A Es i n Patie nts Treate d Wit h 
I C Pis ................................................................................................. 1 2 0
Ta ble A 6
Ma na ge me nt of Re nal ir A Es i n Patie nts Treate d Wit h I C Pis ........... 1 2 4
Ta ble A 7
Ma na ge me nt of Ner v o us S y ste m ir A Es i n Patie nts Treate d Wit h 
I C Pis ................................................................................................. 1 2 6
Ta ble A 8
Ma na ge me nt of He mat ol o gic ir A Es i n Patie nts Treate d Wit h 
I C Pis ................................................................................................. 1 3 1
Ta ble A 9
Ma na ge me nt of Car di o vasc ular ir A Es
i n Patie nts Treate d Wit h 
I C Pis ................................................................................................. 1 3 8
Ta ble A 1 0
Ma na ge me nt of Oc ular ir A Es i n Patie nts Treate d Wit h I C Pis ......... 1 4 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 /1 5 9
T a ble A 1
M a n a ge me nt of S ki n ir A Es i n P atie nts Tre ate d Wit h I C Pis
1. 0 S ki n T o xicities
1. 1 R as h/i n ﬂa m m at or y der m atitis
D e ﬁniti o n: Er yt h e m a m ultif or m e mi n or ( a t ar g et oi d r e a cti o n i n t h e s ki n a n d m u c o u s m e m br a n e s u s u all y tri g g er e d 
b y i nf e cti o n s, s u c h a s h er p e s si m pl e x vir u s e s, b ut c a n b e a s s o ci at e d wit h a n i m m u n e -r el at e d dr u g er u pti o n a n d if 
pr o gr e s s e s t o er yt h e m a m ultif or m e m aj or, it a n d c a n b e a h ar bi n g er of S C A R, s u c h a s S J S), li c h e n oi d (r e s e m bli n g 
t h e ﬂat -t o p p e d, p ol y g o n al, a n d s o m eti m e s s c al y or h y p ertr o p hi c l e si o n s of li c h e n-pl a n u s), e c z e m at o u s 
(i nﬂa m m at or y d er m atiti s c h ar a ct eri z e d b y pr uriti c, er yt h e m at o u s, s c al y, or c r u st e d p a p ul e s or pl a q u e s o n t h e s ki n, 
w hi c h i s v ul n er a bl e t o s u p eri nf e cti o n, p s ori a sif or m [r e s e m bli n g t h e w ell -d e m ar c at e d, er yt h e m at o u s, a n d s c al y 
p a p ul e s a n d pl a q u e s of p s ori a si s], m or billif or m [ a n o n p u st ul ar, n o n b ull o u s m e a sl e s -li k e e x a nt h e m at o u s r a s h of t h e 
s ki n oft e n r ef err e d t o a s “ m a c ul o p a p ul ar” a n d wit h o ut s y st e mi c s y m pt o m s or l a b or at or y a b n or m aliti e s ], e x cl u di n g 
o c c a si o n al i s ol at e d p eri p h er al e o si n o p hili a, p al m o pl a nt ar er yt hr o d y s e st h e si a [ h a n d -f o ot s y n dr o m e; r e d n e s s, 
n u m b n e s s, b ur ni n g, it c hi n g, a n d s u p er ﬁci al d e s q u a m ati o n of t h e p al m s a n d s ol e s], n e utr o p hili c d er m at o s e s [ e. g,
S w e et s y n dr o m e], a n d ot h er s)
Di a g n o sti c w or k -u p
P erti n e nt hi st or y a n d p h y si c al e x a mi n ati o n
R ul e o ut a n y ot h er eti ol o g y of t h e s ki n pr o bl e m, s u c h a s a n i nf e cti o n, a n eff e ct o f a n ot h er dr u g, or a s ki n c o n diti o n 
li n k e d t o a n ot h er s y st e mi c di s e a s e or u nr el at e d pri m ar y s ki n di s or d er
If n e e d e d, a bi ol o gi c c h e c k u p, i n cl u di n g a bl o o d c ell c o u nt a n d li v er a n d ki d n e y t e st s
Dir e ct e d s er ol o gi c st u di e s if a n a ut oi m m u n e c o n diti o n i s s u s p e c t e d, s u c h a s l u p u s or d er m at o m y o siti s: a s cr e e ni n g 
a nti n u cl e ar a nti b o d y t e st, S S -A/ A nti -R o, S S -B/ A nti -L a if pr e d o mi n a ntl y p h ot o di stri b ut e d/ p h ot o s e n siti vit y, 
a nti hi st o n e, d o u bl e - str a n d e d D N A, a n d ot h er r el e v a nt s er ol o gi e s. C o n si d er e x p a n di n g s er ol o gi c st u die s or 
di a g n o sti c w or k -u p if ot h er a ut oi m m u n e c o n diti o n s ar e c o n si d er e d b a s e d o n si g n s, s y m pt o m s S ki n bi o p s y
C o n si d er cli ni c al m o nit ori n g wit h u s e of s eri al cli ni c al p h ot o gr a p h y
R e vi e w f ull li st of p ati e nt m e di c ati o n s t o r ul e o ut ot h er dr u g -i n d u c e d c a u s e f or p h ot o s e n siti vit y
Gr a di n g
M a n a g e m e nt
Gr a di n g a c c or di n g t o C T C A E i s a c h all e n g e f or s ki n. 
I n st e a d, s e v erit y m a y b e b a s e d o n B S A, t ol er a bilit y, 
m or bi dit y, a n d d ur ati o n.
G 1: S y m pt o m s d o n ot aff e ct t h e q u alit y of lif e or 
c o ntr oll e d wit h t o pi c al r e gi m e n a n d/ or or al a nti pr uriti c
C o nti n u e I C Pi
Tr e at wit h t o pi c al e m olli e nt s a n d/ or mil d -m o d er at e 
p ot e n c y t o pi c al c orti c o st er oi d s
C o u n s el p ati e nt s t o a v oi d s ki n irrit a nt s a n d s u n 
e x p o s ur e
G 2: I n ﬂa m m at or y r e a cti o n t h at aff e ct s q u alit y of lif e a n d 
re q uir e s i nt er v e n ti o n b a s e d o n di a g n o si s
C o n si d er h ol di n g I C Pi a n d m o nit or w e e kl y f or 
i m pr o v e m e nt. If n ot r e s ol v e d, i nt err u pt tr e at m e nt u ntil 
s ki n A E h a s r e v ert e d t o Gr a d e 1
C o n si d er i niti ati n g pr e d ni s o n e ( or e q ui v al e nt) at d o si n g 
1 m g/ k g, t a p eri n g o v er at l e a st 4 w e e k s
I n a d diti o n, tr e at wit h t o pi c al e m olli e nt s, or al 
a nti hi st a mi n e s, a n d m e di u m - t o hi g h-p ot e n c y t o pi c al 
c orti c o st er oi d s
D oc u me nt N o.
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 6 /1 5 9
G 3: A s G 2 b ut wit h f ail ur e t o r e s p o n d t o i n di c at e d 
i nt er v e nti o n s f or a G 2 d er m atiti s
H ol d I C Pi t h er a p y a n d c o n s ult wit h d er m at ol o g y t o 
d et e r mi n e a p pr o pri at e n e s s of r e s u mi n g
Tr e at wit h t o pi c al e m olli e nt s, or al a nti hi st a mi n e s, a n d 
hi g h - p ot e n c y t o pi c al c orti c o st er oi d s
I niti at e ( m et h yl) pr e d ni s ol o n e ( or e q ui v al e nt) 1-2 m g/ k g, 
t a p eri n g o v er at l e a st 4 w e e k s
G 4: All s e v er e r a s h e s u n m a n a g e a bl e wit h pri or 
i nt er v e nti o n s a n d i nt ol er a bl e
P er m a n e ntl y di s c o nti n u e I C Pi
S y st e mi c c orti c o st er oi d s: I V ( m et h yl) pr e d ni s ol o n e ( or 
e q ui v al e nt) d o s e d at 1 - 2 m g/ k g wit h sl o w t a p eri n g w h e n 
t h e t o xi cit y r e s ol v e s
M o nit or cl o s el y f or pr o gr e s si o n t o s e v er e c ut a n e o u s 
a d v er s e r e a cti o n
S h o ul d a d mit p ati e nt i m m e di at el y wit h dir e ct o n c ol o g y 
i n v ol v e m e nt a n d wit h a n ur g e nt c o n s ult b y d er m at ol o g y
1. 2 B ull o us der m at oses
D e ﬁniti o n: I n cl u di n g b ull o u s p e m p hi g oi d or ot h er a ut oi m m u n e b ull o u s d er m at o s e s, b ull o u s dr u g r e a cti o n
Di a g n o sti c w or k -u p
P h y si c al e x a mi n ati o n
R ul e o ut a n y ot h er eti ol o g y of t h e s ki n pr o bl e m, s u c h a s a n i nf e cti o n, a n eff e ct of a n ot h er dr u g, or a s ki n c o n diti o n 
li n k e d t o a n ot h er s y st e mi c di s e a s e
If n e e d e d, a bi ol o gi c c h e c k u p, i n cl u di n g a bl o o d c ell c o u nt, li v er, a n d ki d n e y t e st s; c o n si d er s er u m a nti b o d y t e st s t o 
r ul e o ut b ull o u s p e m p hi g oi d or, u n d er t h e g ui d a n c e of d er m at ol o g y, s e n di n g p ati e nt s er u m f or i n dir e ct 
i m m u n oﬂu or e s c e nt t e sti n g t o r ul e o ut ot h er a ut oi m m u n e bli st eri n g di s e a s e s
R ef err al t o d er m at ol o g y f or bli st e r s t h at ar e n ot e x pl ai n e d b y i nf e cti o u s or tr a n si e nt ot h er c a u s e s (e. g, h er p e s 
si m pl e x, h er p e s z o st er, b ull o u s i m p eti g o, b ull o u s i n s e ct bit e, fri cti o n or pr e s s ur e bli st er)
C o n si d er s ki n bi o p s y ( b ot h h e m at o x yli n a n d e o si n e v al u ati o n of l e si o n al s ki n a n d dir e ct i m m u n o ﬂu or e s c e n c e 
e v al u ati o n of p eril e si o n al s ki n)
Gr a di n g
M a n a g e m e nt
G 1: A s y m pt o m ati c, bli st er s c o v eri n g < 1 0 % B S A a n d n o 
a s s o ci at e d er yt h e m a
If bli st er s ar e < 1 0 % B S A, a s y m pt o m ati c, a n d 
n o ni n ﬂa m m at or y ( s u c h a s t h e c a s e wit h fri cti o n bli st er s 
or pr e s s ur e bli st er s), c e s s ati o n of I C Pi i s n ot n e c e s s ar y, 
a n d o nl y o b s er v ati o n a n d/ or l o c al w o u n d c ar e i s 
w arr a nt e d.
W h e n s y m pt o m ati c b ull a e or er o si o n s, w hi c h ar e 
d er o of e d v e si cl e s or b ull a e, ar e o b s er v e d o n t h e s ki n or 
m u c o s al s urf a c e s, t h e c ut a n e o u s ir A E i s b y d e ﬁniti o n 
c o n si d er e d at l e a st G 2
S e e G 2 m a n a g e m e nt r e c o m m e n d ati o n s
G 2: Bli st eri n g t h at aff e ct s q u alit y of lif e a n d r e q uir e s 
i nt er v e nti o n b a s e d o n di a g n o si s n ot m e eti n g crit eri a f or 
Gr a d e > 2
Bli st er s c o v eri n g 1 0 % -3 0 % B S A
H ol d I C Pi t h er a p y a n d c o n s ult wit h d er m at ol o g y f or 
w or k - u p a n d t o d et er mi n e a p pr o pri at e n e s s of r e s u mi n g
Att e nti o n gi v e n t o g e n er al l o c al w o u n d c ar e, w hi c h 
i n cl u d e s pl ai n p etr ol at u m oi nt m e nt a n d b a n d a g e s or 
pl ai n p etr ol at u m oi nt m e nt g a u z e a n d b a n d a g e o v er a n y 
o p e n er o si o n s, w hi c h ar e l eft o v er o n t h e s ki n aft er t h e 
bli st er h a s p o p p e d or if t h e r o of of t h e bli st er e a sil y 
sl o u g h s off
C o u n s el p ati e nt s t o a v oi d s ki n irrit a nt s a n d 
o v er e x p o s ur e t o s u n, w e ar pr ot e cti v e cl ot hi n g, u s e 
s u n s cr e e n s
W o r k- u p f or a ut oi m m u n e b ull o u s di s e a s e a s a b o v e
I niti at e C l a s s 1 hi g h-p ot e n c y t o pi c al c orti c o st er oi d ( e. g,
cl o b et a s ol, b et a m et h a s o n e or e q ui v al e nt) a n d r e a s s e s s 
e v er y 3 d a y s f or pr o gr e s si o n or i m pr o v e m e nt
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 7 /1 5 9
L o w t hr e s h ol d t o i niti at e tr e at m e nt wit h pr e d ni s o n e ( or 
e q ui v al e nt) at 0. 5 -1 m g/ k g d o si n g a n d t a p er o v er at 
l e a st 4 w e e k s
M o nit or p ati e nt s wit h G 2 ir A E s cl o s el y f or pr o gr e s si o n 
t o i n v ol v e m e nt of gr e at er B S A a n d/ or m u c o u s 
m e m br a n e i n v ol v e m e nt. C o n si d er f oll o wi n g p ati e nt s 
cl o s el y u si n g s eri al p h ot o gr a p h y
Pri m er o n m o nit ori n g f or c o m pli c at e d c ut a n e o u s 
a d v er s e dr u g r e a cti o n s:
R e vi e w of s y st e m s: S ki n p ai n (li k e a s u n b ur n), f e v er s, 
m al ai s e, m y al gi a s, art hr al gi a s, a b d o mi n al p ai n, o c ul ar 
di s c o mf ort or p h ot o p h o bi a, s or e s or di s c o mf ort i n t h e 
n ar e s, s or e s or di s c o mf ort i n t h e or o p h ar y n x, 
o d y n o p h a gi a, h o ar s e n e s s, d y s uri a, s or e s or di s c o mf ort 
i n t h e v a gi n al ar e a f or w o m e n or i n v ol vi n g t h e m e at u s of 
t h e p e ni s f or m e n, s or e s i n t h e p eri a n al ar e a, or p ai n 
wit h b o w el m o v e m e nt s
P h y si c al e x a mi n ati o n: I n cl u d e vit al si g n s a n d a f ull s ki n 
e x a mi n ati o n s p e ci ﬁc all y e v al u ati n g all s ki n s urf a c e s a n d 
m u c o u s m e m br a n e s ( e y e s, n ar e s, or o p h ar y n x, g e nit al s, 
a n d p eri a n al ar e a). A s s e s s f or l y m p h a d e n o p at h y, f a ci al 
or di st al e xtr e mit y s w elli n g ( m a y b e si g n s of 
DI H S/ D R E S S). A s s e s s f or p u st ul e s or bli st er s or 
er o si o n s i n a d diti o n t o ar e a s of “ d u s k y er yt h e m a,” w hi c h 
m a y f e el p ai nf ul t o p al p ati o n. T o a s s e s s f or a p o siti v e 
Ni k ol s k y si g n, pl a c e a gl o v e d ﬁn g er t a n g e nti all y o v er 
er yt h e m at o u s s ki n a n d a p pl y fri cti o n p ar all el t o t h e s ki n 
s urf a c e. Ni k ol s k y si g n i s p o siti v e if t hi s r e s ult s i n 
d et a c h e d or sl o u g hi n g e pi d er mi s d e m o n str ati n g p o or 
att a c h m e nt of t h e e pi d er mi s t o t h e d er mi s, w hi c h i s t h e 
c a s e i n s o m e a ut oi m m u n e di s or d er s ( e. g, p e m p hi g u s) 
a n d S J S/ T E N
G 3: S ki n sl o u g hi n g c o v eri n g > 3 0 % B S A wit h 
a s s o ci at e d p ai n a n d li miti n g s elf -c ar e A D L
H ol d I C Pi t h er a p y a n d c o n s ult wit h d er m at ol o g y t o 
d et er mi n e a p pr o pri at e n e s s of r e s u mi n g
A d mi ni st er I V ( m et h yl) pr e d ni s ol o n e ( or e q ui v al e nt) 1 -2 
m g/ k g, t a p eri n g o v er at l e a st 4 w e e k s
If b ull o u s p e m p hi g oi d i s di a g n o s e d, it m a y b e p o s si bl e 
t o a v oi d l o n g-t er m u s e of s y st e mi c c orti c o st er oi d s a n d 
tr e at wit h rit u xi m a b, a s a n alt er n ati v e a p pr o a c h t o 
tr e ati n g t h e ir A E
S e e k i nf e cti o u s di s e a s e c o n s ult ati o n if p ati e nt mi g ht 
h a v e s e c o n d ar y c ell uliti s or if p ati e nt h a s ot h er i nf e cti o n 
ri s k f a ct or s, s u c h a s n e utr o p e ni a, et c.
G 4: Bli st er s c o v eri n g > 3 0 % B S A wit h a s s o ci at e d ﬂui d 
or el e ctr ol yt e a b n or m aliti e s
P er m a n e ntl y di s c o nti n u e I C Pi
A d mit p ati e nt i m m e di at el y a n d pl a c e u n d er s u p er vi si o n 
of a d er m at ol o gi st
A d mi ni st er I V ( m et h yl) pr e d ni s ol o n e ( or e q ui v al e nt) 1 -2 
m g/ k g wit h t a p eri n g o v er at l e a st 4 w e e k s w h e n t h e 
t o xi cit y r e s ol v e s
If b ull o u s p e m p hi g oi d i s di a g n o s e d, it m a y b e p o s si bl e 
t o a v oi d l o n g-t er m u s e of s y st e mi c c orti co st er oi d s a n d 
tr e at wit h rit u xi m a b a s a n alt er n ati v e a p pr o a c h t o 
tr e ati n g t h e ir A E
S e e k i nf e cti o u s di s e a s e c o n s ult ati o n if p ati e nt mi g ht 
h a v e s e c o n d ar y c ell uliti s or if p ati e nt h a s ot h er i nf e cti o n 
ri s k f a ct or s, s u c h a s n e utr o p e ni a, et c
D oc u me nt N o.
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 8 /1 5 9
1. 3 S C A Rs, i ncl u di n g S J S, T E N, ac ute ge ner alize d e x a nt he m at o us p ust ul osis, a n d 
D R E S S/ DI H S
D e ﬁniti o n: S e v er e c h a n g e s i n eit h er str u ct ur e or f u n cti o n s of s ki n, t h e a p p e n d a g e s or t h e m u c o u s m e m br a n e s d u e 
t o a dr u g
Di a g n o sti c w or k -u p
T ot al b o d y s ki n e x a mi n at i o n wit h att e nti o n t o e x a mi ni n g all m u c o u s m e m br a n e s a s w ell a s c o m pl et e r e vi e w of 
s y st e m s
R ul e o ut a n y ot h er eti ol o g y of t h e s ki n pr o bl e m, s u c h a s a n i nf e cti o n, a n eff e ct of a n ot h er dr u g, or a s ki n c o n diti o n 
li n k e d t o a n ot h er s y st e mi c di s e a s e
A bi ol o gi c c h e c k u p, i n cl u di n g a C B C wit h diff er e nti al t e st, a n d li v er a n d ki d n e y f u n cti o n t e st s, i n cl u di n g uri n al y si s, i n 
a d diti o n t o t h e bl o o d w or k; if t h e p ati e nt i s f e bril e, bl o o d c ult ur e s s h o ul d b e c o n si d er e d a s w ell
S ki n bi o p si e s t o a s s e s s f or f ull -t hi c k n e s s e pi der m al n e cr o si s, a s i s s e e n i n S J S/ T E N, a s w ell a s ot h er p o s si bl e 
eti ol o gi e s li k e p ar a n e o pl a sti c p e m p hi g u s or ot h er a ut oi m m u n e bli st eri n g d er m at o s e s or ot h er dr u g r e a cti o n s, s u c h 
a s a c ut e g e n er ali z e d e x a nt h e m at o u s p u s tul o si s
C o n si d er f oll o wi n g p ati e nt s cl o s el y u si n g s eri al cli ni c al p h ot o gr a p h y
If m u c o u s m e m br a n e i n v ol v e m e nt or bli st eri n g i s o b s er v e d o n t h e s ki n, c o n si d er e arl y a d mi s si o n t o a b ur n c e nt er 
f or f urt h er m o nit ori n g a n d m a n a g e m e nt Pri m er o n m o nit ori n g f or c o m pli c at e d c ut a n e o u s a d v er s e dr u g r e a cti o ns:
R e vi e w of s y st e m s: S ki n p ai n (li k e a s u n b ur n), f e v er s, m al ai s e, m y al gi a s, art hr al gi a s, a b d o mi n al p ai n, o c ul ar 
di s c o mf ort or p h ot o p h o bi a, s or e s or di s c o mf ort i n t h e n ar e s, s or e s or di s c o mf ort i n t h e or o p h ar y n x, o d y n o p h a gi a, 
h o ar s e n e s s, d y s uri a, s or e s or di s c o mf ort i n t h e v a gi n al ar e a f or w o m e n or i n v ol vi n g t h e m e at u s of t h e p e ni s f or 
m e n, s or e s i n t h e p eri a n al ar e a, or p ai n wit h b o w el m o v e m e nt s
P h y si c al e x a mi n ati o n: I n cl u d e vit al si g n s a n d a f ull s ki n e x a mi n ati o n s p e ci ﬁc all y e v al u ati n g all s ki n s urf a c e s a n d 
m u c o u s m e m br a n e s ( e y e s, n ar e s, or o p h ar y n x, g e nit al s, a n d p eri a n al ar e a). A s s e s s f or l y m p h a d e n o p at h y, f a ci al or 
di st al e xtr e mit y s w elli n g ( m a y b e si g n s of DI H S/ D R E S S). A s s e s s f or p u st ul e s or bli st er s or er o si o n s i n a d diti o n t o 
ar e a s of “ d u s k y er yt h e m a,” w hi c h m a y f e el p ai nf ul t o p al p ati o n. T o a s s e s s f or a p o siti v e Ni k ol s k y si g n, pl a c e a 
gl o v e d ﬁn g er t a n g e nti all y o v er er yt h e m at o u s s ki n a n d a p pl y fri cti o n p ar all el t o t h e s ki n s urf a c e. Ni k ol s k y si g n i s 
p o siti v e if t hi s r e s ult s i n d et a c h e d or sl o u g hi n g e pi d er mi s d e m o n str ati n g p o or att a c h m e nt of t h e e pi d er mi s t o t h e 
d er mi s, w hi c h i s t h e c a s e i n s o m e a ut oi m m u n e di s or d er s ( e. g, p e m p hi g u s) a n d S J S/ T E N
Gr a di n g
M a n a g e m e nt
All Gr a d e s
I n c a s e s of s u s p e ct e d S J S or a n y m u c o u s m e m br a n e 
i n v ol v e m e nt, di s c o nti n u e I C Pi tr e at m e nt a n d m o nit or 
cl o s el y f or i m pr o v e m e nt, r e g ar dl e s s of gr a d e
G 1: N A
F or S C A R s, t h er e i s n o G 1 c at e g or y; if l o w er B S A i s 
i n v ol v e d wit h b ull a e or er o si o n s, t h er e s h o ul d r e m ai n a 
hi g h c o n c er n t h at t hi s r e a cti o n will pr o gr e s s t o G 3 or G 4
G 2: M or billif or m (“ m a c ul o p a p ul ar”) e x a nt h e m c o v eri n g 
1 0 % - 3 0 % B S A wit h s y st e mi c s y m pt o m s, 
l y m p h a d e n o p at h y, or f a ci al s w elli n g
H ol d I C Pi a n d m o nit or p ati e nt s cl o s el y e v er y 3 d a y s 
wit h G 2 ir A E s f or pr o gr e s si o n t o i n v ol v e m e nt of gr e at er 
B S A a n d/ or m u c o u s m e m br a n e i n v ol v e m e nt
C o n si d er f oll o wi n g p ati e nt s cl o s el y u si n g s eri al 
p h ot o gr a p h y
I niti at e t h er a p y wit h t o pi c al e m olli e nt s, or al 
a nti hi st a mi n e s, a n d m e di u m - t o hi g h-str e n gt h t o pi c al 
c orti c o st er oi d s
C o n si d er i niti ati o n of pr e d ni s o n e ( or e q ui v al e nt) 0. 5 -1 
m g/ k g t a p er e d o v er a t l e a st 4 w e e k s
G 3: S ki n sl o u g hi n g c o v eri n g < 1 0 % B S A wit h m u c o s al 
i n v ol v e m e nt a s s o ci at e d si g n s (e. g, er yt h e m a, p ur p ur a, 
e pi d er m al d et a c h m e nt, m u c o u s m e m br a n e 
d et a c h m e nt)
H ol d I C Pi t h er a p y a n d c o n s ult wit h d er m at ol o g y
Tr e at s ki n wit h t o pi c al e m olli e nt s a n d ot h er p etr ol at u m 
e m olli e nt s, or al a nti hi st a mi n e s, a n d hi g h - str e n gt h 
t o pi c al c orti c o st er oi d s; di m et hi c o n e m a y al s o b e off er e d 
a s a n alt er n ati v e t o p etr ol at u m
A d mi ni st er I V ( m et h yl) pr e d ni s ol o n e ( or e q ui v al e nt) 0. 5 -1 
m g/ k g a n d c o n v ert t o or al c orti c o st er oi d s o n r e s p o n s e, 
w e a n o v er at l e a st 4 w e e k s
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9 /1 5 9
A d mit t o b ur n a n d/ or c o n s ult w o u n d s er vi c e s wit h 
att e nti o n t o s u p p orti v e c ar e, i n cl u di n g ﬂui d a n d 
el e ctr ol yt e b al a n c e, mi ni mi zi n g i n s e n si bl e w at er l o s s e s, 
a n d pr e v e nti n g i nf e cti o n
Gi v e n t h e i m m u n e m e c h a ni s m of a cti o n of t h e s e 
m e di ci n e s, u s e of i m m u n e s u p pr e s si o n i s w arr a nt e d 
a n d s h o ul d b e off er e d
F or m u c o u s m e m br a n e i n v ol v e m e nt of S J S or T E N, 
a p pr o pri at e c o n s ulti n g s er vi c e s s h o ul d b e off er e d t o 
g ui d e m a n a g e m e nt i n pr e v e nti n g s e q u el a e fr o m 
s c arri n g ( e. g, o p ht h al m ol o g y; e ar, n o s e, a n d t hr o at; 
ur ol o g y; g y n e c ol o g y; et c, a s a p pr o pri at e)
G 4: S ki n er yt h e m a a n d bli st eri n g/ sl o u g hi n g c o v eri n g 
≥1 0 % t o > 3 0 % B S A wit h a s s o ci at e d si g n s ( e. g,
er yt h e m a, p ur p ur a, e pi d er m al d et a c h m e nt, m u c o u s 
m e m br a n e d et a c h m e nt) a n d/ or s y st e mi c s y m pt o m s a n d 
c o n c er ni n g a s s o ci at e d bl o o d w or k a b n or m aliti e s ( e. g,
li v er f u n cti o n t e st el e v ati o n s i n t h e s etti n g of 
D R E S S/ DI H S)
P er m a n e ntl y di s c o nti n u e I C Pi
A d mit p ati e nt i m m e di at el y t o a b ur n u nit or I C U wit h 
c o n s ult e d d er m at ol o g y a n d w o u n d c ar e s er vi c e s
C o n si d er f urt h er c o n s ult ati o n s b a s e d o n m a n a g e m e nt 
of m u c o s al s urf a c e s
(e. g, o p ht h al m ol o g y; ur ol o g y; g y n e c ol o g y; e ar, n o s e, 
a n d t hr o at s ur g er y; et c) I niti at e I V ( m et h yl) pr e d ni s ol o n e 
( or e q ui v al e nt) 1-2 m g/ k g, t a p eri n g w h e n t o xi cit y 
r e s ol v e s t o n or m al
I VI G or c y cl o s p ori n e m a y al s o b e c o n si d er e d i n s e v er e 
or c orti c o st er oi d -u nr e s p o n si v e c a s e s
C o n si d er p ai n/ p alli ati v e c o n s ult ati o n a n d/ or a d mi s si o n 
i n p ati e nt s pr e s e nti n g wit h D RE S S m a nif e st ati o n s
A d diti o n al c o n si d er ati o n s: T h e u s u al pr o hi biti o n of c orti c o st er oi d s f or S J S i s n ot r el e v a nt h er e, a s t h e u n d erl yi n g 
m e c h a ni s m i s a T -c ell i m m u n o dir e ct e d t o xi cit y
A d e q u at e s u p pr e s si o n i s n e c e s s ar y wit h c orti c o st er oi d s or ot h er a g e nt s a n d m a y b e pr ol o n g e d i n c a s e s of 
D R E S S/ DI H S
All r e c o m m e n d ati o n s ar e e x p ert c o n s e n s u s b a s e d, wit h b e n e ﬁt s o ut w ei g hi n g h ar m s, a n d str e n gt h of 
r e c o m m e n d ati o n s ar e m o d er at e
A b br e vi ati o n s: A D L = a cti viti e s of d ail y li vi n g; A E = a d v er s e e v e nt; B S A =
b o d y s urf a c e ar e a; C B C = c o m pl et e bl o o d 
c o u nt; C T C A E = C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt s; DI H S = dr u g -i n d u c e d h y p er s e n siti vit y s y n dr o m e; 
D R E S S = dr u g r e a cti o n wit h e o si n o p hili a a n d s y st e mi c s y m pt o m s; G = Gr a d e; I C Pi = i m m u n e c h e c k p oi nt i n hi bit or; 
I C U = i nte n si v e c ar e u nit; ir A E, i m m u n e -r el at e d a d v er s e e v e nt; I V = i ntr a v e n o u s; I VI G = i ntr a v e n o u s i m m u n o gl o b uli n; 
N A = n ot a p pli c a bl e; S C A R = s e v er e c ut a n e o u s a d v er s e r e a cti o n s; S J S = St e v e n s -J o h n s o n s y n dr o m e; T E N S = t o xi c 
e pi d er m al n e cr ol y si s.
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 /1 5 9
T a ble A 2
M a n a ge me nt of GI ir A Es i n P atie nts Tre ate d Wit h I C Pis
2. 0 GI T o xicities
2. 1 C olitis
D e ﬁniti o n: A di s or d er c h ar a ct eri z e d b y i n ﬂa m m ati o n of t h e c ol o n
Di a g n o sti c w or k -u p
G 2
W o r k-u p of bl o o d ( C B C, c o m pr e h e n si v e m et a b oli c p a n el, T S H, E S R, C R P), st o ol ( c ult ur e, Cl o stri di u m diffi cil e, 
p ar a sit e, C M V or ot h er vir al eti ol o g y, o v a a n d p ar a sit e) s h o ul d b e p erf or m e d
C o n si d er t e sti n g f or l a ct of erri n (f or p ati e nt str ati ﬁc ati o n t o d et er mi n e w h o n e e d s m or e ur g e nt e n d o s c o p y) a n d 
c al pr ot e cti n (t o f oll o w-u p o n di s e a s e a cti vit y)
S cr e e ni n g l a b or at ori e s ( HI V, h e p atiti s A a n d B, a n d bl o o d q u a ntif er o n f or T B) t o pr e p ar e p ati e nt s t o st art i n ﬂi xi m a b 
s h o ul d b e r o uti n el y d o n e i n p ati e nt s at hi g h ri s k f or t h o s e i nf e cti o n s a n d a p pr o pri at el y s el e ct e d p ati e nt s b a s e d o n 
i nf e cti o u s di s e a s e e x p ert’ s e v al u ati o n
I m a gi n g (e. g, C T s c a n of a b d o m e n a n d p el vi s a n d GI e n d o s c o p y wit h bi o p s y) s h o ul d b e c o n si d er e d a s t h er e i s 
e vi d e n c e s h o wi n g t h at t h e pr e s e n c e of ul c er ati o n i n t h e c ol o n c a n pr e di ct a c orti c o st er oi d r efr a ct or y c our s e, w hi c h 
m a y r e q uir e e arl y i n ﬂi xi m a b
C o n si d er r e p e ati n g e n d o s c o p y f or p ati e nt s w h o d o n ot r e s p o n d t o i m m u n o s u p pr e s si v e a g e nt s; r e p e ati n g 
e n d o s c o p y f or di s e a s e m o nit ori n g c a n b e c o n si d er e d w h e n cli ni c all y i n di c at e d a n d w h e n pl a n ni n g t o r e s u m e 
t h er a p y
G 3 - 4
All t h e w or k -u p li st e d f or G 2 ( bl o o d, st o ol, i m a gi n g, a n d s c o p e wit h bi o p s y) s h o ul d b e c o m pl et e d i m m e di at el y
C o n si d er r e p e ati n g e n d o s c o p y f or p ati e nt s w h o d o n ot r e s p o n d t o i m m u n o s u p pr e s si v e a g e nt s; r e p e ati n g 
e n d o s c o p y f or di s e a s e m o nit ori n g s h o ul d o nl y b e c o n si d er e d w h e n cli ni c all y i n di c at e d a n d w h e n pl a n ni n g t o 
r e s u m e I C Pi
Gr a di n g ( b a s e d o n C T C A E f or di arr h e a, a s m o st oft e n 
u s e d cli ni c all y)
M a n a g e m e nt
All p ati e nt s
C o u n s el all p ati e nt s t o b e a w ar e of a n d i nf or m t h eir 
h e alt h c ar e pr o vi d er i m m e di at el y if t h e y e x p eri e n c e:
A b d o mi n al p ai n, n a u s e a, cr a m pi n g, bl o o d or m u c u s i n 
st o ol or c h a n g e s i n b o w el h a bit s, f e v er, a b d o mi n al 
di st e nti o n, o b sti p ati o n, c o n sti p ati o n
F or G 2 or hi g h er, c o n si d er p er m a n e ntl y di s c o nti n ui n g 
C T L A -4 a g e nt s a n d m a y r e st art P D -1, P D -L 1 a g e nt s if 
p ati e nt c a n r e c o v er t o G 1 or l e s s; c o n c urr e nt 
i m m u n o s u p pr e s s a nt m ai nt e n a n c e t h er a p y s h o ul d b e 
c o n si d er e d o nl y if cli ni c all y i n di c at e d i n i n di vi d u al c a s e s
G 1: I n cr e a s e of f e w er t h a n 4 st o ol s p er d a y o v er 
b a s eli n e; mil d i n cr e a s e i n o st o m y o ut p ut c o m p ar e d wit h 
b a s eli n e
C o nti n u e I C Pi; alt er n ati v el y, I C Pi m a y b e h el d 
t e m p or aril y a n d r e s u m e d if t o xi cit y d o e s n ot e x c e e d
G 1
M o nit or f or d e h y dr ati o n a n d r e c o m m e n d di et ar y 
c h a n g e s F a cilit at e e x p e dit e d p h o n e c o nt a ct wit h 
p ati e nt/ c ar e gi v er M a y o bt ai n g a str o e nt er ol o g y c o n s ult 
f or pr ol o n g e d G 1 c a s e s
G 2: I n cr e a s e of 4 t o 6 st o ol s p er d a y o v er b a s eli n e; 
m o d er at e i n cr e a s e i n o st o m y o ut p ut c o m p ar e d wit h 
b a s eli n e
S h o ul d h ol d I C Pi t e m p or aril y u ntil p ati e nt’ s s y m pt o m s 
r e c o v er t o G 1; c a n c o n si d er p er m a n e ntl y
di s c o nti n ui n g C T L A -4 a g e nt s a n d m a y r e st art P D -1, 
P D - L 1 a g e nt s if p ati e nt c a n r e c o v er t o G 1 or l e s s
C o n c urr e nt i m m u n o s u p pr e s s a nt m ai nt e n a n c e t h er a p y 
( 1 0 m g pr e d ni s o n e e q ui v al e nt d o s e) m a y b e off er e d 
o nl y if cli ni c all y i n di c at e d i n i n di vi d u al c a s e s
M a y al s o i n cl u d e s u p p orti v e c ar e wit h m e di c ati o n s s u c h 
a s I m o di u m if i nf e cti o n h a s b e e n r ul e d o ut
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 /1 5 9
S h o ul d c o n s ult wit h g a str o e nt er ol o g y f or G 2 or hi g h er
A d mi ni st er c orti c o st er oi d s, u nl e s s di arr h e a i s tr a n si e nt, 
st arti n g wit h i niti al d o s e of 1 m g/ k g/ d a y pr e d ni s o n e or 
e q ui v al e nt
W h e n s y m pt o m s i m pr o v e t o G 1 or l e s s, t a p er 
c orti c o st er oi d s o v er at l e a st 4 -6 w e e k s b ef or e r e s u mi n g 
tr e at m e nt, alt h o u g h r e s u mi n g tr e at m e nt w hil e o n l o w-
d o s e c orti c o st er oi d m a y al s o b e a n o pti o n aft er a n 
e v al u ati o n of t h e ri s k s a n d b e n e ﬁt s
E G D/ c ol o n o s c o p y, e n d o s c o p y e v al u ati o n s h o ul d b e 
hi g hl y r e c o m m e n d e d f or c a s e s Gr a d e ≥2 t o str atif y 
p ati e nt s f or e arl y tr e at m e nt wit h i n ﬂi xi m a b b a s e d o n t h e 
e n d o s c o pi c ﬁn di n g s a n d t o d et er mi n e t h e s af et y of 
r e s u mi n g P D-1, P D -L 1 t h er a p y
St o ol i n ﬂa m m at or y m ar k er s c a n b e c o n si d er e d 
(l a ct of erri n a n d c al pr ot e cti n) i n c a s e s of G 2 or hi g h er t o 
diff er e nti at e f u n cti o n al v er s u s i nﬂa m m at or y di arr h e a, 
a n d u s e c al pr ot e cti n t o m o nit or tr e at m e nt r e s p o n s e if 
pr o vi d er pr ef er s
R e p e at c ol o n o s c o p y i s o pti o n al f or c a s e s of G 2 or 
hi g h er f or di s e a s e a cti vit y m o nit ori n g t o a c hi e v e 
c o m pl et e r e mi s si o n, e s p e ci all y if t h er e i s a pl a n t o 
r e s u m e I C Pi
G 3: I n cr e a s e of s e v e n or m or e st o ol s p er d a y o v er 
b a s eli n e, i n c o nti n e n c e, h o s pit ali z ati o n i n di c at e d, s e v er e 
i n cr e a s e i n o st o m y o ut p ut c o m p ar e d wit h b a s eli n e, 
li miti n g s elf-c ar e A D L
S h o ul d c o n si d er p er m a n e ntl y di s c o nti n ui n g C T L A -4 
a g e nt s a n d m a y r e st art P D -1, P D -L 1 a g e nt s if p ati e nt 
c a n r e c o v er t o G 1 or l e s s.
A d mi ni st er c orti c o st er oi d s (i niti al d o s e of 1 -2 m g/ k g/ d 
pr e d ni s o n e or e q ui v al e nt)
C o n si d e r h o s pit ali z ati o n or o ut p ati e nt f a cilit y f or p ati e nt s 
wit h d e h y dr ati o n or el e ctr ol yt e i m b al a n c e
If s y m pt o m s p er si st ≥3- 5 d a y s or r e c ur aft er 
i m pr o v e m e nt, c o n si d er a d mi ni st eri n g I V c orti c o st er oi d 
or n o n c orti c o st er oi d ( e. g, i nﬂi xi m a b)
C o n si d er c ol o n o s c o p y i n c a s e s w h er e p ati e nt s h a v e 
b e e n o n i m m u n o s u p pr e s si o n a n d m a y b e at ri s k f or 
o p p ort u ni sti c i nf e cti o n s a s a n i n d e p e n d e nt c a u s e f or 
di arr h e a (i . e, C M V c oliti s) a n d f or t h o s e w h o ar e a nti-
T N F or c orti c o st er oi d r efr a ct or y
G 4: Lif e -t hr e at e ni n g c o n s e q u e n c e s; urg e nt i nt er v e nti o n 
i n di c at e d
P er m a n e ntl y di s c o nti n u e tr e at m e nt
S h o ul d a d mit p ati e nt w h e n cli ni c all y i n di c at e d; p ati e nt s 
m a n a g e d a s o ut p ati e nt s s h o ul d b e v er y cl o s el y 
m o nit or e d
A d mi ni st er 1 - 2 m g/ k g/ d m et h yl pr e d ni s ol o n e or 
e q ui v al e nt u ntil s y m pt o m s i m pr o v e t o G 1, a n d t h e n st art 
t a p er o v er 4-6 w e e k s
C o n si d er e arl y i n ﬂi xi m a b 5 -1 0 m g/ k g if s y m pt o m s 
r efr a ct or y t o c orti c o st er oi d wit hi n 2- 3 d a y s C o n si d er 
l o w er GI e n d o s c o p y if s y m pt o m s ar e r efr a ct or y d e s pit e 
tr e at m e nt or t h er e i s c o n c er n of n e w i nf e cti o n s
A d diti o n al c o n si d er ati o n s
T h e u s e of v e d oli z u m a b ( n ot a p pr o v e d i n J a p a n) m a y b e c o n si d er e d i n p ati e nt s r efr a ct or y t o i n ﬂi xi m a b a n d/ or 
c o ntr ai n di c at e d t o T N F- a bl o c k er. T h e d e ci si o n s h o ul d b e m a d e o n a n i n di vi d u al b a si s fr o m g a str o e nt er ol o g y a n d 
o n c ol o g y e v al u ati o n. T hi s i s b a s e d o n c a s e s eri e s s h o wi n g pr o mi si n g r e s ult s
P ati e nt s wit h h e p atiti s a n d ir A E c oliti s ar e r ar e, a n d m a n a g e m e nt s h o ul d i n cl u d e p er m a n e ntl y di s c o nti n ui n g I C Pi 
a n d off eri n g ot h er i m m u n o s u p pr e s s a nt a g e nt s t h at w or k s y st e mi c all y f or b ot h c o n diti o n s
C u rr e ntl y, e nt eriti s al o n e a s t h e c a u s e of di arr h e a i s u n c o m m o n a n d r e q uir e s s m all b o w el bi o p s y a s t h e e v al u ati o n 
t o ol. It m a y b e m a n a g e d si mil ar a s c oliti s, i n cl u di n g c orti c o st er oi d a n d/ or i nﬂi xi m a b, et c
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 2 /1 5 9
2. 2 He p atitis
D e ﬁniti o n: A di s or d er c h ar a ct eri z e d b y a vir al p at h ol o gi c pr o c e s s i n v ol vi n g t h e li v er p ar e n c h y m a
Di a g n o sti c w or k -u p
M o nit or p ati e nt f or a b n or m al li v er bl o o d t e st s: A S T, A L T, a n d bilir u bi n pri or t o e a c h i nf u si o n a n d/ or w e e kl y if G 1 
li v er f u n cti o n t e st el e v ati o n s. N o tr e at m e nt i s r e c o m m e n d e d f or G 1 li v er f u n cti o n t e st a b n or m alit y
F or G 2 or hi g h er:
W o r k-u p f or ot h er c a u s e s of el e v at e d li v er e n z y m e s s h o ul d b e t e st e d, vir al h e p atiti s, al c o h ol hi st or y, ir o n st u d y, 
t hr o m b o e m b oli c e v e nt, li v er ultr a s o u n d, cr o s s-s e cti o n al i m a gi n g f or p ot e nti al li v er m et a st a si s fr o m pri m ar y 
m ali g n a n c y. If s u s pi ci o n f or pri m ar y a ut oi m m u n e h e p atiti s i s hi g h, c a n c o n si d er A N A s, a nti s m o ot h m u s cl e 
a nti b o di e s, a nti n e utr o p hil c yt o pl a s mi c a nti b o di e s. If p ati e nt s wit h el e v at e d al k ali n e p h o s p h at a s e al o n e, g -gl ut a m yl 
tr a n sf er a s e s h o ul d b e t e st e d. F or i s ol at e d el e v ati o n of tr a n s a mi n a s e s, c o n si d er c h e c ki n g C K f or ot h er eti ol o gi e s
Gr a di n g
M a n a g e m e nt
All p ati e nt s
C o u n s el all p ati e nt s t o b e a w ar e of a n d i nf or m t h eir 
h e alt h c ar e pr o vi d er i m m e di at el y if t h e y e x p eri e n c e:
Y ell o wi n g of s k i n or w hit e s of t h e e y e s S e v er e n a u s e a 
or v o miti n g
P ai n o n t h e ri g ht si d e of t h e a b d o m e n Dr o w si n e s s
D ar k uri n e (t e a c ol or e d)
Bl e e di n g or br ui si n g m or e e a sil y t h a n n or m al F e eli n g 
l e s s h u n gr y t h a n u s u al
G 1: A s y m pt o m ati c ( A S T or A L T > U L N t o 3. 0 x U L N 
a n d/ or t ot al bilir u bi n > U L N t o 1. 5 x U L N)
C o nti n u e I C Pi wit h cl o s e m o nit ori n g; c o n si d er alt er n at e 
eti ol o gi e s
M o nit or l a b or at ori e s o n e t o t w o ti m e s w e e kl y
M a n a g e wit h s u p p orti v e c ar e f or s y m pt o m c o ntr ol
G 2: A s y m pt o m ati c ( A S T or A L T > 3. 0 t o ≤5 x U L N 
a n d/ or t ot al bilir u bi n > 1. 5 t o ≤3 x U L N)
H ol d I C Pi t e m p or aril y a n d r e s u m e if r e c o v er t o G 1 or 
l e s s o n pr e d ni s o n e ≤1 0 m g/ d
F or Gr a d e 2 h e p ati c t o xi cit y wit h s y m pt o m s, m a y 
a d mi ni st er c orti c o st er oi d 0. 5 -1 m g/ k g/ d pr e d ni s o n e or 
e q ui v al e nt if t h e a b n or m al el e v ati o n p e r si st s wit h 
si g ni ﬁc a nt cli ni c al s y m pt o m s i n 3 -5 d a y s I n cr e a s e 
fr e q u e n c y of m o nit ori n g t o e v er y 3 d a y s
I nﬂi xi m a b mi g ht n ot b e t h e m o st a p pr o pri at e tr e at m e nt 
o pti o n i n t h e sit u ati o n of i m m u n e- m e di at e d h e p atiti s 
gi v e n t h e p ot e nti al ri s k of i di o s y n cr ati c li v er f ail ur e 
( N ot e: N o cl e ar e vi d e n c e s h o w s t h e li v er t o xi cit y fr o m 
i nﬂi xi m a b fr o m ot h er st u di e s)
I n f oll o w- u p, m a y r e s u m e I C Pi tr e at m e nt f oll o w e d b y 
t a p er o nl y w h e n s y m pt o m s i m pr o v e t o G 1 or l e s s a n d 
c orti c o st er oi d ≤1 0 m g/ d; t a p er o v er at l e a st 1 m o nt h
P ati e nt s s h o ul d b e a d vi s e d t o st o p u n n e c e s s ar y 
m e di c ati o n s a n d a n y k n o w n h e p at ot o xi c dr u g s
G 3: S y m pt o m ati c li v er d y sf u n cti o n, ﬁbr o si s b y bi o p s y, 
c o m p e n s at e d cirr h o si s, r e a cti v ati o n of c hr o ni c h e p atiti s 
( A S T or A L T 5-2 0 x U L N a n d/ or t ot al bilir u bi n 3 -1 0 x 3 
U L N)
P er m a n e ntl y di s c o nti n u e I C Pi
I m m e di at el y st art c orti c o st er oi d 1-2 m g/ k g 
m et h yl pr e d ni s ol o n e or e q ui v al e nt
If c orti c o st er oi d r efr a ct or y or n o i m pr o v e m e nt aft er 3 
d a y s, c o n si d er m y c o p h e n ol at e m of etil or a z at hi o pri n e (if 
u si n g a z at hi o pri n e s h o ul d t e st f or t hi o p uri n e 
m et h yltr a n sf er a s e d e ﬁci e n c y)
L a b or at ori e s at d ail y or e v er y ot h er d a y; c o n si d er 
i n p ati e nt m o nit ori n g f or p ati e nt s wit h A S T/ A L T > 8 x 
U L N a n d/ or el e v at e d T B 3 x U L N
I n cr e a s e fr e q u e n c y of m o nit ori n g t o e v er y 1-2 d a y s
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
I nﬂi xi m a b mi g ht n ot b e t h e m o st a p pr o pri at e tr e at m e nt 
o pti o n i n t h e sit u ati o n of i m m u n e- m e di at e d h e p atiti s 
gi v e n t h e p ot e nti al ri s k of li v er f ail ur e ( N ot e: N o cl e ar 
e vi d e n c e s h o w s t h at t h e li v er t o xi cit y fr o m i n ﬂi xi m a b 
fr o m ot h er st u di e s); alt er n ati v e s i n cl u d e n o n– T N F -a 
a g e nt s a s s y st e mi c i m m u n o s u p pr e s s a nt s If n o 
i m pr o v e m e nt i s a c hi e v e d wit h c orti c o st er oi d s or f or 
p ati e nt s o n c o m bi n ati o n t h er a p y wit h a n o v el a g e nt, 
wit h st a n d ar d c h e m ot h er a p y, or wit h t ar g et e d t h er a p y, 
r ef er t o h e p at ol o gi st f or f urt h er p at h ol o gi c e v al u ati o n of 
h e p atiti s
C orti c o st er oi d t a p er c a n b e att e m pt e d ar o u n d 4 -6 
w e e k s; r e - e s c al at e if n e e d e d; o pti m al d ur ati o n u n cl e ar
G 4: D e c o m p e n s at e d li v er f u n cti o n ( e. g, a s cit e s, 
c o a g ul o p at h y, e n c e p h al o p at h y, c o m a; A S T or A L T > 2 0 
x U L N a n d/ or t ot al bilir u bi n > 1 0 x U L N)
P er m a n e ntl y di s c o nti n u e I C Pi
A d mi ni st er 2 m g/ k g/ d m et h yl pr e d ni s ol o n e e q ui v al e nt s
If c orti c o st er oi d r efr a ct or y or n o i m pr o v e m e nt aft er 3 
d a y s, c o n si d er m y c o p h e n ol at e m of etil
M o nit or l a b or at ori e s d ail y; c o n si d er i n p ati e nt m o nit ori n g
A v oi d t h e u s e of i n ﬂi xi m a b i n t h e sit u ati o n of i m m u n e -
m e di at e d h e p atiti s
H e p at ol o g y c o n s ult if n o i m pr o v e m e nt w a s a c hi e v e d 
wit h c orti c o st er oi d
C orti c o st er oi d t a p er c a n b e att e m pt e d ar o u n d 4 -6 
w e e k s w h e n s y m pt o m s i m pr o v e t o G 1 or l e s s; r e -
e s c al at e if n e e d e d; o pti m al d ur ati o n u n cl e ar
C o n si d e r tr a n sf er t o t erti ar y c ar e f a cilit y if n e c e s s ar y
All r e c o m m e n d ati o n s ar e e x p ert c o n s e n s u s b a s e d, wit h b e n e ﬁt s o ut w ei g hi n g h ar m s, a n d str e n gt h of 
r e c o m m e n d ati o n s i s m o d er at e.
* n ot a p pr o v e d i n J a p a n.
A b br e vi ati o n s: A D L, a cti viti e s of d ail y li vi n g; A L T, a l a ni n e a mi n otr a n sf er a s e; A N A, a nti n u cl e ar a nti b o d y; A S T, 
a s p art at e a mi n otr a n sf er a s e; C B C, c o m pl et e bl o o d c o u nt, C K, cr e ati n e ki n a s e; C M V, c yt o m e g al o vir u s; C R P, 
C-r e a cti v e pr ot ei n; C T, c o m p ut e d t o m o gr a p h y; C T C A E, C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e n t s; C T L A-4, 
c yt ot o xi c T -c ell l y m p h o c yt e -4; E G D, e s o p h a g o g a str o d u o d e n o s c o p y; E S R, er yt hr o c yt e s e di m e nt ati o n r at e; G, Gr a d e ; 
GI, g a str oi nt e sti n al; HI V, h u m a n i m m u n o d efi ci e n c y vir u s; I C Pi, i m m u n e c h e c k p oi nt i n hi bit or; ir A E, i m m u n e-r el at e d 
a d v er s e e v e nt; I V, i ntr a v e n o u s; P D -1; pr o gr a m m e d d e at h 1; P D -L 1, pr o gr a m m e d d e at h -li g a n d 1; T B, t u b er c ul o si s; 
T N F, t u m or n e cr o si s f a ct or; T S H, t h yr oi d -sti m ul ati n g h or m o n e; U L N, u p p er li mit of n or m al.
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
T a ble A 3
M a n a ge me nt of L u n g ir A Es
i n P atie nts Tre ate d Wit h I C Pis
3. 0 L u n g T o xicities
3. 1 P ne u m o nitis
D e ﬁniti o n: F o c al or diff u s e i n ﬂa m m ati o n of t h e l u n g p ar e n c h y m a (t y pi c all y i d e nti ﬁe d o n C T i m a gi n g)
N o s y m pt o m ati c, p at h ol o gi c, or r a di o gr a p hi c f e at ur e s ar e p at h o g n o m o ni c f or p n e u m o niti s
Di a g n o sti c w or k -u p
S h o ul d i n cl u d e t h e f oll o wi n g: C X R, C T, p ul s e o xi m etr y
F or G 2 or hi g h er, m a y i n cl u d e t h e f oll o wi n g i nf e cti o u s w or k - u p: n a s al s w a b, s p ut u m c ult ur e a n d s e n siti vit y, bl o o d 
c ult ur e a n d s e n siti vit y, uri n e c ult ur e a n d s e n siti vit y
Gr a di n g
M a n a g e m e nt
G 1: A s y m pt o m ati c, c o n ﬁn e d t o o n e l o b e of t h e l u n g or 
< 2 5 % of l u n g p ar e n c h y m a, cli ni c al or di a g n o sti c 
o b s er v ati o n s o nl y
C o nti n u e I C Pi 
if cli ni c all y i n di c at e d. M o nit or p arti ci p a nt s w e e kl y or 
m or e fr e q u e ntl y a s n e e d e d wit h hi st or y,
p h y si c al 
e x a mi n ati o n a n d p ul s e o xi m etr y; m a y al s o off er C X R . 
M a y off er o n e r e p e at C T s c a n i n 3-4 w e e k s; i n p ati e nt s 
w h o h a v e h a d b a s eli n e t e sti n g, m a y off er a r e p e at 
s pir o m etr y/ D L C O i n 3 -4 w e e k s
If s y m pt o m s a p p e ar a n d/ or c h a n g e s i n t h e p h y si c al
e x a m ar e n ot e d , tr e at a s G 2
G 2: S y m pt o m ati c, i n v ol v e s m or e t h a n o n e l o b e of t h e 
l u n g or 2 5 %- 5 0 % of l u n g p ar e n c h y m a, m e di c al 
i nt er v e nti o n i n di c at e d, li miti n g i n str u m e nt al A D L
H ol d I C Pi u ntil r e s ol uti o n t o G 1 or l e s s
Pr e d ni s o n e 1 - 2 m g/ k g/ d a n d t a p er b y 5-1 0 m g/ w k o v er 
4- 6 w e e k s C o n si d er br o n c h o s c o p y wit h B A L
C o n si d er e m piri c al a nti bi oti c s
M o nit or e v er y 3 d a y s wit h hi st or y a n d p h y si c al 
e x a mi n ati o n a n d p ul s e o xi m etr y, c o n si d er C X R; n o 
cli ni c al i m pr o v e m e nt aft er 4 8 - 7 2 h o ur s of pr e d ni s o n e, 
tr e at a s G 3
G 3: S e v er e s y m pt o m s, h o s pit al i z ati o n r e q uir ed, 
i n v ol v e s all l u n g l o b e s or 5 0 % of l u n g p ar e n c h y m a, 
li miti n g s elf-c ar e
A D L, o x y g e n i n di c at e d
G 4: Lif e -t hr e at e ni n g r e s pir at or y c o m pr o mi s e, ur g e nt 
i nt er v e nti o n i n di c at e d (i nt u b ati o n)
P er m a n e ntl y di s c o nti n u e I C Pi
E m piri c al a nti bi oti c s; ( m et h y l) pr e d ni s ol o n e I V 1-2 
m g/ k g/ d; n o i m pr o v e m e nt aft er 4 8 h o ur s, m a y a d d 
i nﬂi xi m a b 5 m g/ k g or m y c o p h e n ol at e m of etil I V 1 g 
t wi c e a d a y or I VI G f or 5 d a y s or c y cl o p h o s p h a mi d e; 
t a p er c orti c o st er oi d s o v er 4-6 w e e k s
P ul m o n ar y a n d i nf e cti o u s di s e a s e c o n s ult s if n e c e s s ar y
Br o n c h o s c o p y wit h B A L ± tr a n s br o n c hi al bi o p s y
P ati e nt s s h o ul d b e h o s pit ali z e d f or f urt h er m a n a g e m e nt
A d diti o n al c o n si d er ati o n s
GI a n d P n e u m o c y sti s pr o p h yl a xi s wit h P PI a n d B a ctri m m a y b e off er e d t o p ati e nt s o n pr ol o n g e d c orti c o st er oi d u s e 
( > 1 2 w e e k s), a c c or di n g t o i n stit uti o n al g ui d eli n e s
C o n si d er c al ci u m a n d vit a mi n D s u p pl e m e nt ati o n wit h pr ol o n g e d c orti c o st er oi d u s e
T h e r ol e of pr o p h yl a cti c ﬂu c o n a z ol e wit h pr ol o n g e d c orti c o st er oi d u s e ( > 1 2 w e e k s) r e m ai n s u n cl e ar, a n d 
p h y si ci a n s s h o ul d pr o c e e d a c c or di n g t o i n stit uti o n al g ui d eli n e s
Br o n c h o s c o p y + bi o p s y; if cli ni c al pi ct ur e i s c o n si st e nt wit h p n e u m o niti s, n o n e e d f or bi o p s y
All r e c o m m e n d ati o n s ar e e x p ert c o n s e n s u s b a s e d, wit h b e n e ﬁt s o ut w ei g hi n g h ar m s, a n d str e n gt h of 
r e c o m m e n d ati o n s ar e m o d er ate.
A b br e vi ati o n s: A D L, a cti viti e s of d ail y li vi n g; B A L, br o n c h o al v e ol ar l a v a g e; C T, c o m p ut e d t o m o gr a p h y; C X R, c h e st x -
r a y; D L C O, diff u si n g c a p a cit y of l u n g f or c ar b o n m o n o xi d e; G, Gr a d e ; GI, g a str oi nt e sti n al; I C Pi, i m m u n e c h e c k p oi nt 
i n hi bit or; ir A E, i m m u n e-r el at e d a d v er s e e v e nt; I V, i ntr a v e n o u s; I VI G, i ntr a v e n o u s i m m u n o gl o b uli n; P PI, pr ot o n p u m p 
i n hi bit or.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
T a ble A 4  
M a n a ge me nt of E n d ocri ne ir A Es i n P atie nts Tre ate d Wit h I C Pis
4. 0 E n d ocri ne T o xicit y
C o u n s el p ati e nt s t o i nf or m t h eir h e alt h c ar e pr o vi d er i m m e di at el y if t h e y e x p eri e n c e a n y c h a n g e s i n t h eir h e alt h 
si n c e t h eir l a st vi sit, e s p e ci all y a n y of t h e f oll o wi n g:
H e a d a c h e s t h at will n ot g o a w a y or u n u s u al h e a d a c h e 
p att er n s
Vi si o n c h a n g e s
R a pi d h e art b e at
I n cr e a s e d s w e ati n g
E xtr e m e tir e d n e s s or w e a k n e s s
M u s cl e a c h e s
W e i g ht g ai n or w ei g ht l o s s
Di z zi n e s s or f ai nti n g
F e eli n g m or e h u n gr y or t hir st y t h a n u s u al
H air l o s s
C h a n g e s i n m o o d or b e h a vi or, s u c h a s d e cr e a s e d s e x 
dri v e, irrit a bilit y, or f or g etf ul n e s s F e eli n g c ol d
C o n sti p ati o n
V oi c e g et s d e e p er
Uri n ati n g m or e oft e n t h a n u s u al
N a u s e a or v o miti n g
A b d o mi n al p ai n
4. 1 T h yr oi d
4. 1. 1 Pri m ar y h y p ot h yr oi dis m
D e ﬁniti o n: El e v at e d T S H, n or m al or l o w F T 4
Di a g n o sti c w or k -u p
T S H a n d F T 4 e v er y 4 -6 w e e k s a s p art of r o uti n e cli ni c al m o nit ori n g o n t h er a p y or f or c a s e d et e cti o n i n 
s y m pt o m ati c p ati e nt s
Gr a di n g
M a n a g e m e nt
G 1: T S H < 1 0 mI U/ L a n d a s y m pt o m ati c
G 2: M o d er at e s y m pt o m s; a bl e t o p erf or m A D L; T S H 
p er si st e ntl y > 1 0 mI U/ L
S h o ul d c o nti n u e I C Pi wit h cl o s e f oll o w -u p a n d 
m o ni t ori n g of T S H, F T 4 M a y h ol d I C Pi u ntil s y m pt o m s 
r e s ol v e t o b a s eli n e
C o n si d er e n d o cri n e c o n s ult ati o n
Pr e s cri b e t h yr oi d h or m o n e s u p pl e m e nt ati o n i n 
s y m pt o m ati c p ati e nt s wit h a n y d e gr e e of T S H el e v ati o n 
or i n a s y m pt o m ati c p ati e nt s wit h T S H l e v el s t h at p er si st 
> 1 0 mI U/ L ( m e a s ur e d 4 w e e k s a p art)
M o nit or T S H e v er y 6 -8 w e e k s w hil e titr ati n g h or m o n e 
r e pl a c e m e nt t o n or m al T S H F T 4 c a n b e u s e d i n t h e 
s h ort -t er m ( 2 w e e k s) t o e n s ur e a d e q u a c y of t h er a p y i n 
t h o s e wit h fr a n k h y p ot h yr oi di s m w h er e t h e F T 4 w a s 
i niti all y l o w
O n c e a d e q u at el y tr e at e d, s h o ul d m o nit or t h yr oi d 
f u n cti o n ( at l e a st T S H) e v er y 6 w e e k s w hil e o n a cti v e 
I C Pi t h er a p y or a s n e e d e d f or s y m pt o m s t o e n s ur e 
a p pr o pri at e r e pl a c e m e nt; r e p e at t e sti n g a n n u all y or a s 
i n di c at e d b y s y m pt o m s o n c e st a bl e
G 3 -4: S e v er e s y m pt o m s, m e di c all y si g ni ﬁc a nt or lif e -
t hr e at e ni n g c o n s e q u e n c e s, u n a bl e t o p erf or m A D L
H ol d I C Pi u ntil s y m pt o m s r e s ol v e t o b a s eli n e wit h 
a p pr o pri at e s u p pl e m e nt ati o n
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 6 /1 5 9
E n d o cri n e c o n s ult ati o n
M a y a d mit f or I V t h er a p y if si g n s of m y x e d e m a 
( br a d y c ar di a, h y p ot h er mi a) T h yr oi d s u p pl e m e nt ati o n 
a n d r e a s s e s s m e nt a s i n G 2
A d diti o n al c o n si d er ati o n s
F or p ati e nt s wit h o ut ri s k f a ct or s, f ull r e pl a c e m e nt c a n b e e sti m at e d wit h a n i d e al b o d y w ei g ht – b a s e d d o s e of 
a p pr o xi m at el y 1. 6 µ g/ k g/ d
F or el d erl y or fr a gil e p ati e nt s wit h m ulti pl e c o m or bi diti e s, c o n si d er titr ati n g u p fr o m l o w d o s e, st arti n g at 2 5 -5 0 m g
E x tr e m e el e v ati o n s of T S H c a n b e s e e n i n t h e r e c o v er y p h a s e of t h yr oi diti s a n d c a n b e w at c h e d i n a s y m pt o m ati c 
p ati e nt s t o d et er mi n e w h et h er t h er e i s r e c o v er y t o n or m al wit hi n 3 -4 w e e k s
U n d er g ui d a n c e of e n d o cri n ol o g y, c o n si d er t a p eri n g h or m o n e r e pl a c e m e nt a n d r et e sti n g i n p ati e nt s wit h a hi st or y 
of t h yr oi diti s (i niti al t h yr ot o xi c p h a s e)
A dr e n al d y sf u n cti o n, if pr e s e nt, m u st al w a y s b e r e pl a c e d b ef or e t h yr oi d h or m o n e t h er a p y i s i niti at e d 
4. 1. 2 H y pert h yr oi dis m
D e ﬁniti o n: S u p pr e s s e d T S H a n d hi g h n or m al or el e v at e d F T 4 a n d/ or trii o d ot h yr o ni n e
Di a g n o sti c w or k -u p
M o nit or T S H, F T 4 e v er y 4 -6 w e e k s fr o m t h e st art of t h er a p y or a s n e e d e d f or c a s e d et e cti o n i n s y m pt o m ati c 
p ati e nt s
C o n si d er T S H r e c e pt or a nti b o di e s if t h er e ar e cli ni c al f e at ur e s a n d s u s pi ci o n of Gr a v e di s e a s e ( e. g,
o p ht h al m o p at h y)
Cl o s e m o nit ori n g of t h yr oi d f u n cti o n e v er y 2- 3 w e e k s aft er di a g n o si s t o c at c h tr a n siti o n t o h y p ot h yr oi di s m i n 
p ati e nt s wit h t h yr oi diti s a n d h y p ert h yr oi di s m
Gr a di n g
M a n a g e m e nt
G 1: A s y m pt o m ati c or mil d s y m pt o m s
C a n c o nti n u e I C Pi wit h cl o s e f oll o w -u p a n d m o nit ori n g 
of T S H, F T 4 e v er y 2 -3 w e e k s u ntil it i s cl e ar w h et h er 
t h er e will b e p er si st e nt h y p ert h yr oi di s m ( s e e b el o w) or 
h y p ot h yr oi di s m ( s e e 4. 1. 1)
C o n si d er h ol di n g I C Pi u ntil s y m pt o m s r et ur n t o b a s eli n e
C o n si d er e n d o cri n e c o n s ult ati o n
b- Bl o c k er ( e. g, at e n ol ol, pr o pr a n ol ol) f or s y m pt o m ati c 
r eli ef
H y dr ati o n a n d s u p p orti v e c ar e
C orti c o st er oi d s ar e n ot u s u all y r e q uir e d t o s h ort e n 
d ur ati o n
F or p er si st e nt h y p ert h yr oi di s m ( > 6 w e e k s) or cli ni c al 
s u s pi ci o n, w or k -u p f or Gr a v e s di s e a s e ( T SI or T R A b) 
a n d c o n si d er t hi o n a mi d e ( m et hi m a z ol e or P T U) R ef er 
t o e n d o cri n ol o g y f or Gr a v e s di s e a s e
G 3 -4: S e v er e s y m pt o m s, m e di c all y si g ni ﬁc a nt or lif e -
t hr e at e ni n g c o n s e q u e n c e s, u n a bl e t o p erf or m A D L
H ol d I C Pi u ntil s y m pt o m s r e s ol v e t o b a s eli n e wit h 
a p pr o pri at e t h er a p y
E n d o cri n e c o n s ult ati o n
b- Bl o c k er ( e. g, at e n ol ol, pr o pr a n ol ol) f or s y m pt o m ati c 
r eli ef
F or s e v er e s y m pt o m s or c o n c er n f or t h yr oi d st or m, 
h o s pit ali z e p ati e nt a n d i niti at e pr e d ni s o n e 1 -2 m g/ k g/ d 
or e q ui v al e nt t a p er e d o v er 1 -2 w e e k s; c o n si d er al s o 
u s e of S S KI or t hi o n a mi d e ( m et hi m a z ol e or P T U).
A d diti o n al c o n si d er ati o n s
T h yr oi diti s i s tr a n si e nt a n d r e s ol v e s i n a c o u pl e of w e e k s t o pri m ar y h y p ot h yr oi di s m or n or m al. H y p ot h yr oi di s m c a n 
b e tr e at e d a s a b o v e. Gr a v e s di s e a s e i s g e n er all y p er si st e nt a n d i s d u e t o i n cr e a s e d t h yr oi d h or m o n e pr o d u cti o n 
t h at c a n b e tr e at e d wit h a ntit h yr oi d m e di c al t h er a p y. P h y si c al e x a mi n ati o n ﬁn di n g s of o p ht h al m o p at h y or t h yr oi d 
br uit ar e di a g n o sti c of Gr a v e s a n d s h o ul d pr o m pt e arl y e n d o c ri n e r ef err al.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
4. 2 A dre n al – pri m ar y a dre n al i ns uf ﬁcie nc y
D e ﬁniti o n: A dr e n al gl a n d f ail ur e l e a di n g t o l o w m or ni n g c orti s ol, hi g h m or ni n g A C T H, a s w ell a s h y p o n atr e mi a a n d 
h y p er k al e mi a wit h ort h o st a si s a n d v ol u m e d e pl eti o n d u e t o l o s s of al d o st er o n e
Di a g n o sti c w or k -u p f or p ati e nt s i n w h o m a dr e n al 
i n s ufﬁci e n c y i s s u s p e ct e d:
E v al u at e A C T H ( A M), c orti s ol l e v el ( A M)
B a si c m et a b oli c p a n el ( N a, K, C O 2 , gl u c o s e)
C o n si d er A C T H sti m ul ati o n t e st f or i n d et er mi n at e 
r e s ult s
If pri m ar y a dr e n al i n s ufﬁci e n c y ( hi g h A C T H, l o w 
c orti s ol) i s f o u n d bi o c h e mi c all y:
E v al u at e f or pr e ci pit ati n g c a u s e of cri si s s u c h a s 
i nf e cti o n P erf or m a n a dr e n al C T f or 
m et a st a si s/ h e m orr h a g e
Gr a di n g
M a n a g e m e nt
G 1: A s y m pt o m ati c or mil d s y m pt o m s
C o n si d er h ol di n g I C Pi u ntil p ati e nt i s st a bili z e d o n 
r e pl a c e m e nt h or m o n e
E n d o cri n e c o n s ult ati o n
R e pl a c e m e nt t h er a p y wit h pr e d ni s o n e ( 5- 1 0 m g d ail y) 
or h y dr o c orti s o n e ( 1 0 -2 0 m g or all y e v er y m or ni n g, 5 -1 0 
m g or all y i n e arl y aft er n o o n)
M a y r e q uir e ﬂu dr o c orti s o n e ( 0. 1 m g/ d) f or 
mi n er al o c orti c oi d r e pl a c e m e nt i n pri m ar y a dr e n al 
i n s ufﬁci e n c y
Titr at e d o s e u p or d o w n a s s y m pt o m s di ct at e
G 2: M o d er at e s y m pt o m s, a bl e t o p erf or m A D L
C o n si d er h ol di n g I C Pi u ntil p ati e nt i s st a bili z e d o n 
r e pl a c e m e nt h or m o n e
E n d o cri n e c o n s ult ati o n
I niti at e o utp ati e nt tr e at m e nt at t w o t o t hr e e ti m e s 
m ai nt e n a n c e
(if pr e d ni s o n e, 2 0 m g d ail y; if h y dr o c orti s o n e, 2 0-3 0 m g 
i n t h e m or ni n g, a n d 1 0- 2 0 m g i n t h e aft er n o o n) t o 
m a n a g e a c ut e s y m pt o m s.
T a p er str e s s - d o s e c orti c o st er oi d s d o w n t o m ai nt e n a n c e 
d o s e s o v er 5 -1 0 d a y s
M ai nt e n a n c e t h er a p y a s i n G 1.
G 3 -4: S e v er e s y m pt o m s, m e di c all y si g ni ﬁc a nt or lif e -
t hr e at e ni n g c o n s e q u e n c e s, u n a bl e t o p erf or m A D L
H ol d I C Pi u ntil p ati e nt i s st a bili z e d o n r e pl a c e m e nt 
h or m o n e
E n d o cri n e c o n s ult ati o n
S e e i n cli ni c or, f or aft er h o ur s, m a k e a n e m er g e n c y 
d e p art m e nt r ef err al f or n or m al s ali n e ( at l e a st 2 L) a n d 
I V str e s s-d o s e c orti c o st er oi d s o n pr e s e nt ati o n
( h y dr o c orti s o n e 1 0 0 m g or d e x a m et h a s o n e 4 m g if t h e 
di a g n o si s i s n ot cl e ar a n d sti m ul ati o n t e sti n g will b e 
n e e d e d)
T a p er str e s s -d o s e c orti c o st er oi d s d o w n t o m ai nt e n a n c e 
d o s e s o v er 7 - 1 4 d a y s aft er di s c h ar g e
M ai nt e n a n c e t h er a p y a s i n G 1
A d diti o n al c o n si d er ati o n s
Pri m ar y a n d s e c o n d ar y a dr e n al i n s uf ﬁci e n c y c a n b e di sti n g ui s h e d b y t h e r el ati o n s hi p b et w e e n A C T H a n d c orti s ol. 
If t h e A C T H i s lo w wit h l o w c orti s ol, t h e n m a n a g e m e nt i s a s p er 4. 3.
P ati e nt s o n c orti c o st er oi d s f or m a n a g e m e nt of ot h er c o n diti o n s will h a v e l o w m or ni n g c orti s ol a s a r e s ult of 
i atr o g e ni c, s e c o n d ar y a dr e n al i n s ufﬁci e n c y. A C T H will al s o b e l o w i n t h e s e p ati e nt s. A di a g n o s i s of a dr e n al 
i n s ufﬁci e n c y i s c h all e n gi n g t o m a k e i n t h e s e sit u ati o n s ( s e e n e xt s e cti o n o n h y p o p h y siti s).
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
E m er g e nt t h er a p y f or s o m e o n e wit h s u s p e ct e d a dr e n al i n s uf ﬁci e n c y i s b e st d o n e wit h d e x a m et h a s o n e a s a 
sti m ul ati o n t e st c a n still b e p erf or m e d. If t h e di a g n o si s i s alr e a d y c o n ﬁr m e d, c a n u s e h y dr o c orti s o n e 1 0 0 m g.
All p ati e nt s n e e d e d u c ati o n o n str e s s d o si n g a n d a m e di c al al ert br a c el et f or a dr e n al i n s uf ﬁci e n c y t o tri g g er str e s s -
d o s e c orti c o st er oi d s b y E M S.
E n d o cri n e c o n s ult ati o n pri or t o s ur g er y or a n y p r o c e d ur e f or str e s s- d o s e pl a n ni n g.
4. 3 Pit uit ar y - h y p o p h ysitis
D e ﬁniti o n: I n ﬂa m m ati o n of t h e pit uit ar y wit h v ar yi n g eff e ct s o n h or m o n e f u n cti o n. M o st c o m m o nl y pr e s e nti n g wit h 
c e ntr al a dr e n al i n s uf ﬁci e n c y. M a y al s o h a v e c e ntr al h y p ot h yr oi di s m, di a b et e s i n si pi d u s, a n d h y p o g o n a di s m. 
Di a g n o sti c w or k -u p
Di a g n o si s: L o w A C T H wit h a l o w c orti s ol. L o w or n or m al T S H wit h a l o w F T 4. H y p er n atr e mi a a n d v ol u m e d e pl eti o n 
wit h di a b et e s i n si pi d u s. L o w t e st o st er o n e or e str a di ol wit h l o w L H a n d F S H.
T e sti n g:
E v al u at e A C T H, c orti s ol ( A M), T S H, F T 4, el e ctr ol yt e s
C o n si d er e v al u ati n g L H, F S H, a n d t e st o st er o n e l e v el s i n m al e s or e str o g e n i n pr e m e n o p a u s al f e m al e s wit h f ati g u e, 
l o s s of li bi d o, a n d m o o d c h a n g e s C o n si d er M RI of t h e br ai n wit h or wit h o ut c o ntr a st wit h pit uit ar y/s ell ar c ut s i n 
p ati e nt s wit h m ulti pl e e n d o cri n e a b n or m aliti e s ± n e w s e v er e h e a d a c h e s or c o m pl ai nt s of vi si o n c h a n g e s
Gr a di n g
M a n a g e m e nt
G 1: A s y m pt o m ati c or mil d s y m pt o m s
C o n si d er h ol di n g I C Pi u ntil p ati e nt i s st a bili z e d o n 
r e pl a c e m e nt h or m o n e s
E n d o cri n e c o n s ult ati o n
H or m o n al s u p pl e m e nt ati o n a s i n G 1
G 3 -4: S e v er e s y m pt o m s, m e di c all y si g ni ﬁc a nt or lif e -
t hr e at e ni n g c o n s e q u e n c e s, u n a bl e t o p erf or m A D L
H ol d I C Pi u ntil p ati e nt i s st a bili z e d o n r e pl a c e m e nt 
h or m o n e s
E n d o cri n e c o n s ult ati o n
H or m o n al s u p pl e m e nt ati o n a s i n G 1
C o n si d er i niti al p ul s e d o s e t h er a p y wit h pr e d ni s o n e 1 -2 
m g/ k g or al d ail y ( or e q ui v al e nt) t a p er e d o v er at l e a st 1 -
2 w e e k s
A d diti o n al c o n si d er ati o n s
B e a w ar e of t h e n e e d t o st art c orti c o st er oi d s ﬁr st w h e n pl a n ni n g h or m o n e r e pl a c e m e nt t h er a p y f or m ulti pl e 
d e ﬁci e n ci e s
All p ati e nt s n e e d i n str u cti o n o n d o u bli n g d o s e s f or ill n e s s ( str e s s d o si n g) a n d a m e di c al al ert br a c el et f or a dr e n al 
i n s ufﬁci e n c y t o tri g g er str e s s -d o s e c orti c o st er oi d s b y E M S
C orti c o st er oi d u s e c a n c a u s e i s ol at e d c e ntr al a dr e n al i n s uf ﬁci e n c y
W o r k-u p c a n n ot b e d o n e wit h a si m pl e A M c orti s ol i n a p ati e nt o n c orti c o st er oi d s f or ot h er c o n diti o n s
L a b or at or y c o n ﬁr m ati o n of a dr e n al i n s uf ﬁci e n c y s h o ul d n ot b e att e m pt e d u ntil tr e at m e nt wit h c orti c o st er oi d s f or 
ot h er di s e a s e i s r e a d y t o b e di s c o nti n u e d . F or l o n g -t er m e x p o s ur e, c o n s ult e n d o cri n ol o g y f or r e c o v er y a n d 
w e a ni n g pr ot o c ol u si n g h y dr o c orti s o n e.
4. 4 Di a betes
D e ﬁniti o n: T 2 D M i s a c o m bi n ati o n of i n s uli n r e si st a n c e a n d i n s uf ﬁci e n c y t h at m a y r e q uir e or al or i n s uli n t h er a p y. It 
m a y b e n e w -o n s et or e x a c er b at e d d uri n g t h er a p y f or n o ni m m u n ol o gi c r e a s o n s, s u c h a s c orti c o st er oi d e x p o s ur e.
A ut oi m m u n e T 1 D M r e s ult s fr o m i sl et c ell d e str u cti o n a n d i s oft e n a c ut e o n s et, wit h k et o si s a n d a n i n s uli n 
r e q uir e m e nt
Di a g n o sti c w or k -u p
M o nit or p ati e nt s f or h y p er gl y c e mi a or ot h er si g n s a n d s y m pt o m s of n e w or w or s e ni n g D M, i n cl u di n g m e a s uri n g 
gl u c o s e at b a s eli n e a n d wit h e a c h tr e at m e nt c y cl e d uri n g i n d u cti o n f or 1 2 w e e k s, t h e n e v er y 3 -6 w e e k s t h er e aft er. 
T o g ui d e t h e w or k -u p i n n e w -o n s et h y p er gl y c e mi a, cli ni ci a n s s h o ul d c o n si d er a p ati e nt’ s m e di c al b a c k gr o u n d, 
e x p o s ur e hi st or y, a n d ri s k f a ct or s f or e a c h s u bt y p e of D M.
L a b or at or y e v al u ati o n i n s u s p e ct e d T 1 D M s h o ul d i n cl u d e t e sti n g f or k et o si s i n uri n e a n d a n a s s e s s m e nt of t h e 
a ni o n g a p o n a m et a b oli c p a n el. A nti – gl ut a mi c a ci d d e c ar b o x yl a s e, a nti – i sl et c ell, or a nti– i n s uli n a nti b o di e s ar e 
hi g hl y s p e ci ﬁc f or a ut oi m m u n e di a b et e s. I n s uli n a n d C - p e pti d e l e v el s c a n al s o a s si st i n t h e di a g n o si s.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
Gr a di n g
M a n a g e m e nt
G 1: A s y m pt o m ati c or mil d s y m pt o m s; f a sti n g gl u c o s e 
v al u e > U L N ( 1 6 0 m g/ d L); f a sti n g gl u c o s e v al u e > U L N 
( 8. 9 m m ol/ L); n o e vi d e n c e of k et o si s or l a b or at or y 
e vi d e n c e of T 1 D M
C a n c o nti n u e I C Pi wit h cl o s e cli ni c al f oll o w -u p a n d 
l a b or at or y e v al u ati o n
M a y i niti at e or al t h er a p y f or t h o s e wit h n e w -o n s et T 2 D M
S cr e e n f or T 1 D M if a p pr o pri at e, f or e x a m pl e, a c ut e 
o n s et wit h pri or n or m al v al u e s or cli ni c al c o n c er n f or 
k et o si s
G 2: M o d er at e s y m pt o m s, a bl e t o p erf or m A D L, f a sti n g 
gl u c o s e v al u e > 1 6 0 -2 5 0 m g/ d L; f a sti n g gl u c o s e 
v al u e > 8. 9 - 1 3. 9 m m ol/ L, k et o si s or e vi d e n c e of T 1 D M at 
a n y gl u c o s e l e v el
M a y h ol d I C Pi u ntil gl u c o s e c o ntr ol i s o bt ai n e d
Titr at e or al t h er a p y or a d d i n s uli n f or w or s e ni n g c o ntr ol 
i n T 2 D M S h o ul d a d mi ni st er i n s uli n f or T 1 D M ( or a s 
d ef a ult t h er a p y if t h er e i s c o nf u si o n a b o ut t y p e)
Ur g e nt e n d o cri n e c o n s ult ati o n f or a n y p ati e nt wit h 
T 1 D M; i n t h e a b s e n c e of e n d o cri n ol o g y, i nt er n al 
m e di ci n e m a y s uf ﬁc e
C o n si d er a d mi s si o n f or T 1 D M if e arl y o ut p ati e nt 
e v al u ati o n i s n ot a v ail a bl e or si g n s of k et o a ci d o si s ar e 
pr e s e nt
G 3 -4: S e v er e s y m pt o m s, m e di c all y si g ni ﬁc a nt or lif e-
t hr e at e ni n g c o n s e q u e n c e s, u n a bl e t o p erf or m A D L
G 3: > 2 5 0 - 5 0 0 m g/ d L ( > 1 3. 9-2 7. 8 m m ol/ L)
G 4: > 5 0 0 m g/ d L ( > 2 7. 8 m m ol/ L)
H ol d I C Pi u ntil gl u c o s e c o ntr ol i s o bt ai n e d o n t h er a p y 
wit h r e d u cti o n of t o xi cit y t o G 1 or l e s s
Ur g e nt e n d o cri n e c o n s ult ati o n f or all p ati e nt s
I niti at e i n s uli n t h er a p y f or all p ati e nt s
A d mit f or i n p ati e nt m a n a g e m e nt: C o n c er n s f or 
d e v el o pi n g D K A, S y m pt o m ati c p ati e nt s r e g ar dl e s s of 
di a b et e s t y p e, N e w -o n s et T 1 D M u n a bl e t o s e e 
e n d o cri n ol o g y
A d diti o n al c o n si d er ati o n s
I n s uli n t h er a p y c a n b e u s e d a s t h e d ef a ult i n a n y c a s e wit h h y p er gl y c e mi a
L o n g - a cti n g t h er a p y al o n e i s n ot u s u all y s ufﬁci e nt f or T 1 D M, w h er e h alf of d ail y r e q uir e m e nt s ar e u s u all y gi v e n i n 
di vi d e d d o s e s a s pr a n di al c o v er a g e a n d h alf a s l o n g a cti n g.
I n s uli n d o s e s will b e l o w er i n T 1 D M b e c a u s e of pr e s er v e d s e n siti vit y (t ot al d ail y r e q uir e m e nt c a n b e e sti m at e d at 
0. 3 - 0. 4 u nit s/ k g/ d).
I n T 2 D M, sli di n g-s c al e c o v er a g e wit h m e al s o v er a f e w d a y s pr o vi d e s d at a t o e sti m at e a p ati e nt’ s d ail y 
r e q uir e m e nt s a n d c a n b e u s e d t o m or e r a pi dl y titr at e b a s al n e e d s.
All r e c o m m e n d ati o n s ar e e x p ert c o n s e n s u s b a s e d, wit h b e n e ﬁt s o ut w ei g hi n g h ar m s, a n d str e n gt h of 
r e c o m m e n d ati o n s ar e m o d er at e.
A b br e vi ati o n s: A C T H, a dr e n o c orti c otr o pi c h or m o n e; A D L, a cti viti e s of d ail y li vi n g; C T, c o m p ut e d t o m o gr a p h y; D K A, 
di a b eti c k et o a ci d o si s; D M, di a b et e s m ellit u s; E M S, e m er g e n c y m e di c al s er vi c e s; F S H, f olli cl e -sti m ul ati n g h or m o n e; 
F T 4, fr e e t h yr o xi n e; G, Gr a d e ; I C Pi, i m m u n e c h e c k p oi nt i n hi bit or; ir A E, i m m u n e-r el at e d a d v er s e e v e nt; L H, l ut ei ni zi n g 
h or m o n e; M RI, m a g n e ti c r e s o n a n c e i m a gi n g; P T U, pr o p ylt hi o ur a cil; 2 L, s e c o n d -li n e; S S KI, p ot a s si u m i o di d e; T 1 D M, 
t y p e 1 di a b et e s m ellit u s; T 2 D M, t y p e 2 di a b et e s m ellit u s; T R A b, t h yr oi d- sti m ul ati n g h or m o n e r e c e pt or a nti b o d y; T S H, 
t h yr oi d- sti m ul ati n g h or m o n e; T SI, t h yr oi d-sti m u l ati n g i m m u n o gl o b uli n; U L N, u p p er li mit of n or m al.
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 0 /1 5 9
T a ble A 5  
M a n a ge me nt of M usc ul os kelet al ir A Es i n P atie nts Tre ate d Wit h I C Pis
5. 0 M usc ul os kelet al T o xicities
5. 1 I n ﬂa m m at or y art hritis
D e ﬁniti o n: A di s or d er c h ar a ct eri z e d b y i nﬂa m m ati o n of t h e j oi nt s
Cli ni c al s y m pt o m s: J oi nt p ai n a c c o m p a ni e d b y j oi nt s w elli n g; i n ﬂa m m at or y s y m pt o m s, s u c h a s stiff n e s s aft er 
i n a cti vit y or i n t h e m or ni n g, l a sti n g > 3 0 mi n ut e s t o 1 h o ur; i m pr o v e m e nt of s y m pt o m s wit h N S AI D s or 
c orti c o st er oi d s b ut n o t wit h o pi oi d s or ot h er p ai n m e di c ati o n s m a y al s o b e s u g g e sti v e of i nﬂa m m at or y art hriti s.
Di a g n o sti c w or k -u p
G 1
C o m pl et e r h e u m at ol o gi c hi st or y a n d e x a mi n ati o n of all p eri p h er al j oi nt s f or t e n d er n e s s, s w elli n g, a n d r a n g e of 
m oti o n; e x a mi n ati o n of t h e s pi n e
C o n si d er pl ai n x -r a y/i m a gi n g t o e x cl u d e m et a st a s e s a n d e v al u at e j oi nt d a m a g e 
( er o si o n s), if a p pr o pri at e
C o n si d er a ut oi m m u n e bl o o d p a n el i n cl u di n g A N A, R F, a n d a nti -C C P, a n d a nti -i nﬂa m m at or y m ar k er s ( E S R a n d 
C R P) if s y m pt o m s p er si st; if s y m pt o m s ar e s u g g e sti v e of r e a cti v e art hriti s or aff e ct t h e s pi n e, c o n si d er H L A B 2 7 
t e sti n g
G 2
C o m pl et e hi st or y a n d e x a mi n ati o n a s a b o v e; l a b or at or y t e st s a s a b o v e
C o n si d er U S ±
M RI of aff e ct e d j oi nt s if cli ni c all y i n di c at e d ( e. g, p er si st e nt art hriti s u nr e s p o n si v e t o t r e at m e nt, 
s u s pi ci o n f or diff er e nti al di a g n o s e s s u c h a s m et a st ati c l e si o n s or s e pti c art hriti s)
C o n si d er e arl y r ef err al t o a r h e u m at ol o gi st, if t h er e i s j oi nt s w elli n g ( s y n o viti s) or if s y m pt o m s of art hr al gi a p er si st 
> 4 w e e k s
G 3 - 4
A s f or G 2
S e e k r h e u m at ol o gi st a d vi c e a n d r e vi e w
M o nit ori n g: P ati e nt s wit h i n ﬂa m m at or y art hriti s s h o ul d b e m o nit or e d wit h s eri al r h e u m at ol o gi c e x a mi n ati o n s, 
i n cl u di n g i nﬂa m m at or y m ar k er s, e v er y 4 - 6 w e e k s aft er tr e at m e nt i s i n stit ut e d.
Gr a di n g
M a n a g e m e nt
All Gr a d e s
Cli ni ci a n s s h o u l d f oll o w r e p ort s of n e w j oi nt p ai n t o 
d et er mi n e w h et h er i n ﬂa m m at or y art hriti s i s pr e s e nt; 
q u e sti o n w h et h er s y m pt o m n e w si n c e r e c ei vi n g I C Pi
G 1: Mil d p ai n wit h i n ﬂa m m ati o n, er yt h e m a, or j oi nt 
s w elli n g
C o nti n u e I C Pi
I niti at e a n al g e si a wit h a c et a mi n o p h e n a n d/ or N S AI D s
G 2: M o d er at e p ai n a s s o ci at e d wit h si g n s of 
i nﬂa m m ati o n, er yt h e m a, or j oi nt s w elli n g, li miti n g 
i n str u m e nt al A D L
H ol d I C Pi a n d r e s u m e u p o n s y m pt o m c o ntr ol a n d o n 
pr e d ni s o n e ≤1 0 m g/ d 
E s c al at e a n al g e si a a n d c o n si d er hi g h er d o s e s of 
N S AI D S a s n e e d e d
If i n a d e q u at el y c o ntr oll e d, i niti at e pr e d ni s o n e or 
pr e d ni s ol o n e 1 0 -2 0 m g/ d or e q ui v al e nt f or 4 -6 w e e k s
If i m pr o v e m e nt, sl o w t a p er a c c or di n g t o r e s p o n s e 
d uri n g t h e n e xt 4- 6 w e e k s; if n o i m pr o v e m e nt aft er i niti al 
4- 6 w e e k s, tr e at a s G 3
If u n a bl e t o l o w er c orti c o st er oi d d o s e t o < 1 0 m g/ d aft er 
3 m o nt h s, c o n si d er D M A R D
C o n si d er i ntr a -arti c ul ar c orti c o st er oi d i nj e cti o n s f or l ar g e 
j oi nt s
R ef err al t o r h e u m at ol o g y
G 3 -4: S e v er e p ai n a s s o ci at e d wit h si g n s of 
i nﬂa m m ati o n, er yt h e m a, or j oi nt s w elli n g; irr e v er si bl e 
j oi nt d a m a g e; di s a bli n g; li miti n g s elf-c ar e A D L
F or G 3: H ol d I C Pi t e m p or aril y a n d m a y r e s u m e i n 
c o n s ult ati o n wit h r h e u m at ol o g y, if r e c o v er t o G 1 or l e s s
F or G 4: p er m a n e ntl y di s c o nti n u e I C Pi
I niti at e or al pr e d ni s o n e 0. 5-1 m g/ k g
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
If f ail ur e of i m pr o v e m ent aft er 4 w e e k s or w or s e ni n g i n 
m e a nti m e, c o n si d er s y nt h eti c or bi ol o gi c D M A R D
S y nt h eti c: m et h otr e x at e, l e ﬂu n o mi d e
Bi ol o gi c: c o n si d er a nti c yt o ki n e t h er a p y s u c h a s T N F- a 
or I L - 6 r e c e pt or i n hi bit or s. N ot e: A s c a uti o n, I L-6 
i n hi biti o n c a n c a u s e i nt e sti n al p erf or ati o n; w hil e t hi s i s 
e xtr e m el y r ar e, it s h o ul d n ot b e u s e d i n p ati e nt s wit h 
c oliti s.) T e st f or vir al h e p atiti s B, C, a n d l at e nt/ a cti v e T B 
t e st pri or t o D M A R D tr e at m e nt
R ef err al t o r h e u m at ol o g y.
A d diti o n al c o n si d er ati o n s
E arl y r e c o g niti o n i s criti c al t o a v oi d er o si v e j oi nt d a m a g e.
C orti c o st er oi d s c a n b e u s e d a s p art of i niti al t h er a p y i n i n ﬂa m m at or y art hriti s, b ut d u e t o li k el y pr ol o n g e d tr e at m e nt 
r e q uir e m e nt s, p h y si ci a n s s h o ul d c o n si d er st arti n g c orti c o st er oi d-s p ari n g a g e nt s e arli er t h a n o n e w o ul d wit h ot h er 
ir A E s
Oli g o art hriti s c a n b e tr e at e d e arl y o n wit h i ntr a - arti c ul ar c orti c o st er oi d s; c o n si d er e arl y r ef err al.
C o n si d er P C P pr o p h yl a xi s f or p ati e nt s tr e at e d wit h hi g h d o s e of c orti c o st er oi d s f or 1 2 w e e k s, a s p er l o c al 
g ui d eli n e s.
5. 2 M y ositis
D e ﬁnit i o n: A di s or d er c h ar a ct eri z e d b y m u s cl e i nﬂa m m ati o n wit h w e a k n e s s a n d el e v at e d m u s cl e e n z y m e s ( C K). 
M u s cl e p ai n c a n b e pr e s e nt i n s e v er e c a s e s. C a n b e lif e- t hr e at e ni n g if r e s pir at or y m u s cl e s or m y o c ar di u m ar e 
i n v ol v e d
Di a g n o sti c w or k -u p
C o m pl et e r h e u m at ol o gi c a n d n e ur ol o gi c hi st or y r e g ar di n g diff er e nti al di a g n o si s; r h e u m at ol o gi c a n d n e ur ol o gi c 
e x a mi n ati o n, i n cl u di n g m u s cl e str e n gt h; a n d e x a mi n ati o n of t h e s ki n f or ﬁn di n g s s u g g e sti v e of d er m at o m y o siti s. 
M u s cl e w e a k n e s s i s m or e t y pi c al of m y o siti s t h a n p ai n. C o n si d er pr e e xi sti n g c o n diti o n s t h at c a n c a u s e si mil ar 
s y m pt o m s.
Bl o o d t e sti n g t o e v al u at e m u s cl e i n ﬂa m m ati o n
C K, tr a n s a mi n a s e s ( A S T, A L T), L D H, a n d al d ol a s e c a n al s o b e el e v at e d
Tr o p o ni n t o e v al u at e m y o c ar di al i n v ol v e m e nt a n d ot h er c ar di a c t e sti n g, s u c h a s e c h o c ar di o gr a m, a s n e e d e d
I nﬂa m m at or y m ar k er s ( E S R a n d C R P)
C o n si d er E M G, i m a gi n g ( M RI), a n d/ or bi o p s y o n a n i n di vi d u al b a si s w h e n di a g n o si s i s u n c ert ai n a n d o v erl a p wit h 
n e ur ol o gi c s y n dr o m e s, s u c h a s m y a st h e ni a gr a vi s, i s s u s p e ct e d
C o n si d er p ar a n e o pl a st i c a ut o a nti b o d y t e sti n g f or m y o siti s a n d n e ur ol o gi c c o n diti o n s, s u c h a s m y a st h e ni a gr a vi s 
M o nit ori n g: C K, E S R, C R P
G 1: C o m pl et e e x a mi n ati o n a n d l a b or at or y w or k- u p a s a b o v e
G 2: C o m pl et e hi st or y a n d e x a mi n ati o n a s a b o v e; a ut oi m m u n e m y o siti s bl o o d p a n el; E M G , M RI of aff e ct e d j oi nt s
E arl y r ef err al t o a r h e u m at ol o gi st or n e ur ol o gi st
G 3 -4: A s f or G 2
Ur g e nt r ef err al t o a r h e u m at ol o gi st or n e ur ol o gi st
Gr a di n g
M a n a g e m e nt
G 1: Mil d w e a k n e s s wit h or wit h o ut p ai n
C o nti n u e I C Pi
If C K i s el e v at e d a n d p ati e nt h a s m u s cl e w e a k n e s s, 
m a y off er or al c orti c o st er oi d s, a n d tr e at a s G 2
Off er a n al g e si a wit h a c et a mi n o p h e n or N S AI D s if t h er e 
ar e n o c o ntr ai n di c ati o n s
G 2: M o d er at e w e a k n e s s wit h or wit h o ut p ai n, li miti n g 
a g e -a p pr o pri at e i n str u m e nt al A D L
H ol d I C Pi t e m p or aril y a n d m a y r e s u m e u p o n s y m pt o m 
c o ntr ol, if C K i s n or m al a n d pr e d ni s o n e d o s e 1 0 m g; if 
w or s e n s, tr e at a s p er G 3
N S AI D s a s n e e d e d
R ef err al t o r h e u m at ol o gi st or n e ur ol o gi st
If C K i s el e v at e d t hr e e ti m e s or m or e), i niti at e 
pr e d ni s o n e or e q ui v al e nt at 0. 5- 1 m g/ k g
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
M a y r e q uir e p er m a n e nt di s c o nti n u ati o n of I C Pi i n m o st 
p ati e nt s wit h G 2 s y m pt o m s a n d o bj e cti v e ﬁn di n g s 
( el e v at e d e n z y m e s, a b n or m al E M G, a b n or m al m u s cl e 
M RI or bi o p s y)
G 3 -4: S e v er e w e a k n e s s wit h or wit h o ut p ai n, li miti n g 
s elf -c ar e A D L
F or G 3: H ol d I C Pi u nti l G 1 or l e s s a n d p er m a n e ntl y 
di s c o nti n u e if a n y e vi d e n c e of m y o c ar di al i n v ol v e m e nt
F or G 4: p er m a n e ntl y di s c o nti n u e I C Pi
C o n si d er h o s pit ali z ati o n f or s e v er e w e a k n e s s
R ef err al t o r h e u m at ol o gi st or n e ur ol o gi st
I niti at e pr e d ni s o n e 1 m g/ k g or e q ui v al e nt. C o n si der 1 -2 
m g/ k g of m et h yl pr e d ni s ol o n e I V or hi g h er - d o s e b ol u s if 
s e v er e c o m pr o mi s e ( w e a k n e s s s e v er el y li miti n g 
m o bilit y, c ar di a c, r e s pir at or y, d y s p h a gi a) 
C o n si d er pl a s m a p h er e si s
C o n si d er I VI G t h er a p y
C o n si d er ot h er i m m u n o s u p pr e s s a nt t h er a p y, s u c h a s 
m et h otr e x at e, a z at hi o pri n e, or m y c o p h e n ol at e m of etil, if 
s y m pt o m s a n d C K l e v el s d o n ot i m pr o v e or w or s e n 
aft er 4 -6 w e e k s; rit u xi m a b i s u s e d i n pri m ar y m y o siti s 
b ut c a uti o n i s a d vi s e d gi v e n it s l o n g bi ol o gi c d ur ati o n
I n c a s e of m a n a g e m e nt wit h rit u xi m a b, I C Pi tr e atm e nt
s h o ul d b e di s c o nti n u e d
A d diti o n al c o n si d er ati o n s: C a uti o n i s a d vi s e d wit h r e c h all e n gi n g
5. 3 P ol y m y al gi a -li ke s y n dr o me
D e ﬁniti o n: C h ar a ct eri z e d b y m ar k e d p ai n a n d stiff n e s s i n pr o xi m al u p p er a n d/ or l o w er e xtr e miti e s a n d n o si g n s of 
tr u e m u s cl e i nﬂa m m ati o n s u c h a s C K el e v ati o n or E M G ﬁn di n g s of m y o siti s. N o tr u e m u s cl e w e a k n e s s, dif ﬁc ult y i n 
a cti v e m oti o n r el at e d t o p ai n
Di a g n o sti c w or k -u p
G 1
C o m pl et e r h e u m at ol o gi c hi st or y r e g ar di n g diff er e nti al di a g n o si s a n d e x a mi n ati o n of all j oi nt s a n d s ki n
C h e c k f or s y m pt o m s of t e m p or al art eriti s, s u c h a s h e a d a c h e or vi s u al di st ur b a n c e s; r ef er t o o p ht h al m ol o gi st if 
pr e s e nt, a n d c o n si d er t e m p or al art er y bi o p s y A N A, R F, a nti- C C P
C K t o e v al u at e diff er e nti al di a g n o si s of m y o siti s
I nﬂa m m at or y m ar k er s ( E S R, C R P)
M o nit ori n g: E S R, C R P
G 2: C o m pl et e hi st or y a n d e x a mi n ati o n a s a b o v e; a ut oi m m u n e t e st s a s r e q uir e d f or diff er e nti al di a g n o si s; e arl y 
r ef err al t o a r h e u m at ol o gi st
G 3 -4: A s f or G 2; s e e r h e u m at ol o gi st a d vi c e a n d r e vi e w
Gr a di n g
M a n a g e m e nt
G 1: Mil d stiff n e s s a n d p ai n
C o nti n u e I C Pi
I niti at e a n al g e si a wit h a c et a mi n o p h e n a n d/ or N S AI D s if 
t h er e ar e n o c o ntr ai n di c ati o n s
G 2: M o d er at e stiff n e s s a n d p ai n, li miti n g a g e -
a p pr o pri at e i n str u m e nt al A D L
C o n si d er h ol di n g I C Pi a n d r e s u mi n g u p o n s y m pt o m 
c o ntr ol, pr e d ni s ol o n e < 1 0 m g; if w or s e n s, tr e at a s p er 
G 3
I niti at e pr e d ni s o n e 2 0 m g/ d or e q ui v al e nt; if s y m pt o m s 
i m pr o v e, st art t o t a p er d o s e aft er 3-4 w e e k s
If n o i m pr o v e m e nt or n e e d f or hi g h er d o s a g e s aft er 4 
w e e k s, e s c al at e t o G 3 C o n si d er r ef err al t o 
r h e u m at ol o g y
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 3 /1 5 9
G 3 -4: S e v er e stiff n e s s a n d p ai n, li miti n g s elf -c ar e A D L
F or G 3: H ol d I C Pi a n d m a y r e s u m e, i n c o n s ult ati o n wit h 
r h e u m at ol o g y, if r e c o v er t o G 1 or l e s s; h o w e v er, n ot e 
t h at c a s e s of t o xi cit y r et ur ni n g u p o n r e c h all e n g e h a v e 
b e e n r e p ort e d. I C Pi s h o ul d b e p er m a n e ntl y
di s c o nt i n u e d i n s u c h c a s e s
F or G 4: p er m a n e ntl y di s c o nti n u e I C Pi
R ef err al t o r h e u m at ol o g y
S h o ul d i niti at e pr e d ni s o n e 2 0 m g/ d or e q ui v al e nt. If n o 
i m pr o v e m e nt or n e e d f or hi g h er d o s a g e s f or pr ol o n g e d 
ti m e, m a y off er a c orti c o st er oi d-s p ari n g a g e nt s u c h a s 
m et h otr e x a t e or I L- 6 i n hi biti o n wit h t o cili z u m a b
( N ot e: A s c a uti o n, I L- 6 i n hi biti o n c a n c a u s e i nt e sti n al 
p erf or ati o n; w hil e t hi s i s e xtr e m el y r ar e, it s h o ul d n ot b e 
u s e d i n p ati e nt s wit h c oliti s or GI m et a st a s e s). C o n si d er 
a d mi s si o n f or p ai n c o ntr ol
All r e c o m m e n d at i o n s ar e e x p ert c o n s e n s u s b a s e d, wit h b e n eﬁt s o ut w ei g hi n g h ar m s, a n d str e n gt h of 
r e c o m m e n d ati o n s ar e m o d er at e.
A b br e vi ati o n s: A D L, a cti viti e s of d ail y li vi n g; A L T, al a ni n e a mi n otr a n sf er a s e; A N A, a nti n u cl e ar a nti b o di e s; A S T, 
a s p art at e a mi n otr a n sf er a s e; C C P , citr ulli n at e d pr ot ei n a nti b o d y; C K, cr e ati n e ki n a s e; C R P, C-r e a cti v e pr ot ei n; 
D M A R D, di s e a s e -m o dif yi n g a ntir h e u m ati c dr u g; E M G, el e ctr o m y o gr a p h y; E S R, er yt hr o c yt e s e di m e nt ati o n r at e; G, 
Gr a d e ; H L A, h u m a n l e u k o c yt e a nti g e n; I C Pi, i m m u n e c h e c k p oi nt i n hi bitor; I L, i nt erl e u ki n; ir A E, i m m u n e -r el at e d 
a d v er s e e v e nt; I V, i ntr a v e n o u s; I VI G, i ntr a v e n o u s i m m u n o gl o b uli n; L D H, l a ct at e d e h y dr o g e n a s e; M RI, m a g n eti c 
r e s o n a n c e i m a gi n g, N S AI D, n o n st er oi d al a nti-i nﬂa m m at or y dr u g; P C P, P n e u m o c y sti s p n e u m o ni a; R F, r h e u m at oi d 
f a ct or; T B, t u b er c ul o si s; T N F, t u m or n e cr o si s f a ct or.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 4 /1 5 9
T a ble A 6
M a n a ge me nt of Re n al ir A Es i n P atie nts Tre ate d Wit h I C Pis
6. 0 Re n al T o xicities
N e p hriti s a n d r e n al d y sf u n cti o n: di a g n o si s a n d m o nit ori n g
F or a n y s u s p e ct e d i m m u n e- m e di at e d a d v er s e r e a cti o n s, e x cl u d e ot h er c a u s e s
M o nit or p ati e nt s f or el e v at e d s er u m cr e ati ni n e pri or t o e v er y d o s e
R o uti n e uri n al y si s i s n ot n e c e s s ar y, ot h er t h a n t o r ul e o ut U TI s, et c; n e p hr ol o g y m a y c o n si d er f urt h er
If n o p ot e nti al alt er n ati v e c au s e of A KI i d e nti ﬁe d, t h e n o n e s h o ul d f or e g o bi o p s y a n d pr o c e e d dir e ctl y wit h 
i m m u n o s u p pr e s si v e t h er a p y S wift tr e at m e nt of a ut oi m m u n e c o m p o n e nt i m p ort a nt
6. 1 Ne p hritis
D e ﬁniti o n: I n ﬂa m m ati o n of t h e ki d n e y aff e cti n g t h e str u ct ur e
Gr a di n g
M a n a g e m e nt
G 1: Cr e ati ni n e l e v el i n cr e a s e > U L N - 1. 5 x U L N 
C o n si d er t e m p or aril y h ol di n g I C Pi, p e n di n g 
c o n si d er ati o n of p ot e nti al alt er n ati v e eti ol o gi e s (r e c e nt 
I V c o ntr a st, m e di c ati o n s, ﬂui d st at u s) a n d b a s eli n e r e n al 
f u n cti o n. A c h a n g e t h at i s still < 1. 5 U L N c o ul d b e 
m e a ni n gf ul
G 2: Cr e ati ni n e > 1. 5 - 3. 0 x b a s eli n e; > 1. 5 - 3. 0 x U L N 
H ol d I C Pi 
C o n s ult n e p hr ol o g y
E v al u at e f or ot h er c a u s e s (r e c e nt I V c o ntr a st, 
m e di c ati o n s, ﬂui d st at u s, et c); if ot h er eti ol o gi e s r ul e d 
o ut, a d mi ni st er 0. 5 -1 m g/ k g/ d pr e d ni s o n e e q ui v al e nt s
If w or s e ni n g or n o i m pr o v e m e nt: 1 t o 2 m g/ k g/ d 
pr e d ni s o n e e q ui v al e nt s a n d p er m a n e ntl y di s c o nti n u e 
tr e at m e nt
If i m pr o v e d t o G 1 or l e s s, t a p er c orti c o st er oi d s o v er 4-6 
w e e k s If n o r e c urr e n c e of c hr o ni c r e n al i n s uf ﬁci e n c y, 
di s c u s s r e s u m pti o n of I C PI w it h p ati e nt aft er t a ki n g i nt o 
a c c o u nt t h e ri s k s a n d b e n e ﬁt s.
G 3: Cr e ati ni n e > 3. 0 x b a s eli n e; > 3. 0 - 6. 0 x U L N 
P er m a n e ntl y di s c o nti n u e I C Pi
G 4: Lif e -t hr e at e ni n g c o n s e q u e n c e s; di al y si s i n di c at e d
P er m a n e ntl y di s c o nti n u e I C Pi
C o n s ult n e p hr ol o g y
E v al u at e f or ot h er c a u s e s (r e c e nt I V c o ntr a st, 
m e di c ati o n s, ﬂui d st at u s, et c)
A d mi ni st er c orti c o st er oi d s (i niti al d o s e of 1 -2 m g/ k g/ d 
pr e d ni s o n e or e q ui v al e nt)
A d diti o n al c o n si d er ati o n s
M o nit or cr e ati ni n e w e e kl y
R e ﬂe x ki d n e y bi o p s y s h o ul d b e di s c o ur a g e d u ntil c orti c o st er oi d tr e at m e nt h a s b e e n att e m pt e d
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 /1 5 9
6. 2 S y m pt o m atic ne p hritis: f oll o w- u p
Gr a di n g
M a n a g e m e nt
G 1
I m pr o v e d t o b a s eli n e, r e s u m e r o uti n e cr e ati ni n e 
m o nit ori n g
G 2
If i m pr o v e d t o G 1, t a p er c orti c o st er oi d s o v er at l e a st 3 
w e e k s b ef or e r e s u mi n g tr e at m e nt wit h r o uti n e 
cr e ati ni n e m o nit ori n g If el e v ati o n s p er si st > 7 d a y s or 
w or s e n a n d n o ot h er c a u s e f o u n d, tr e at a s G 3
G 3
If i m pr o v e d t o G 1, t a p er c orti c o st er oi d s o v er at l e a st 4 
w e e k s 
If el e v ati o n s p er si st 3-5 d a y s or w or s e n, c o n si d er 
a d diti o n al i m m u n o s u p pr e s si o n (e. g, m y c o p h e n ol at e)
G 4
If i m pr o v e d t o G 1, t a p er c orti c o st er oi d s o v er at l e a st 4 
w e e k s
If el e v ati o n s p er si st 2-3 d a y s or w or s e n, c o n si d er 
a d diti o n al i m m u n o s u p pr e s si o n ( e. g, m y c o p h e n ol at e)
All r e c o m m e n d ati o n s ar e e x p ert c o n s e n s u s b a s e d, wit h b e n e ﬁt s o ut w ei g hi n g h ar m s, a n d str e n gt h of 
r e c o m m e n d ati o n s ar e m o d er at e.
A b br e vi ati o n s: A KI, a c ut e ki d n e y i nj ur y; G, Gr a d e ; I C Pi, i m m u n e c h e c k p oi nt i n hi bit or; ir A E, i m m u n e-r el at e d a d v er s e 
e v e nt; I V, i ntr a v e n o u s; U L N, u p p er li mit of n or m al; U TI, uri n ar y tr a ct i nf e cti o n.
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 6 /1 5 9
T a ble A 7
M a n a ge me nt of Ner v o us S yste m ir A Es i n P atie nts Tre ate d Wit h I C Pis
7. 0 Ner v o us S yste m T o xicities
7. 1 M y ast he ni a gr a vis
D e ﬁniti o n: F ati g a bl e or ﬂu ct u ati n g m u s cl e w e a k n e s s, g e n er all y m or e pr o xi m al t h a n di st al. Fr e q u e ntl y h a s o c ul ar 
a n d/ or b ul b ar i n v ol v e m e nt ( pt o si s, e xtr a o c ul ar m o v e m e nt a b n or m aliti e s r e s ulti n g i n d o u bl e vi si o n, d y s p h a gi a, 
d y s art hri a, f a ci al m u s cl e w e a k n e s s). M a y h a v e n e c k a n d/ or r e s pir at or y m u s cl e w e a k n e s s. ( N ot e: M a y o c c ur wit h 
m y o siti s a n d/ or m y o c ar diti s. R e s pir at or y s y m pt o m s m a y r e q uir e e v al u ati o n t o r ul e o ut p n e u m o niti s, m y o c ar diti s. 
Mill er F i s h er v ari a nt of G uill ai n-B arr é s y n dr o m e ( o p ht h al m o p ar e si s) a n d t h e o c ul o b ul b ar m y o siti s ( pt o si s, 
o p ht h al m o p ar e si s, d y s p h a gi a, n e c k a n d r e s pir at or y w e a k n e s s) wit h I C Pi m a y h a v e o v erl a p pi n g s y m pt o m s.
Di a g n o sti c w or k -u p
A C h R a n d a nti stri at e d m u s cl e a nti b o di e s i n bl o o d; if A C h R a nti b o di e s ar e n e g ati v e, c o n si d er m u s cl e s p e ci ﬁc 
ki n a s e a n d li p o pr ot ei n -r el at e d 4 a nti b o di e s i n bl o o d P ul m o n ary f u n cti o n a s s e s s m e nt wit h NI F a n d V C
C P K, al d ol a s e, E S R, C R P f or p o s si bl e c o n c urr e nt m y o siti s
C o n si d er M RI of br ai n a n d/ or s pi n e, d e p e n di n g o n s y m pt o m s t o r ul e o ut C N S i n v ol v e m e nt b y di s e a s e or alt er n at e 
di a g n o si s
If r e s pir at or y i n s ufﬁci e n c y or el e v at e d C P K, tr o p o ni n T, p erf or m c ar di a c e x a mi n ati o n wit h E C G a n d T T E f or 
p o s si bl e c o n c o mit a nt m y o c ar diti s
N e ur ol o gi c c o n s ult ati o n
El e ctr o di a g n o siti c st u di e s, i n cl u di n g n e ur o m u s c ul ar j u n cti o n t e sti n g wit h r e p etiti v e sti m ul ati o n a n d/ or jitt er st u di e s, 
N C S t o e x cl u d e n e ur o p at h y, a n d n e e dl e E M G t o e v al u at e f or m y o siti s
Gr a di n g
M a n a g e m e nt
All gr a d e s
All gr a d e s w arr a nt w or k- u p a n d i nt er v e nti o n gi v e n 
p ot e nti al f or pr o gr e s si v e m y a st h e ni a gr a vi s t o l e a d t o 
r e s pir at or y c o m pr o mi s e
N o G 1
G 2: S o m e s y m pt o m s i nt erf eri n g wit h A D L M G F A 
s e v erit y cl a s s 1 ( o c ul ar s y m pt o m s a n d ﬁn di n g s o nl y) 
a n d M G F A s e v erit y cl a s s 2 ( mil d g e n er ali z e d 
w e a k n e s s)
H ol d I C Pi a n d m a y r e s u m e i n G 2 p ati e nt s ( M G F A 1 a n d 
2) o nl y if s y m pt o m s r e s ol v e 
S h o ul d c o n s ult n e ur ol o g y
P yri d o sti g mi n e st arti n g at 3 0 m g o r all y t hr e e ti m e s a 
d a y a n d gr a d u all y i n cr e a s e t o m a xi m u m of 1 2 0 m g 
or all y f o ur ti m e s a d a y a s t ol er at e d a n d b a s e d o n 
s y m pt o m s A d mi ni st er c orti c o st er oi d s ( pr e d ni s o n e, 1 -1. 5 
m g/ k g or all y d ail y) if s y m pt o m s G 2; w e a n b a s e d o n 
s y m pt o m i m pr o v e m e nt
G 3 -4: Li miti n g s elf -c ar e a n d ai d s w arr a nt e d, w e a k n e s s 
li miti n g w al ki n g, A N Y d y s p h a gi a, f a ci al w e a k n e s s, 
r e s pir at or y m u s cl e w e a k n e s s, or r a pi dl y pr o gr e s si v e 
s y m pt o m s, or M G F A s e v erit y cl a s s 3 -4 m o d er at e t o 
s e v er e g e n er ali z e d w e a k n e s s t o m y a st h e ni c cri si s
P er m a n e ntl y di s c o nti n u e I C Pi
A d mit p ati e nt, m a y n e e d I C U -l e v el m o nit ori n g
N e ur ol o g y c o n s ult
C o nti n u e c orti c o st er oi d s a n d i niti at e I VI G 2 g/ k g I V o v er 
5 d a y s ( 0. 4 g/ k g/ d) or pl a s m a p h er e si s f or 5 d a y s
Fr e q u e nt p ul m o n ar y f u n cti o n a s s e s s m e nt
D ail y n e ur ol o gi c r e vi e w
A d diti o n al c o n si d er ati o n s
A v oi d m e di c ati o n s t h at c a n w or s e n m y a st h e ni a: β- bl o c k er s, I V m a g n e si u m, ﬂu or o q ui n ol o n e s, a mi n o gl y c o si d e s, 
a n d m a cr oli d e s I niti all y a 5 -d a y c o ur s e of pl a s m a p h er e si s or a 2 g/ k g c o ur s e of I VI G o v er 5 d a y s
1- 2 m g/ k g m et h yl pr e d ni s ol o n e d ail y, w e a n b a s e d o n s y m pt o m i m pr o v e m e nt
P yri d o sti g mi n e, w e a n b a s e d o n i m pr o v e m e nt
I C Pi- a s s o ci at e d m y a st h e ni a gr a vi s m a y b e m o n o p h a si c, a n d a d diti o n al c orti c o st er oi d-s p ari n g a g e nt s m a y n ot b e 
r e q uir e d
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 7 /1 5 9
7. 2 G uill ai n -B arré s y n dr o me
D e ﬁniti o n: Pr o gr e s si v e, m o st oft e n s y m m etri c al m u s cl e w e a k n e s s wit h a b s e nt or r e d u c e d d e e p t e n d o n r e ﬂe x e s. 
Oft e n st art s wit h s e n s or y s y m pt o m s/ n e ur o p at hi c p ai n l o c ali z e d t o l o w er b a c k a n d t hi g h s. M a y i n v ol v e e xtr e miti e s 
(t y pi c all y a s c e n di n g w e a k n e s s b ut n ot al w a y s), f a ci al, r e s pir at or y, a n d b ul b ar a n d o c ul o m ot or n er v e s. M a y h a v e 
d y sr e g ul ati o n of a ut o n o mi c n er v e s.
Di a g n o sti c w or k -u p
N e ur ol o gi c c o n s ult ati o n
M RI of s pi n e wit h or wit h o ut c o ntr a st (r ul e o ut c o m pr e s si v e l e si o n a n d e v al u at e f or n er v e r o ot 
e n h a n c e m e nt/t hi c k e ni n g)
L u m b ar p u n ct ur e: C S F t y pi c all y h a s el e v at e d pr ot ei n a n d oft e n el e v at e d W B C s; e v e n t h o u g h t hi s i s n ot t y pi c all y 
s e e n i n cl a s si c G uill ai n -B arr é s y n dr o m e, c yt ol o g y s h o ul d b e s e nt wit h a n y C S F s a m pl e fr o m a p ati e nt wit h c a n c er.
S er u m a n ti b o d y t e st s f or G uill ai n-B arr é s y n dr o m e v ari a nt s ( G Q 1 b f or Mill er Fi s h er v ari a nt a/ w at a xi a a n d 
o p ht h al m o pl e gi a) El e ctr o di a g n o sti c st u di e s t o e v al u at e p ol y n e ur o p at h y
P ul m o n ar y f u n cti o n t e sti n g ( NI F/ V C)
Fr e q u e nt n e ur o c h e c k s
Gr a di n g
M a n a g e m e nt
All gr a d e s
W a rr a nt w or k-u p a n d i nt er v e nti o n gi v e n p ot e nti al f or 
pr o gr e s si v e G uill ai n - B arr é s y n dr o m e t o l e a d t o 
r e s pir at or y c o m pr o mi s e
N ot e: T h er e i s n o G 1 t o xi cit y
G 1: Mil d, n o n e
N A
G 2: M o d er at e, s o m e i nt erf er e n c e wit h A D L, s y m pt o m s 
c o n c er ni n g t o p ati e nt
Di s c o nti n u e I C Pi
G 3 -4: S e v er e , li miti n g s elf-c ar e a n d ai d s w arr a nt e d, 
w e a k n e s s, li miti n g w al ki n g, A N Y d y s p h a gi a, f a ci al 
w e a k n e s s, r e s pir at or y m u s cl e w e a k n e s s, or r a pi dl y 
pr o gr e s si v e s y m pt o m s
P er m a n e ntl y di s c o nti n u e I C Pi. A d mi s si o n t o i n p ati e nt 
u nit wit h c a p a bilit y of r a pi d tr a n sf er t o I C U-l e v el 
m o nit ori n g St art I VI G ( 0. 4 g/ k g/ d f or 5 d a y s f or a t ot al 
d o s e of 2 g/ k g) or pl a s m a p h er e si s. C orti c o st er oi d s ar e 
u s u all y n ot r e c o m m e n d e d f or i di o p at hi c G uill ai n -B arr é 
s y n dr o m e; h o w e v er, i n I C Pi -r el at e d f or m s, a tri al i s 
r e a s o n a bl e ( m et h yl pr e d ni s ol o n e 2- 4 m g/ k g/ d), f oll o w e d 
b y sl o w c orti c o st er oi d t a p er
P ul s e c orti c o st er oi d d o si n g ( m et h yl pr e d ni s ol o n e 1 g/ d 
f or 5 d a y s) m a y al s o b e c o n si d er e d f or G 3-4 al o n g wit h 
I VI G or pl a s m a p h er e si s
Fr e q u e nt n e ur o c h e c k s a n d p ul m o n ar y f u n cti o n 
m o nit ori n g
M o nit or f or c o n c urr e nt a ut o n o mi c d y sf u n cti o n
N o n o pi oi d m a n a g e m e nt of n e ur o p at hi c p ai n
Tr e at m e nt of c o n sti p ati o n/il e u s
A d diti o n al c o n si d er ati o n s
Sl o w pr e d ni s o n e t a p er aft er c orti c o st er oi d p ul s e pl u s I VI G or pl a s m a p h er e si s M a y r e q uir e r e p e at I VI G c o ur s e s
C a uti o n wit h r e c h all e n gi n g f or s e v er e c a s e s
7. 3 Peri p her al ne ur o p at h y
D e ﬁniti o n: C a n pr e s e nt a s a s y m m etri c or s y m m etri c s e n s or y, m ot or, or s e n s or y m ot or d e ﬁcit. F o c al 
m o n o n e ur o p at hi e s, i n cl u di n g cr a ni al n e ur o p at hi e s ( e. g, f a ci al n e ur o p at hi e s/ B ell p al s y) m a y b e pr e s e nt. N u m b n e s s 
a n d p ar e st h e si a s m a y b e p ai nf ul or p ai nl e s s. H y p o - or ar e ﬂe xi a or s e n s or y at a xi a m a y b e pr e s e nt.
Di a g n o sti c w or k -u p
G 1
S cr e e n f or r e v er si bl e n e ur o p at h y c a u s e s: di a b eti c s cr e e n, B 1 2, f ol at e, T S H, HI V, c o n si d er s er u m pr ot ei n 
el e ctr o p h or e si s, a n d ot h er v a s c uliti c a n d a ut oi m m u n e s cr e e n N e ur ol o gi c c o n s ult ati o n
C o n si d er M RI of s pi n e wit h or wit h o ut c o ntr a st
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
G 2: i n a d diti o n t o a b o v e
M RI s pi n e a d vi s e d/ M RI of br ai n if cr a ni al n er v e C o n si d er E M G/ N C S
C o n si d er n e ur ol o g y c o n s ult ati o n
G 3 -4: g o t o G uill ai n -B arr é s y n dr o m e al g orit h m
Gr a di n g
M a n a g e m e nt
G 1: Mil d, n o i nt erf er e n c e wit h f u n cti o n a n d s y m pt o m s 
n ot c o n c er ni n g t o p ati e nt. N ot e: A n y cr a ni al n er v e 
pr o bl e m s h o ul d b e m a n a g e d a s m o d er at e
L o w t hr e s h ol d t o h ol d I C Pi a n d m o nit or s y m pt o m s f or a 
w e e k If t o c o nti n u e, m o nit or v er y cl o s el y f or a n y 
s y m pt o m pr o gr e s si o n
G 2: M o d er at e, s o m e i nt erf er e n c e wit h A D L, s y m pt o m s 
c o n c er ni n g t o p ati e nt (i .e, p ai n b ut n o w e a k n e s s or g ait 
li mit ati o n)
H ol d I C Pi a n d r e s u m e o n c e r et ur n t o G 1
I niti al o b s er v ati o n O R i niti at e pr e d ni s o n e 0. 5-1 m g/ k g (if 
pr o gr e s si n g fr o m mil d)
N e ur o nti n, pr e g a b ali n, or d ul o x eti n e f or p ai n
G 3 -4: S e v er e, li miti n g s elf -c ar e a n d ai d s w arr a nt e d, 
w e a k n e s s li miti n g w al ki n g or r e s pir at or y pr o bl e m s (i .e, 
l e g w e a k n e s s, f o ot dr o p, r a pi dl y a s c e n di n g s e n s or y 
c h a n g e s) S e v er e m a y b e G uill ai n- B arr é s y n dr o m e a n d 
s h o ul d b e m a n a g e d a s s u c h
P er m a n e ntl y di s c o nti n u e I C Pi
A d mit p ati e nt
N e ur ol o gi c c o n s ult ati o n
I niti at e I V m et h yl pr e d ni s ol o n e 2-4 m g/ k g a n d pr o c e e d 
a s p er G uill ai n -B arr é s y n dr o m e m a n a g e m e nt
7. 4 A ut o n o mic ne ur o p at h y
D e ﬁniti o n: N er v e s t h at c o ntr ol i n v ol u nt ar y b o dil y f u n cti o n s ar e d a m a g e d. T hi s m a y aff e ct bl o o d pr e s s ur e, 
t e m p er at ur e c o ntr ol, di g e sti o n, bl a d d er f u n cti o n, a n d s e x u al f u n cti o n. A c a s e of s e v er e e nt eri c n e ur o p at h y wit h 
I C Pi h a s b e e n r e p ort e d. C a n pr e s e nt with GI dif ﬁc ulti e s s u c h a s n e w s e v er e c o n sti p ati o n, n a u s e a, uri n ar y 
pr o bl e m s, s e x u al dif ﬁc ulti e s, s w e ati n g a b n or m aliti e s, sl u g gi s h p u pil r e a cti o n, a n d ort h o st ati c h y p ert e n si o n.
Di a g n o sti c w or k -u p
A n e v al u ati o n b y n e ur ol o gi st or r el e v a nt s p e ci ali st, d e p e n di n g o n or g a n s y st e m, wit h t e sti n g t h at m a y i n cl u d e
S cr e e ni n g f or ot h er c a u s e s of a ut o n o mi c d y sf u n cti o n: di a b eti c s cr e e n, a dr e n al i n s uf ﬁci e n c y, HI V, p ar a pr ot ei n e mi a, 
a m yl oi d o si s, b ot uli s m; c o n si d er c hr o ni c di s e a s e s s u c h a s P ar ki n s o n a n d ot h er a ut oi m m u n e s cr e e ni n g
A M  ort h o st ati c vit al s
C o n si d er el e ctr o di a g n o sti c st u di e s t o e v al u at e f or c o n c urr e nt p ol y n e ur o p at h y
C o n si d er p ar a n e o pl a sti c L a m b ert- E at o n m y a st h e ni c s y n dr o m e, a nti n e utr o p hil c yt o pl a s mi c a nti b o di e s, a n d 
g a n gli o ni c A C h R a nti b o d y t e sti n g
Gr a di n g
M a n a g e m e nt
G 1: Mil d, n o i nt erf er e n c e wit h f u n cti o n a n d s y m pt o m s 
n ot c o n c er ni n g t o p ati e nt
L o w t hr e s h ol d t o h ol d I C Pi a n d m o nit or s y m pt o m s f or a 
w e e k; if t o c o nti n u e, m o nit or v er y cl o s el y f or a n y 
s y m pt o m pr o gr e s si o n
G 2: M o d er at e, s o m e i nt erf er e n c e wit h A D L, s y m pt o m s 
c o n c er ni n g t o p ati e nt
H ol d I C Pi a n d r e s u m e o n c e r et ur n t o G 1
I niti al o b s er v ati o n O R i niti at e pr e d ni s o n e 0. 5-1 m g/ k g (if 
pr o gr e s si n g fr o m mil d)
N e ur ol o gi c c o n s ult ati o n
G 3 -4: S e v er e, li miti n g s elf -c ar e a n d ai d s w arr a nt e d
P er m a n e ntl y di s c o nti n u e I C Pi
A d mit p ati e nt
I niti at e m et h yl pr e d ni s ol o n e 1 g d ail y f or 3 d a y s f oll o w e d 
b y or al c orti c o st er oi d t a p er N e ur ol o gi c c o n s ult ati o n
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
7. 5 Ase ptic me ni n gitis
D e ﬁniti o n: m a y pr e s e nt wit h h e a d a c h e, p h ot o p h o bi a, a n d n e c k stiff n e s s; oft e n af e bril e b ut m a y b e f e bril e. T h er e 
m a y b e n a u s e a/ v o miti n g. M e nt al st at u s s h o ul d b e n or m al ( di sti n g ui s h e s fr o m e n c e p h aliti s).
Di a g n o sti c w or k -u p
M RI of br ai n wit h or wit h o ut c o ntr a st + pit uit ar y pr ot o c ol
A M  c orti s ol, A C T H t o r ul e o ut a dr e n al i n s ufﬁci e n c y
C o n si d er l u m b ar p u n ct ur e: m e a s u r e o p e ni n g pr e s s ur e; c h e c k c ell c o u nt a n d pr ot ei n gl u c o s e; a n d p erf or m Gr a m 
st ai n, c ult ur e, P C R f or H S V, a n d ot h er vir al P C R s d e p e n di n g o n s u s pi ci o n, c yt ol o g y
M a y s e e el e v at e d W B C c o u nt wit h n or m al gl u c o s e, n or m al c ult ur e, a n d Gr a m st ai n; m a y s e e r e a cti v e l y m p h o c yt e s 
or hi sti o c yt e s o n c yt ol o g y
Gr a di n g
M a n a g e m e nt
G 1: Mil d, n o i nt erf er e n c e wit h f u n cti o n a n d s y m pt o m s 
n ot c o n c er ni n g t o p ati e nt. N ot e: A n y cr a ni al n er v e 
pr o bl e m s h o ul d b e m a n a g e d a s m o d er at e.
G 2: M o d er at e, s o m e i nt erf er e n c e wit h A D L, s y m pt o m s 
c o n c er ni n g t o p ati e nt (i. e, p ai n b ut n o w e a k n e s s or g ait 
li mit ati o n)
G 3 -4: S e v er e, li miti n g s elf -c ar e a n d ai d s w arr a nt e d
F or G 1 -3: H ol d I C Pi a n d di s c u s s r e s u m pti o n wit h 
p ati e nt o nl y aft er t a ki n g i nt o a c c o u nt t h e ri s k s a n d 
b e n e ﬁt s
F or G 4: p er m a n e ntl y di s c o nti n u e I C Pi.
I n c a s e of a n y a s e pti c m e ni n giti s e v e nt s ( G 1-4),
c o n si d er e m piri c al a nti vir al (I V a c y cl o vir) a n d 
a nti b a ct eri al t h er a p y u ntil C S F r e s ult s O n c e b a ct eri al 
a n d vir al i nf e cti o n ar e n e g ati v e, m a y cl o s el y m o nit or off 
c orti c o s t er oi d s or c o n si d er or al pr e d ni s o n e 0. 5-1 m g/ k g 
or I V m et h yl pr e d ni s ol o n e 1 m g/ k g if m o d er at e/ s e v er e 
s y m pt o m s
7. 6 E nce p h alitis
D e ﬁniti o n: A s f or a s e pti c m e ni n giti s, n e e d t o e x cl u d e i nf e cti o u s c a u s e s, e s p e ci all y vir al (i .e, H S V).
C o nf u si o n, alt er e d b e h a vi or, h e a d a c h e s, s ei z ur e s, s h ort -t er m m e m or y l o s s, d e pr e s s e d l e v el of c o n s ci o u s n e s s, 
f o c al w e a k n e s s, s p e e c h a b n or m alit y 
Di a g n o sti c w or k -u p
N e ur ol o gi c c o n s ult ati o n
M RI of br ai n wit h or wit h o ut c o ntr a st m a y r e v e al T 2/ ﬂui d -att e n u at e d i n v er si o n r e c o v er y c h a n g e s t y pi c al of w h at i s 
s e e n i n a ut oi m m u n e e n c e p h al o p at hi e s or li m bi c e n c e p h aliti s or m a y b e n or m al
L u m b ar p u n ct ur e: c h e c k c ell c o u nt a n d pr ot ei n gl u c o s e a n d p erf or m Gr a m st ai n, c ult ur e, P C R f or H S V a n d ot h er 
vir al P C R s d e p e n di n g o n s u s pi ci o n, c yt ol o g y, oli g o cl o n al b a n d s, a ut oi m m u n e e n c e p h al o p at h y, a n d p ar a n e o pl a sti c 
p a n el s.
M a y s e e el e v at e d W B C c o u nt wit h l y m p h o c yti c pr e d o mi n a n c e a n d/ or el e v at e d pr ot ei n
E E G t o e v al u at e f or s u b cli ni c al s ei z ur e s
Bl o o d: m et a b oli c, C B C, E S R, C R P, A N C A (if s u s p e ct v a s c uliti c pr o c e s s), t h yr oi d p a n el i n cl u di n g T P O a n d 
t h yr o gl o b uli n R ul e o ut c o n c urr e nt a n e mi a/t hr o m b o c yt o p e ni a, w hi c h c a n pr e s e nt wit h s e v er e h e a d a c h e s a n d 
c o nf u si o n
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
Gr a di n g
M a n a g e m e nt
G 1: Mil d, n o i nt erf er e n c e wit h f u n cti o n a n d s y m pt o m s 
n ot c o n c er ni n g t o p ati e nt. N ot e: A n y cr a ni al n er v e 
pr o bl e m s h o ul d b e m a n a g e d a s m o d er at e.
G 2: M o d er at e, s o m e i nt erf er e n c e wit h A D L, s y m pt o m s 
c o n c er ni n g t o p ati e nt (i .e, p ai n b ut n o w e a k n e s s or g ait 
li mit ati o n)
G 3 -4: S e v er e, li miti n g s elf -c ar e a n d ai d s w arr a nt e d
F or G 1, 2, a n d 3: H ol d I C Pi a n d di s c u s s r e s u m pti o n 
wit h p ati e nt o nl y aft er t a ki n g i nt o a c c o u nt t h e ri s k s a n d 
b e n e ﬁt s
F or G 4: p er m a n e ntl y di s c o nti n u e I C Pi
A s a b o v e f or a s e pti c m e ni n giti s i n c a s e of a n y 
e n c e p h aliti s e v e nt s, s u g g e st c o n c urr e nt I V a c y cl o vir 
u ntil P C R r e s ult s o bt ai n e d a n d n e g ati v e
Tri al of m et h yl pr e d ni s ol o n e 1 -2 m g/ k g
If s e v er e or pr o gr e s si n g s y m pt o m s or oli g o cl o n al b a n d s 
pr e s e nt, c o n si d er p ul s e c orti c o st er oi d s 
m et h yl pr e d ni s ol o n e 1 g I V d ail y f or 3 -5 d a y s pl u s I VI G 2 
g/ k g o v er 5 d a y s If p o siti v e f or a ut oi m m u n e 
e n c e p h al o p at h y a nti b o d y a n d li mit e d or n o 
i m pr o v e m e nt, c o n si d er rit u xi m a b or pl a s m a p h er e si s i n 
c o n s ult ati o n wit h n e ur ol o g y .
I n c a s e of m a n a g e m e nt wit h rit u xi m a b, I C Pi tr e at m e nt
s h o ul d b e di s c o nti n u e d .
7. 7 Tr a ns verse m yelitis
D e ﬁniti o n: A c ut e or s u b a c ut e w e a k n e s s or s e n s or y c h a n g e s bil at er al, oft e n wit h i n cr e a s e d d e e p t e n d o n r e ﬂe x e s
Di a g n o sti c w or k -u p
N e ur ol o gi c c o n s ult ati o n
M RI of s pi n e ( wit h t hi n a xi al c ut s t hr o u g h t h e r e gi o n of s u s p e ct e d a b n or m alit y) a n d M RI of br ai n
L u m b ar p u n ct ur e: c ell c o u nt, pr ot ei n, gl u c o s e, oli g o cl o n al b a n d s, vir al P C R s, c yt ol o g y, o n c o n e ur al a nti b o di e s 
Bl o o d: B 1 2, HI V, R P R, A N A, R o/ L a, T S H, a q u a p ori n -4 I g G
E v al u ati o n f or uri n ar y r et e nti o n, c o n sti p ati o n
Gr a di n g
M a n a g e m e nt
G 1: Mil d, n o i nt erf er e n c e wit h f u n cti o n a n d s y m pt o m s 
n ot c o n c er ni n g t o p ati e nt. N ot e: A n y cr a ni al n er v e 
pr o bl e m s h o ul d b e m a n a g e d a s m o d er at e.
G 2: M o d er at e, s o m e i nt erf er e n c e wit h A D L, s y m pt o m s 
c o n c er ni n g t o p ati e nt (i .e, p ai n b ut n o w e a k n e s s or g ait 
li mit ati o n)
G 3 -4: S e v er e, li miti n g s elf -c ar e a n d ai d s w arr a nt e d
P er m a n e ntl y di s c o nti n u e I C Pi
M et h yl pr e d ni s ol o n e 2 m g/ k g
Str o n gl y c o n si d er hi g h er d o s e s of 1 g/ d f or 3- 5 d a y s 
Str o n gl y c o n si d er I VI G
All r e c o m m e n d ati o n s ar e e x p ert c o n s e n s u s b a s e d, wit h b e n e ﬁt s o ut w ei g hi n g h ar m s, a n d str e n gt h of 
r e c o m m e nd ati o n s ar e m o d er at e.
A b br e vi ati o n s: A C h R, a c et yl c h oli n e r e c e pt or; A C T H, a dr e n o c orti c otr o pi c h or m o n e; A D L, a cti viti e s of d ail y li vi n g; A N A, 
a nti n u cl e ar a nti b o d y; A N C A, a nti n e utr o p hil c yt o pl a s mi c a nti b o di e s; C B C, c o m pl et e bl o o d c o u nt; C N S, c e ntr al n er v o u s 
s y st e m; C P K, cr e ati n e p h o s p h o ki n a s e; C R P, C- r e a cti v e pr ot ei n; C S F, c er e br o s pi n al fl ui d; E C G, el e ctr o c ar di o gr a m; 
E E G, el e ctr o e n c e p h al o gr a m; E M G, el e ctr o m y o gr a p h y; E S R, er yt hr o c yt e s e di m e nt ati o n r at e; G, Gr a d e ; GI, 
g a str oi nt e sti n al; HI V, h u m a n i m m u n o d efi ci e n c y vir u s; H S V, h er p e s si m pl e x vir u s; I C Pi, i m m u n e c h e c k p oi nt i n hi bit or; 
I C U, i nt e n si v e c ar e u nit; I g G, i m m u n o gl o b uli n G; I V, i ntr a v e n o u s; I VI G, i ntr a v e n o u s i m m u n o gl o b uli n; ir A E, i m m u n e-
r el at e d a d v er s e e v e nt; M G F A, M y a st h e ni a Gr a vi s F o u n d ati o n of A m eri c a; M RI, m a g n eti c r e s o n a n c e i m a gi n g; N A, n ot 
a p pli c a bl e; N C S, n er v e c o n d u cti o n st u d y; NI F, n e g ati v e i n s pir at or y f or c e; P C R, p ol y m er a s e c h ai n r e a cti o n; R P R, 
r a pi d pl a s m a r e a gi n, T P O, t h yr oi d p er o xi d a s e; T S H, t h yr oi d-sti m ul ati n g h or m o n e; T T E, tr a n st h or a ci c 
e c h o c ar di o gr a m; V C, vit al c a p a cit y ; WB C, w hit e bl o o d c ell c o u nt .
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
T a ble A 8  
M a n a ge me nt of He m at ol o gic ir A Es i n P atie nts Tre ate d Wit h I C Pis
8. 0 He m at ol o gic T o xicities
8. 1 A ut oi m m u ne he m ol ytic a ne mi a
D e ﬁniti o n: A c o n diti o n i n w hi c h R B C s ar e d e str o y e d a n d r e m o v e d fr o m t h e bl o o d str e a m b ef or e t h eir n or m al 
lif e s p a n i s o v er. S y m pt o m s i n cl u d e w e a k n e s s, p al e n e s s, j a u n di c e, d ar k- c ol or e d uri n e, f e v er, i n a bilit y t o d o p h y si c al 
a cti vit y, a n d h e art m ur m ur.
Di a g n o sti c w or k -u p
Hi st or y a n d p h y si c al e x a mi n ati o n ( wit h s p e ci al c o n si d er ati o n of hi st or y of n e w dr u g s a n d i n s e ct, s pi d er, or s n a k e 
bit e s)
Bl o o d c h e mi str y, C B C wit h e vi d e n c e of a n e mi a, m a cr o c yt o si s, e vi d e n c e of h e m ol y si s o n p eri p h er al s m e ar; L D H, 
h a pt o gl o bi n, bilir u bi n, r e ti c ul o c yt e c o u nt, fr e e H g b DI C p a n el, w hi c h c o ul d i n cl u d e P T NI R i nf e cti o u s c a u s e s
A ut oi m m u n e s er ol o g y
P ar o x y s m al n o ct ur n al h e m o gl o bi n uri a s cr e e ni n g
Dir e ct a n d i n dir e ct bilir u bi n; L D H; dir e ct a g gl uti ni n t e st; a n d if n o o b vi o u s c a u s e, b o n e m arr o w a n al y si s, 
 
a n al y si s t o e v al u at e f or m y el o d y s pl a sti c s y n dr o m e s
E v al u ati o n f or vir al/ b a ct eri al ( m y c o pl a s m a, et c) c a u s e s of h e m ol y si s st u di e s
Pr ot ei n el e ctr o p h or e si s, cr y o gl o b uli n a n al y si s
W o r k-u p f or b o n e m arr o w f ail ur e s y n dr o m e if r efr a ct or y, i n cl u di n g B 1 2, f ol at e, c o p p er, p ar v o vir u s, F E, t h yr oi d, 
i nf e cti o n
Gl u c o s e - 6-p h o s p h at e d e h y dr o g e n a s e
E v al u ati o n of c o m m o n dr u g c a u s e s (ri b a viri n, rif a m pi n, d a p s o n e, i nt erf er o n, c e p h al o s p ori n s, p e ni cilli n s , N S AI D s, 
q ui ni n e/ q ui ni di n e, ﬂu d ar a bi n e, ci pr o ﬂo x a ci n, l or a z e p a m, di cl of e n a c, et c)
A s s e s s m e nt of m et h e m o gl o bi n e mi a
Gr a di n g
M a n a g e m e nt
G 1: H g b < L L N t o 1 0. 0 g/ d L; < L L N t o 6. 2 m m ol/ L; < 
L L N t o 1 0 0 g/ L
C o nti n u e I C Pi wit h cl o s e cli ni c al f oll o w -u p a n d 
l a b or at or y e v al u ati o n
G 2: H g b < 1 0. 0 t o 8. 0 g/ d L; < 6. 2t o 4. 9 m m ol/ L; < 1 0 0 t o 
8 0 g/ L
H ol d I C Pi a n d str o n gl y c o n si d er p er m a n e nt 
di s c o nti n u ati o n
A d mi ni st er 0. 5 - 1 m g/ k g/ d pr e d ni s o n e e q ui v al e nt s
G 3: H g b < 8. 0 g/ d L; < 4. 9 m m ol/ L; < 8 0 g/ L; tr a n sf u si o n 
i n di c at e d
P er m a n e ntl y di s c o nti n u e I C Pi
S h o ul d u s e cli ni c al j u d g m e nt a n d c o n si d er a d mitti n g t h e 
p ati e nt
H e m at ol o g y c o n s ult
Pr e d ni s o n e 1 - 2 m g/ k g/ d ( or al or I V d e p e n di n g o n 
s y m pt o m s/ s p e e d of d e v el o p m e nt)
If w or s e ni n g or n o i m pr o v e m e nt, 1-2 m g/ k g/ d 
pr e d ni s o n e e q ui v al e nt s a n d p er m a n e ntl y di s c o nti n u e 
I C Pi tr e at m e nt
C o n si d er R B C tr a n sf u si o n p er e xi sti n g g ui d eli n e s; d o 
n ot tr a n sf u s e m or e t h a n t h e mi ni m u m n u m b er of R B C 
u nit s n e c e s s ar y t o r eli e v e s y m pt o m s of a n e m i a or t o 
r et ur n a p ati e nt t o a s af e H g b r a n g e ( 7-8 g/ d L i n st a bl e, 
n o n c ar di a c i n p ati e nt s)
S h o ul d off er p ati e nt s s u p pl e m e nt ati o n wit h f oli c a ci d 1 
m g o n c e d ail y
D oc u me nt N o.
O bject N o.
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 2 /1 5 9
G 4: Lif e -t hr e at e ni n g c o n s e q u e n c e s, ur g e nt i nt er v e nti o n 
i n di c at e d
P er m a n e ntl y di s c o nti n u e I C Pi
A d mit p ati e nt
H e m at ol o g y c o n s ult
I V pr e d ni s o n e c orti c o st er oi d s 1-2 m g/ k g/ d
If n o i m pr o v e m e nt or if w or s e ni n g w hil e o n 
c orti c o st er oi d s or s e v er e s y m pt o m s o n pr e s e nt ati o n, 
i niti at e ot h er i m m u n o s u p pr e s si v e dr u g s, s u c h a s 
rit u xi m a b, I VI G, c y cl o s p ori n A, a n d m y co p h e n ol at e 
m of etil
R B C tr a n sf u si o n p er e xi sti n g g ui d eli n e s; di s c u s s wit h 
bl o o d b a n k t e a m pri or t o tr a n sf u si o n s t h at a p ati e nt wit h 
p o s si bl e I C Pi s eri o u s A E i s i n h o u s e.
A d diti o n al c o n si d er ati o n s: M o nit or H g b l e v el s o n a w e e kl y b a si s u ntil t h e c orti c o st er o i d t a p eri n g pr o c e s s i s 
c o m pl et e; t h er e aft er, l e s s -fr e q u e nt t e sti n g i s n e e d e d
8. 2 Ac q uire d T T P
D e ﬁniti o n: A di s or d er c h ar a ct eri z e d b y t h e pr e s e n c e of mi cr o a n gi o p at hi c h e m ol yti c a n e mi a, t hr o m b o c yt o p e ni c 
p ur p ur a, f e v er, r e n al a b n or m aliti e s, a n d n e ur ol o gi c a b n or m aliti e s, s u c h a s s ei z ur e s, h e mi pl e gi a, a n d vi s u al 
di st ur b a n c e s. It i s a n a c ut e or s u b a c ut e c o n diti o n. 
Di a g n o sti c w or k -u p
Hi st or y wit h s p e ci ﬁc q u e sti o n s r el at e d t o dr u g e x p o s ur e ( e. g, c h e m ot h er a p y, sir oli m u s, t a cr oli m u s, o p a n a E R 
a nti bi oti c s, q ui ni n e) P h y si c al e x a mi n ati o n, p eri p h er al s m e ar
A D A M T S 1 3 a cti vit y l e v el a n d i n hi bit or tit er
L D H, h a pt o g l o bi n, r eti c ul o c yt e c o u nt, bilir u bi n, uri n al y si s t o r ul e o ut ot h er c a u s e s
P T, a cti v at e d P T T, ﬁbri n o g e n
Bl o o d gr o u p a n d a nti b o d y s cr e e n, dir e ct a nti gl o b uli n t e st, C M V s er ol o g y
C o n si d er C T/ M RI br ai n, e c h o c ar di o gr a m, E C G
Vir al st u di e s
N ot e: T hi s di s or d er i s u s u all y a s s o ci at e d wit h a s e v er e dr o p i n pl at el et s a n d h e m ol y si s/ a n e mi a pr e ci pit o u sl y
Gr a di n g
M a n a g e m e nt
All gr a d e s
T h e ﬁr st st e p i n t h e m a n a g e m e nt of T T P i s a hi g h i n d e x 
of s u s pi ci o n f or t h e di a g n o si s a n d ti m el y r e c o g niti o n; 
h e m at ol o g y c o n s ult s h o ul d i m m e di at el y b e c all e d, a s 
d el a y i n i d e nti ﬁc ati o n i s a s s o ci at e d wit h i n cr e a s e d 
m ort alit y/ m or bi dit y.
I niti all y, t h e p ati e nt s h o ul d b e st a bili z e d a n d a n y criti c al 
or g a n d y sf u n cti o n st a bili z e d
G 1: E vi d e n c e of R B C d e str u cti o n ( s c hi st o c yt o si s) 
wit h o ut a n e mi a, r e n al i n s uf ﬁci e n c y, or 
t hr o m b o c yt o p e ni a cli ni c all y
G 2: E vi d e n c e of R B C d e str u cti o n ( s c hi st o c yt o si s) 
wit h o ut cli ni c al c o n s e q u e n c e wit h G 2 a n e mi a a n d 
t hr o m b o c yt o p e ni a
H ol d I C Pi a n d di s c u s s r e s u m pti o n wit h p ati e nt o nl y aft er 
t a ki n g i nt o a c c o u nt t h e ri s k s a n d be n e ﬁt s, n oti n g t h at 
t h er e ar e c urr e ntl y n o d at a t o r e c o m m e n d r e st arti n g 
I C Pi t h er a p y H e m at ol o g y c o n s ult
A d mi ni st er 0. 5 -1 m g/ k g/ d pr e d ni s o n e
G 3: L a b or at or y ﬁn di n g s wit h cli ni c al c o n s e q u e n c e s ( G 3 
t hr o m b o c yt o p e ni a, a n e mi a, r e n al i n s ufﬁci e n c y > 2)
G 4: Lif e -t hr e at e ni n g c o n s e q u e n c e s (e. g, C N S 
h e m orr h a g e or t hr o m b o si s/ e m b oli s m or r e n al f ail ur e)
F or G 3: H ol d I C Pi a n d di s c u s s r e s u m pti o n wit h p ati e nt 
o nl y aft er t a ki n g i nt o a c c o u nt t h e ri s k s a n d b e n e ﬁt s, 
n oti n g t h at t h er e ar e c urr e ntl y n o d at a t o r e c o m m e n d 
r e st arti n g I C Pi t h er a p y
F or G 4: p er m a n e ntl y di s c o nti n u e I C Pi
H e m at ol o g y c o n s ult
I n c o nj u n cti o n wit h h e m at ol o g y, i niti at e P E X a c c or di n g 
t o e xi sti n g g ui d eli n e s wit h f urt h er P E X d e p e n d e nt o n 
cli ni c al pr o gr e s s
D oc u me nt N o.
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
A d mi ni st er m et h yl pr e d ni s ol o n e 1 g I V d ail y f or 3 d a y s, 
wit h t h e ﬁr st d o s e t y pi c all y a d mi ni st er e d i m m e di at el y 
aft er t h e ﬁr st P E X
M a y off er rit u xi m a b
I n c a s e of m a n a g e m e nt wit h rit u xi m a b, I C Pi tr e at m e nt
will b e di s c o nti n u e d
8. 3 He m ol ytic ure mic s y n dr o me
D e ﬁniti o n: A di s or d er c h ar a ct eri z e d b y a f or m of t hr o m b oti c mi cr o a n gi o p at h y wit h r e n al f ail ur e, h e m ol yti c a n e mi a, 
a n d s e v er e t hr o m b o c yt o p e ni a. Si g n s a n d s y m pt o m s of h e m ol yti c ur e mi c s y n dr o m e c a n i n cl u d e:
Bl o o d y di arr h e a
D e cr e a s e d uri n ati o n or bl o o d i n t h e uri n e
A b d o mi n al p ai n, v o miti n g, a n d o c c a si o n all y f e v er
P all o r
S m all, u n e x pl ai n e d br ui s e s or bl e e di n g fr o m t h e n o s e a n d m o ut h F ati g u e a n d irrit a bilit y
C o nf u si o n or s ei z ur e s
Hi g h bl o o d pr e s s ur e
S w elli n g of t h e f a c e, h a n d s, f e et, or e ntir e b o d y
Di a g n o sti c w or k -u p
Hi st or y a n d p h y si c al e x a mi n ati o n ( s p e ci al c o n si d er ati o n f or n e w hi st or y of hi g h -ri s k dr u g s, h y p ert e n si o n, or c ar di a c 
c a u s e s) C B C wit h i n di c e s
Bl o o d s m e ar m or p h ol o g y. N ot e t h at t h e pr e s e n c e of s c hi st o c yt e s o n s m e ar i s criti c al f or di a g n o si s.
S er u m cr e ati ni n e
A D A M T S 1 3 (t o r ul e o ut T T P)
H o m o c y st ei n e/ m et h yl m al o ni c a ci d
C o m pl e m e nt t e sti n g C 3, C 4, C H 5 0 ( c o m pl e m e nt i n hi bit or y a nti b o di e s f or s u s p e ct e d f a mili al)
E v al u at e r eti c ul o c yt e c o u nt a n d m e a n c or p u s c ul ar v ol u m e
E v al u ati o n of i nf e cti o u s c a u s e, i n cl u di n g s cr e e ni n g f or E B V, C M V, H H V 6
E v al u ati o n f or n utriti o n al c a u s e s of m a cr o c yt o si s ( B 1 2 a n d f ol at e)
P a n cr e ati c e n z y m e s
E v al u ati o n f or di arr h e al c a u s e s, s hi g a t o xi n, E s c h eri c hi a c oli 0 1 5 7, et c
Dir e ct a nti b o d y t e st ( C o o m b s t e st), h a pt o gl o bi n, L D H, a n d ot h er eti ol o gi e s of a n e mi a
E v al u ati o n f or c o m m o n dr u g s c a u si n g h e m ol y si s (t a cr oli m u s, c y cl o s p ori n e, sir oli m u s, et c)
E v al u ati o n f or c o n c urr e nt c o nf u si o n
Gr a di n g
M a n a g e m e nt
G 1 -2: E vi d e n c e of R B C d e str u cti o n ( s c hi st o c yt o si s) 
wit h o ut cli ni c al c o n s e q u e n c e s of a n e mi a, 
t hr o m b o c yt o p e ni a G r a d e 2
G 3: L a b or at or y ﬁn di n g s wit h cli ni c al c o n s e q u e n c e s 
(e. g, r e n al i n s ufﬁci e n c y, p et e c hi a e)
G 4: Lif e -t hr e at e ni n g c o n s e q u e n c e s (e. g, C N S 
t hr o m b o si s/ e m b oli s m or r e n al f ail ur e)
F or G 1 a n d G 2: C o nti n u e I C Pi wit h cl o s e cli ni c al f oll o w -
u p a n d l a b or at or y e v al u ati o n
S u p p orti v e c ar e 
F or G 3 a n d G 4: P er m a n e ntl y di s c o nti n u e I C Pi
B e gi n t h er a p y wit h e c uli z u m a b t h er a p y 9 0 0 m g w e e kl y 
f or f o ur d o s e s, 1, 2 0 0 m g w e e k 5, t h e n 1, 2 0 0 m g e v er y 2 
w e e k s
R e d bl o o d tr a n sf u si o n a c c or di n g t o e xi sti n g g ui d eli n e s
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 4 /1 5 9
8. 4 A pl astic a ne mi a
D e ﬁniti o n: C o n diti o n i n w hi c h t h e b o d y st o p s pr o d u ci n g e n o u g h n e w bl o o d c ell s 
Di a g n o sti c w or k -u p
Hi st or y a n d p h y si c al e x a mi n ati o n ( cl o s e att e nti o n t o m e di c ati o n s, e x p o s ur e t o r a di ati o n, t o xi n s, r e c e nt vir al 
i nf e cti o n s) C B C, s m e ar, r eti c ul o c yt e c o u nt
Vir al st u di e s, i n cl u di n g C M V, H H V 6, E B V, p ar v o vir u s
N utriti o n al a s s e s s m e nt s i n cl u di n g B 1 2, f ol at e, ir o n, c o p p er, c er ul o pl a s mi n, vit a mi n D
S er u m L D H, r e n al f u n cti o n
W o r k-u p f or i nf e cti o u s c a u s e s
I d e ntif y m arr o w h y p o/ a pl a si a
B o n e m arr o w bi o p s y a n d a s pir at e a n al y si s
P eri p h er al bl o o d a n al y si s, i n cl u di n g n e utr o p hil c o u nt, pr o p orti o n of G PI -n e g ati v e c ell s b y ﬂo w f or P N H
Fl o w c yt o m etr y t o e v al u at e l o s s of G PI -a n c h or e d pr ot ei n s
T y p e a n d s cr e e n p ati e nt f or tr a n sf u si o n s a n d n otif y bl o o d b a n k t h at all tr a n sf u si o n s n e e d t o b e irr a di at e d a n d 
ﬁlt er e d
Gr a di n g
M a n a g e m e nt
G 1: N o n s e v er e, < 0. 5 p ol y m or p h o n u cl e ar c ell s x 1 0 9 / L 
h y p o c ell ul ar m arr o w, wit h m arr o w c ell ul arit y < 2 5 %, 
p eri p h er al pl at el et c o u nt > 2 0, 0 0 0, r eti c ul o c yt e c o u nt 
< 2 0, 0 0 0
H ol d I C Pi a n d pr o vi d e gr o wt h f a ct or s u p p ort a n d cl o s e 
cli ni c al f oll o w -u p, a n d l a b or at or y e v al u ati o n 
S u p p orti v e tr a n sf u si o n s a s p er l o c al g ui d eli n e s
G 2: S e v er e, h y p o c ell ul ar m arr o w < 2 5 % a n d t w o of t h e 
f oll o wi n g: A N C < 5 0 0, p eri p h er al pl at el et < 2 0, 0 0 0, a n d 
r eti c ul o c yt e < 2 0, 0 0 0
H ol d I C Pi a n d pr o vi d e gr o wt h f a ct or s u p p ort a n d cl o s e 
cli ni c al l a b or at or y e v al u ati o n s d ail y
A d mi ni st er A T G + c y cl o s p ori n e; H L A t y pi n g a n d 
e v al u ati o n f or b o n e m arr o w tr a n s pl a nt ati o n if p ati e nt i s 
c a n di d at e; all bl o o d pr o d u ct s s h o ul d b e irr a di at e d a n d 
ﬁlt er e d
S u p p orti v e c ar e wit h gr a n ul o c yt e c ol o n y- sti m ul ati n g 
f a ct or m a y b e a d d e d i n a d diti o n
G 3 - 4: V er y s e v er e, A N C > 2 0 0, pl at el et c o u nt > 2 0, 0 0 0, 
r eti c ul o c yt e c o u nt > 2 0, 0 0 0, pl u s h y p o c ell ul ar m arr o w 
> 2 5 %
F or G 3: H ol d I C Pi a n d m o nit or w e e kl y f or i m pr o v e m e nt; 
if n ot r e s olv e d, di s c o nti n u e tr e at m e nt u ntil A E h a s 
r e v ert e d t o G 1
F or G 4: p er m a n e ntl y di s c o nti n u e I C Pi
H e m at ol o g y c o n s ult, gr o wt h f a ct or s u p p ort
H or s e A T G pl u s c y cl o s p ori n e
If n o r e s p o n s e, r e p e at i m m u n o s u p pr e s si o n wit h r a b bit 
A T G pl u s c y cl o s p ori n e, c y cl o p h o s p h a mi d e
F or r efr a ct or y p ati e nt s, c o n si d er eltr o m b o p a g pl u s 
s u p p orti v e c ar e
8. 5 L y m p h o pe ni a
D e ﬁniti o n: A n a b n or m all y l o w l e v el of l y m p h o c yt e s i n P B; f or a d ult s, c o u nt s of < 1, 5 0 0/ m m 3 
Di a g n o sti c w or k -u p
Hi st or y a n d p h y si c al e x a mi n ati o n ( s p e ci al att e nti o n f or l y m p h o c yt e -d e pl eti n g t h er a p y s u c h a s ﬂu d ar a bi n e, A T G, 
c orti c o st er oi d s, c yt ot o xi c c h e m ot h er a p y, r a di ati o n e x p o s ur e, et c, a s w ell a s hi st or y of a ut oi m m u n e di s e a s e, f a mil y 
hi st or y of a ut oi m m u n e di s e a s e) E v al u ati o n of n utriti o n al st at e a s c a u s e
S pl e e n si z e
C B C wit h diff er e nti al, p eri p h er al s m e ar a n d r eti c ul o c yt e c o u nt s
C X R f or e v al u ati o n of pr e s e n c e of t h y m o m a
B a ct eri al c ult ur e s a n d e v al u ati o n f or i nf e cti o n (f u n g al, vir al, b a ct eri al s p e ci ﬁc all y C M V/ HI V)
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 /1 5 9
Gr a di n g
M a n a g e m e nt
G 1 -2: 5 0 0 -1, 0 0 0 P B l y m p h o c yt e c o u nt
G 3: 2 5 0 -4 9 9 P B l y m p h o c yt e c o u nt
G 4: < 2 5 0 P B l y m p h o c yt e c o u nt
C o nti n u e I C Pi f or G 1 t o G 2
C o nti n u e I C Pi, c h e c ki n g 
F or G 3 si n gl e l a b or at or y v al u e s o ut of n or m al r a n g e 
wit h o ut a n y cli ni c al c orr el at e s, h ol d tr e at m e nt u ntil 
r e s ol uti o n t o G 1
F or G 4, f or si n gl e l a b or at or y v al u e s o ut of n or m al r a n g e 
wit h o ut a n y cli ni c al c orr el at e s, p er m a n e nt tr e at m e nt 
di s c o nti n u ati o n i s n ot r e q uir e d.  Tr e at m e nt s h o ul d b e 
h el d u ntil t h e eti ol o g y i s d et er mi n e d.  P er m a n e nt 
tr e atm e nt di s c o nti n u ati o n will o nl y b e r e q uir e d, if 
l y m p h o p e ni a i s c o n si d er e d of i m m u n e-r el at e d i n n at ur e, 
n o cl e ar alt er n ati v e e x pl a n ati o n e xi st s f or t h e e v e nt, a n d 
G r a d e 4 l y m p h o p e ni a d o e s n ot r e s ol v e wit hi n 1 4 d a y s.  
If t h e e v e nt i s n ot c o n si d er e d i m m u n e-r elat e d a n d 
r e s ol v e s t o G ≤1 r e st arti n g tr e at m e nt m a y b e 
c o n si d er e d.
C h e c k C B C w e e kl y f or m o nit ori n g, i niti ati o n of C M V 
s cr e e ni n g C o n si d er h ol di n g I C Pi
I niti at e M y c o b a ct eri u m a vi u m
c o m pl e x pr o p h yl a xi s a n d 
P n e u m o c y sti s jir o v e cii pr o p h yl a xi s, C M V s cr e e ni n g. 
HI V/ h e p atiti s s cr e e ni n g if n ot alr e a d y d o n e
M a y c o n si d er E B V t e sti n g if e vi d e n c e of 
l y m p h a d e n o p at h y/ h e p atiti s, f e v er s, h e m ol y si s 
c o n si st e nt wit h l y m p h o pr olif er ati v e di s e a s e
8. 6 I m m u ne t hr o m b oc yt o pe ni a
D e ﬁniti o n: A n a ut oi m m u n e di s or d er c h ar a ct eri z e d b y i m m u n ol o gi c d e str u cti o n of ot h er wi s e n or m al pl at el et s 
Di a g n o sti c w or k -u p
Hi st or y a n d p h y si c al e x a mi n ati o n ( s p e ci al att e nti o n f or l y m p h o c yt e -d e pl eti n g t h er a p y, s u c h a s ﬂu d ar a bi n e, A T G, 
c orti c o st er oi d s, c y t ot o xi c t h er a p y) F a mil y hi st or y of a ut oi m m u nit y or p er s o n al hi st or y of a ut oi m m u n e di s e a s e
Hi st or y of vir al ill n e s s
C B C
P eri p h er al bl o o d s m e ar, r eti c ul o c yt e c o u nt
B o n e m arr o w e v al u ati o n o nl y if a b n or m aliti e s i n t h e a b o v e t e st r e s ult s a n d f urt h er i n v e sti g ati o n i s n e c e s s ar y f or a 
di a g n o si s
P ati e nt s wit h n e wl y di a g n o s e d i m m u n e t hr o m b o c yt o p e ni a s h o ul d u n d er g o t e sti n g f or HI V, h e p atiti s C vir u s, 
h e p atiti s B vir u s, a n d H eli c o b a ct er p yl ori Dir e ct a nti g e n t e st s h o ul d b e c h e c k e d t o r ul e o ut c o n c urr e nt E v a n 
s y n dr o m e
N utriti o n al e v al u ati o n
B o n e m arr o w e v al u ati o n if ot h er c ell li n e s aff e ct e d a n d c o n c er n f or a pl a sti c a n e mi a
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 6 /1 5 9
Gr a di n g
M a n a g e m e nt
G 1: Pl at el et c o u nt < 1 0 0/ µ L
G 2: Pl at el et c o u nt < 7 5/ µ L
C o nti n u e I C Pi wit h cl o s e cli ni c al f oll o w-u p a n d 
l a b or at or y e v al u ati o n
H ol d I C Pi b ut m o nit or f or i m pr o v e m e nt; if n ot r e s ol v e d, 
i nt err u pt tr e at m e nt u ntil A E h a s r e v ert e d t o G 1
A d mi ni st er pr e d ni s o n e 1 m g/ k g/ d ( d o s a g e r a n g e, 0. 5 -2 
m g/ k g/ d) or all y f or 2 -4 w e e k s aft er w hi c h ti m e t hi s 
m e di c ati o n s h o ul d b e t a p er e d o v er 4 -6 w e e k s t o t h e 
l o w e st eff e cti v e d o s e I VI G m a y b e u s e d i n c o nj u n cti o n 
wit h c orti c o st er oi d s if a m or e -r a pi d i n cr e a s e i n pl at el et 
c o u nt i s r e q uir e d.
G 3: Pl at el et c o u nt < 5 0/ µ L
H ol d I C Pi b ut m o nit or f or i m pr o v e m e nt; if n ot r e s ol v e d, 
i nt err u pt tr e at m e nt u ntil A E h a s r e v ert e d t o G 1
G 4: Pl at el et c o u nt < 2 5/ µ L
P er m a n e ntl y di s c o nti n u e I C Pi
H e m at ol o g y c o n s ult
Pr e d ni s o n e 1 - 2 m g/ k g/ d ( or al or I V d e p e n di n g o n 
s y m pt o m s)
If w or s e ni n g or n o i m pr o v e m e nt, 1-2 m g/ k g/ d 
pr e d ni s o n e e q ui v al e nt s a n d p er m a n e ntl y di s c o nti n u e 
tr e at m e nt
I VI G us e d wit h c orti c o st er oi d s w h e n a m or e -r a pi d 
i n cr e a s e i n pl at el et c o u nt i s r e q uir e d
If I VI G i s u s e d, t h e d o s e s h o ul d i niti all y b e 1 g/ k g a s a 
o n e -ti m e d o s e. T hi s d o s a g e m a y b e r e p e at e d if 
n e c e s s ar y
If pr e vi o u s tr e at m e nt wit h c orti c o st er oi d s a n d/ or I VI G 
u n s u c c e s sf ul, s u b s e q u e nt tr e at m e nt m a y i n cl u d e 
rit u xi m a b, t hr o m b o p oi eti n r e c e pt or a g o ni st s, or m or e-
p ot e nt i m m u n o s u p pr e s si o n ( Fr o m A m eri c a n S o ci et y of 
H e m at ol o g y g ui d eli n e o n i m m u n e t hr o m b o c yt o p e ni a 9 7; 
c o n s ult f or f urt h er d et ail s)
8. 7 Ac q uire d he m o p hili a
D e ﬁniti o n: Di s or d er c a u s e d b y t h e d e v el o p m e nt of a ut o a nti b o di e s (i n hi bit or s) dir e ct e d a g ai n st pl a s m a c o a g ul ati o n 
f a ct or s 
Di a g n o sti c w or k -u p
F ull bl o o d c o u nt t o a s s e s s pl at el et n u m b er, ﬁbri n o g e n, P T, P T T, I N R; t h e t y pi c al ﬁn di n g i n p ati e nt s wit h a c q uir e d
h e m o p hili a A i s a pr ol o n g e d a cti v at e d P T T wit h a n or m al P T
M RI, C T, a n d ultr a s o n o gr a p h y m a y b e i n di c at e d t o l o c ali z e, q u a ntif y, a n d s eri all y m o nit or t h e l o c ati o n a n d 
r e s p o n s e of bl e e di n g M e di c ati o n r e vi e w t o a s s e s s f or alt er n ati v e c a u s e s
D et er mi n ati o n of B et h e s d a u nit l e v el of i n hi bit or
Gr a di n g
M a n a g e m e nt
G 1: Mil d, 5 % -4 0 % of n or m al f a ct or a cti vit y i n bl o o d, 
0. 0 5 - 0. 4 I U/ m L of w h ol e bl o o d
H ol d I C Pi a n d di s c u s s r e s u m pti o n wit h p ati e nt o nl y aft er 
t a ki n g i nt o a c c o u nt t h e ri s k s a n d b e n eﬁt s
A d mi ni st er 0. 5 -1 m g/ k g/ d pr e d ni s o n e
Tr a n sf u si o n s u p p ort a s r e q uir e d
Tr e at m e nt of bl e e di n g di s or d er s wit h h e m at ol o g y 
c o n s ult
G 2: M o d er at e, 1 % - 5 % of n or m al f a ct or a cti vit y i n bl o o d, 
0. 0 1 - 0. 0 5 I U/ m L of w h ol e bl o o d
H e m at ol o g y c o n s ult
A d mi ni str ati o n of f a ct or r e pl a c e m e nt ( c h oi c e b a s e d o n 
B et h e s d a u nit of tit er)
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 7 /1 5 9
A d mi ni st er 1 m g/ k g/ d pr e d ni s o n e ± rit u xi m a b ( d o s e, 3 7 5 
m g/ m 2 w e e kl y f or 4 w e e k s) a n d/ or c y cl o p h o s p h a mi d e 
( d o s e, 1-2 m g/ k g/ d); c h oi c e of rit u xi m a b v 
c y cl o p h o s p h a mi d e i s p ati e nt s p e ci ﬁc a n d s h o ul d b e 
d o n e wit h a s si st a n c e of h e m at ol o g y c o n s ult; 
pr e d ni s o n e, rit u xi m a b, a n d c y cl o p h o s p h a mi d e s h o ul d 
b e gi v e n f or at l e a st 5 w e e k s
F a ct or s s h o ul d b e pr o vi d e d t o i n cr e a s e l e v el d uri n g 
bl e e di n g e pi s o d e s, wit h c h oi c e of f a ct or b a s e d o n 
pr e s e n c e or a b s e n c e of i n hi bit or
G 3 -4: S e v er e, < 1 % of n or m al f a ct or a cti vit y i n bl o o d, 
< 0. 0 1 I U/ m L of w h ol e bl o o d
P er m a n e ntl y di s c o nti n u e I C Pi
A d mit p ati e nt
H e m at ol o g y c o n s ult
A d mi ni str ati o n of f a ct or r e pl a c e m e nt, c h oi c e b a s e d o n 
B et h e s d a u nit l e v el of i n hi bit or B y p a s si n g a g e nt s m a y 
b e u s e d (f a ct or VII, f a ct or VIII i n hi bit or b y p a s s a cti vit y); 
c a uti o n s h o ul d b e t a k e n i n t h e el d erl y a n d t h o s e wit h 
c or o n ar y art er y di s e a s e
Pr e d ni s o n e 1 - 2 m g/ k g/ d ( or al or I V d e p e n di n g o n 
s y m pt o m s) ± rit u xi m a b ( d o s e, 3 7 5 m g/ m2 w e e kl y f or 4 
w e e k s) a n d/ or c y cl o p h o s p h a mi d e ( d o s e, 1 -2 m g/ k g/ d).
Tr a n sf u si o n s u p p ort a s r e q uir e d f or bl e e di n g
If w or s e ni n g or n o i m pr o v e m e nt a d d c y cl o s p ori n e or 
i m m u n o s u p pr e s si o n/i m m u n o a d s or pti o n
A d diti o n al c o n si d er ati o n s: T h e A m eri c a n H e art A s s o ci ati o n r e q uir e s s p e ci ali st cli ni c al a n d l a b or at or y e x p erti s e . 
C o n s ult a n d/ or tr a n sf er t o a s p e ci ali st c e nt er i s oft e n a p pr o pri at e. If c o n s ult ati o n wit h or tr a n sf er t o a h e m o p hili a 
c e nt er i s n ot i m m e di at el y p o s si bl e, t h e n i n v e sti g ati o n a n d tr e at m e nt s h o ul d b e i niti at e d w hil e a li ai s o n i s b ei n g 
e st a bli s h e d.
All r e c o m m e n d ati o n s ar e e x p ert c o n s e n s u s b a s e d, wit h b e n e ﬁt s o ut w ei g hi n g h ar m s, a n d str e n gt h of 
r e c o m m e n d ati o n s ar e m o d er at e.
A b br e vi ati o n s: A E, a d v er s e e v e nt; A N C, a b s ol ut e n e utr o p hil c o u nt ; A T G, a ntit h y m o c yt e gl o b uli n; C B C, c o m pl et e 
bl o o d c o u nt; C M V, c yt o m e g al o vir u s; C N S, c e ntr al n er v o u s s y st e m; C T, c o m p ut e d t o m o gr a p h y; C X R, c h e st x -r a y; 
DI C, di s s e mi n at e d i ntr a v a s c ul ar c o a g ul ati o n; E B V, E p st ei n -B arr vir u s; E C G, el e ctr o c ar di o gr a m; E R, e xt e n d e d 
r el e a s e; F E, f erriti n; G, Gr a d e ; G PI, gl y c o s yl p h o s p h atid yli n o sit ol; H g b, h e m o gl o bi n; H H V 6, h u m a n h er p e s vir u s 6; HI V, 
h u m a n i m m u n o d efi ci e n c y vir u s; H L A, h u m a n l e u k o c yt e a nti g e n; I C Pi, i m m u n e c h e c k p oi nt i n hi bit or; I N R, i nt er n ati o n al 
n or m ali z e d r ati o; ir A E, i m m u n e -r el at e d a d v er s e e v e nt; I V, i ntr a v e n o u s; I VI G, i ntr a v e n o u s i m m u n o gl o b uli n; L D H, 
l a ct at e d e h y dr o g e n a s e; L L N, l o w er li mit of n or m al; M RI, m a g n eti c r e s o n a n c e i m a gi n g; N S AI D, n o n st er oi d al a nti-
i nﬂa m m at or y dr u g; P B, p eri p h er al bl o o d; P E X, pl a s m a e x- c h a n g e; P N H, p ar o x y s m al n o ct ur n al h e m o gl o bi n uri a; P T, 
pr ot hr o m bi n ti m e; P T T, p arti al t hr o m b o pl a sti n ti m e; R B C, r e d bl o o d c ell c o u nt; T T P, t hr o m b oti c t hr o m b o c yt o p e ni c 
p ur p ur a.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 8 /1 5 9
T a ble A 9
M a n a ge me nt of C ar di o v asc ul ar ir A Es i n P atie nts Tre ate d Wit h I C Pis
9. 0 C ar di o v asc ul ar T o xicities
9. 1 M y oc ar ditis, 
peric ar ditis, arr h yt h mi as, i mp aire d ve ntric ul ar f u ncti o n wit h he art 
f ail ure a n d v asc ulitis
D e ﬁniti o n: Si g n s a n d s y m pt o m s m a y i n cl u d e c h e st p ai n, arr h yt h mi a, p al pit ati o n s, p eri p h er al e d e m a, pr o gr e s si v e or 
a c ut e d y s p n e a, pl e ur al eff u si o n, f ati g u e
Di a g n o sti c w or k -u p
At b a s eli n e
E C G
C o n si d er tr o p o ni n, e s p e ci all y i n p ati e nt tr e at e d wit h c o m bi n ati o n i m m u n e t h er a pi e s U p o n si g n s/ s y m pt o m s 
( c o n si d er c ar di ol o g y c o n s ult)
E C G
Tr o p o ni n
B N P E c h o c ar di o gr a m C X R
A d diti o n al t e sti n g t o b e g ui d e d b y c ar di ol o g y a n d m a y i n cl u d e
Str e s s t e st
C ar di a c c at h eri z ati o n C ar di a c M RI
Gr a di n g
M a n a g e m e nt
G 1: A b n or m al c ar di a c  
 t e sti n g, i n cl u di n g 
a b n or m al E C G
G 2: A b n or m al s cr e e ni n g t e st s wit h mil d s y m pt o m s
G 3: M o d er at el y a b n or m al t e sti n g or s y m pt o m s wit h mil d 
a cti vit y
G 4: M o d er at e t o s e v er e d e c o m p e n s ati o n, I V m e di c ati o n 
or i nt er v e nti o n r e q uir e d, lif e -t hr e at e ni n g c o n diti o n s
All gr a d e s w arr a nt w or k- u p a n d i nt er v e nti o n gi v e n 
p ot e nti al f or c ar di a c c o m pr o mi s e
C o n si d er t h e f oll o wi n g:
F or G 1: H ol d I C Pi
F or G 2, G 3, a n d G 4: P er m a n e ntl y di s c o nti n u e I C Pi
F or G 1 -G 4: Hi g h -d o s e c orti c o st er oi d s ( 1 -2 m g/ k g of 
pr e d ni s o n e) i niti at e d r a pi dl y ( or al or I V d e p e n di n g o n 
s y m pt o m s)
A d mit p ati e nt, c ar di ol o g y c o n s ult ati o n
I m m e di at e tr a n sf er t o a c or o n ar y c ar e u nit f or p ati e nt s 
wit h el e v at e d tr o p o n i n or c o n d u cti o n a b n or m aliti e s
I n p ati e nt s wit h o ut a n i m m e di at e r e s p o n s e t o hi g h-d o s e 
c orti c o st er oi d s, c o n si d er e arl y i n stit uti o n of c ar di a c 
tr a n s pl a nt r ej e cti o n d o s e s of c orti c o st er oi d s 
( m et h yl pr e d ni s ol o n e 1 g e v er y d a y) a n d t h e a d diti o n of 
eit h er m y c o p h e n ol at e, i n ﬂi xi m a b, or a ntit h y m o c yt e 
gl o b uli n
Q u alif yi n g st at e m e nt: Tr e at m e nt r e c o m m e n d ati o n s ar e b a s e d o n a n e c d ot al e vi d e n c e a n d t h e lif e -t hr e at e ni n g 
n at ur e of c ar di o v a s c ul ar c o m pli c ati o n s. T h e a p pr o pri at e n e s s of r e c h all e n gi n g r e m ai n s u n k n o w n. N ot e t h at 
i n ﬂi xi m a b h a s b e e n a s s o ci at e d wit h h e art f ail ur e a n d i s c o ntr ai n di c at e d at hi g h d o s e s i n p ati e nt s wit h m o d er at e-
s e v er e h e art f ail ur e.
9. 2 Ve n o us t hr o m b oe m b olis m
D e ﬁniti o n: A di s or d er c h ar a ct eri z e d b y o c cl u si o n of a v e s s el b y a t hr o m b u s t h at h a s mi gr at e d fr o m a di st al sit e vi a 
t h e bl o o d str e a m. Cli ni c al si g n s a n d s y m pt o m s ar e v ari a bl e a n d m a y i n cl u d e p ai n, s w elli n g, i n cr e a s e d s ki n v ei n 
vi si bilit y, er yt h e m a, a n d c y a n o si s a c c o m p a ni e d b y u n e x pl ai n e d f e v er f or D V T a n d d y s p n e a, pl e uriti c p ai n, c o u g h, 
w h e e zi n g, or h e m o pt y si s f or P E
Di a g n o sti c w or k -u p
E v al u ati o n of si g n s a n d s y m pt o m s of P E or D V T m a y i n cl u d e Cli ni c al pr e di cti o n r ul e t o str atif y p ati e nt s wit h 
s u s p e ct e d v e n o u s t hr o m b o e m b oli s m V e n o u s ultr a s o u n d f or s u s p e ct e d D V T
C T P A f or s u s p e ct e d P E
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9 /1 5 9
C a n al s o c o n si d er D -di m er f or l o w -ri s k p ati e nt s b a s e d o n ri s k str atiﬁc ati o n b y cli ni c al pr e di cti o n r ul e f or D V T/ P E 
w h e n C T or D o p pl er ar e n ot a v ail a bl e or a p pr o pri at e V e ntil ati o n/ p erf u si o n s c a n i s al s o a n o pti o n w h e n C T P A i s n ot 
a p pr o pri at e
C o n si d er ot h er t e sti n g, i n cl u di n g E C G, C X R, B N P a n d tr o p o ni n l e v el s, a n d art eri al bl o o d g a s
Gr a di n g
M a n a g e m e nt
G 1: V e n o u s t hr o m b o si s ( e. g, s u p er ﬁci al t hr o m b o si s)
C o nti n u e I C Pi
W a r m c o m pr e s s
Cli ni c al s ur v eill a n c e
G 2: V e n o u s t hr o m b o si s ( e. g, u n c o m pli c at e d D V T),
m e di c al i nt er v e nti o n i n di c at e d
C o nti n u e I C Pi b a s e d o n b e n efit -ri s k a s s e s s m e nt of
i n di vi d u al p ati e nt
C o n si d er c o n s ult fr o m c ar di ol o g y or ot h er r el e v a nt
s p e ci alti e s
L M W H  i s s u g g e st e d o v er V K A, d a bi g atr a n, ri v ar o x a b a n
a pi x a b a n, or e d o x a b a n f or i niti al a n d l o n g -t er m
tr e at m e nt
I V h e p ari n i s a n a c c e pt a bl e alt er n ati v e f or i niti al u s e,
a n d or al a nti c o a g ul a nt s ar e a c c e pt a bl e f or t h e l o n g t er m
G 3: T hr o m b o si s ( e. g, u n c o m pli c at e d P E [ v e n o u s], 
n o n e m b oli c c ar di a c m ur al [ art eri al] t hr o m b u s), m e di c al 
i nt er v e nti o n i n di c at e d
H ol d I C Pi u ntil A E r e v ert s b a c k t o G 1 or l e s s. If r e v ert s 
t o G 2, u s e b e n efit-ri s k a s s e s s m e nt f or I C Pi c o nti n u ati o n
C o n si d er c o n s ult fr o m c ar di ol o g y or ot h er r el e v a nt 
s p e ci alti e s
L M W H  i s s u g g e st e d o v er V K A, d a bi g atr a n, ri v ar o x a b a n 
a pi x a b a n, or e d o x a b a n f or i niti al a n d l o n g -ter m 
tr e at m e nt
I V h e p ari n i s a n a c c e pt a bl e alt er n ati v e f or i niti al u s e, 
a n d or al a nti c o a g ul a nt s ar e a c c e pt a bl e f or t h e l o n g t er m
G 4: Lif e -t hr e at e ni n g (e. g, P E, c er e br o v a s c ul ar e v e nt, 
art eri al i n s uf ﬁci e n c y), h e m o d y n a mi c or n e ur ol o gi c 
i n st a bilit y, ur g e nt i nter v e nti o n i n di c at e d
P er m a n e ntl y di s c o nti n u e I C Pi
A d mit p ati e nt c o n s ult fr o m c ar di ol o g y or ot h er r el e v a nt 
s p e ci alti e s
R e s pir at or y a n d h e m o d y n a mi c s u p p ort
L M W H  i s s u g g e st e d o v er V K A, d a bi g atr a n, ri v ar o x a b a n, 
a pi x a b a n, or e d o x a b a n f or i niti al a n d l o n g -t er m 
tre at m e nt
I V h e p ari n i s a n a c c e pt a bl e alt er n ati v e f or i niti al u s e, 
a n d or al a nti c o a g ul a nt s ar e a c c e pt a bl e f or t h e l o n g t er m
F urt h er cli ni c al m a n a g e m e nt a s i n di c at e d b a s e d o n 
s y m pt o m s
A d diti o n al c o n si d er ati o n s
W h il e it m a y b e i m p o s si bl e t o d et er mi n e t h e eti ol o g y of t hr o m b o e m b oli c di s e a s e i n p ati e nt s wit h a d v a n c e d c a n c er 
a n d t h e r ol e, if a n y, t h at I C Pi tr e at m e nt pl a y s, it i s r e a s o n a bl e t o p er m a n e ntl y di s c o nti n u e t h e p ot e nti al i n citi n g 
a g e nt s gi v e n t h e s e v erit y a n d lif e -t hr e at e ni n g p ot e nti al of G 4 c o m pli c ati o n s. F or G 3 e v e nt s, I C Pi m u st b e wit h h el d 
a n d cli ni ci a n s ar e t o u s e cli ni c al j u d g m e nt a n d t a k e i nt o a c c o u nt t h e ri s k s a n d b e n e ﬁt s w h e n d e ci di n g w h et h er t o 
r e st art I C Pi tr e at m e nt.
A nti c o a g ul a nt t h er a p y d ur ati o n s h o ul d c o nti n u e f or a mi ni m u m of 9- 1 2 m o nt h s t o i n d e ﬁnit el y i n t h e s etti n g of a cti v e 
c a n c er u nl e s s p ati e nt i s a s y m pt o m ati c, d oi n g w ell, or i n r e mi s si o n.
All r e c o m m e n d ati o n s ar e e x p ert c o n s e n s u s b a s e d, wit h b e n e ﬁt s o ut w ei g hi n g h ar m s, a n d str e n gt h of 
r e c o m m e nd ati o n s ar e m o d er at e.
A b br e vi ati o n s: B N P, br ai n n atri ur eti c p e pti d e; C T, c o m p ut e d t o m o gr a p h y; C T P A, c o m p ut e d t o m o gr a p h y p ul m o n ar y 
a n gi o gr a p h y; C X R, c h e st x -r a y; D V T, d e e p v ei n t hr o m b o si s; E C G, el e ctr o c ar di o gr a m; G, Gr a d e ; I C Pi, i m m u n e 
c h e c k p oi nt i n hi bit or; ir A E, i m m u n e -r el at e d a d v er s e e v e nt; I V, i ntr a v e n o u s; L MW H , l o w-m ol e c ul ar -w ei g ht h e p ari n; 
M RI, m a g n eti c r e s o n a n c e i m a gi n g; P E, p ul m o n ar y e m b oli s m; V K A, vit a mi n K a g o ni st.
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 0 /1 5 9
T a ble A 1 0  
M a n a ge me nt of Oc ul ar ir A Es i n P atie nts Tre ate d Wit h I C Pis
1 0. 0 Oc ul ar T o xicities
C o u n s el all p ati e nt s t o i nf or m t h eir h e alt h c ar e pr o vi d er i m m e di at el y if t h e y e x p eri e n c e a n y of t h e f oll o wi n g o c ul ar 
s y m pt o m s
Bl urr e d vi si o n
C h a n g e i n c ol or vi si o n P h ot o p h o bi a
Di st orti o n
S c ot o m a s
Vi s u al ﬁel d c h a n g e s D o u bl e vi si o n T e n d er n e s s
P ai n wit h e y e m o v e m e nt E y eli d s w elli n g Pr o pt o si s
E v al u ati o n, u n d er t h e g ui d a n c e of o p ht h al m ol o g y
C h e c k vi si o n i n e a c h e y e s e p ar at el y
C ol or vi si o n
R e d r e ﬂe x
P u pil si z e, s h a p e, a n d r e a cti vit y
F u n d o s c o pi c e x a mi n ati o n
I n s p e cti o n of a nt eri or p art of e y e wit h p e nli g ht
Pri or c o n diti o n s
E x cl u d e p ati e nt s wit h hi st or y of a cti v e u v eiti s
Hi st or y of r e c urr e nt u v eiti s r e q uiri n g s y st e mi c i m m u n o s u p pr e s si o n or c o nti n u o u s l o c al t h er a p y
A d diti o n al c o n si d er ati o n s
O c ul ar ir A E s ar e m a n y ti m e s s e e n i n t h e c o nt e xt of ot h er or g a n ir A E s
Hi g h l e v el of cli ni c al s u s pi ci o n a s s y m pt o m s m a y n ot al w a y s b e a s s o ci at e d wit h s e v erit y B e st t o tr e at aft er 
o p ht h al m ol o gi st e y e e x a mi n ati o n
1 0. 1 U veitis/iritis
D e ﬁniti o n: I n ﬂa m m ati o n of t h e mi d d l e l a y er of t h e e y e Di a g n o sti c w or k- u p: a s p er a b o v e
Gr a di n g
M a n a g e m e nt
G 1: A s y m pt o m ati c
C o nti n u e I C Pi
R ef er t o o p ht h al m ol o g y wit hi n 1 w e e k
Arti ﬁci al t e ar s
G 2: M e di c al i nt er v e nti o n r e q uir e d, a nt eri or u v eiti s
H ol d I C Pi t e m p or aril y u ntil aft er o p ht h al m ol o g y c o n s ult
Ur g e nt o p ht h al m ol o g y r ef err al
T o pi c al c orti c o st er oi d s, c y cl o pl e gi c a g e nt s, s y st e mi c 
c orti c o st er oi d s
M a y r e s u m e I C Pi tr e at m e nt o n c e off s y st e mi c 
c orti c o st er oi d s, w hi c h ar e p ur el y i n di c at e d f or o c ul ar 
a d v er s e ef f e ct s or o n c e c orti c o st er oi d s f or ot h er 
c o n c urr e nt s y st e mi c ir A E s ar e r e d u c e d t o ≤1 0 m g; 
c o nti n u e d t o pi c al/ o c ul ar c orti c o st er oi d s ar e p er mitt e d 
w h e n r e s u mi n g t h er a p y t o m a n a g e a n d mi ni mi z e l o c al 
t o xi cit y R e-tr e at aft er r et ur n t o G 1 or l e s s
G 3: P o st eri or or p a n u v eiti s
P er m a n e ntl y di s c o nti n u e I C Pi
Ur g e nt o p ht h al m ol o g y r ef err al.
S y st e mi c c orti c o st er oi d s a n d 
i ntr a vitr e al/ p eri o c ul ar/t o pi c al c orti c o st er oi d s
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 /1 5 9
G 4: 2 0/ 2 0 0 or w or s e
P er m a n e ntl y di s c o nti n u e I C Pi
E m er g e nt o p ht h al m ol o g y r ef err al
S y st e mi c c orti c o st er oi d s (I V pr e d ni s o n e 1- 2 m g/ k g or 
m et h yl pr e d ni s ol o n e 0. 8 -1. 6 m g/ k g) a n d 
i ntr a vitr e al/ p eri o c ul ar/t o pi c al c orti c o st er oi d s p er 
o p ht h al m ol o gi st o pi ni o n
A d diti o n al c o n si d er ati o n s: C o n si d er u s e of i n ﬂi xi m a b or ot h er T N F - α bl o c k er s i n c a s e s t h at ar e s e v er e a n d 
r efr a ct or y t o st a n d ar d tr e at m e nt
1 0. 2 E piscleritis
D e ﬁniti o n: I n ﬂa m m at or y c o n diti o n aff e cti n g t h e e pi s cl er al ti s s u e b et w e e n t h e c o nj u n cti v a a n d t h e s cl er a t h at o c c ur s 
i n t h e a b s e n c e of a n i nf e cti o n Di a g n o sti c w or k- up: A s p er 1 0. 0
Gr a di n g
M a n a g e m e nt
G 1: A s y m pt o m ati c
C o nti n u e I C Pi
R ef er t o o p ht h al m ol o g y wit hi n 1 w e e k
Arti ﬁci al t e ar s
G 2: Vi si o n 2 0/ 4 0 or b ett er
H ol d I C Pi t h er a p y t e m p or aril y u ntil aft er o p ht h al m ol o g y 
c o n s ult
Ur g e nt o p ht h al m ol o g y r ef err al
T o pi c al c orti c o st er oi d s, c y cl o pl e gi c a g e nt s, s y st e mi c 
c orti c o st er oi d s
G 3: S y m pt o m ati c a n d vi si o n w or s e t h a n 2/ 4 0
P er m a n e ntl y di s c o nti n u e I C Pi
Ur g e nt o p ht h al m ol o g y r ef err al.
S y st e mi c c orti c o st er oi d s a n d t o pi c al c orti c o st er oi d s wit h 
c y cl o pl e gi c a g e nt s
G 4: 2 0/ 2 0 0 o r w or s e
P er m a n e ntl y di s c o nti n u e I C Pi
E m er g e nt o p ht h al m ol o g y r ef err al.
S y st e mi c c orti c o st er oi d s a n d t o pi c al c orti c o st er oi d s wit h 
c y cl o pl e gi c a g e nt s
A d diti o n al c o n si d er ati o n s: C o n si d er u s e of i n ﬂi xi m a b or ot h er T N F - α bl o c k er s i n c a s e s t h at ar e s e v er e a n d 
r efr a ct or y t o st a n d ar d tr e at m e nt
1 0. 3 Ble p h aritis
D e ﬁniti o n: I n ﬂa m m ati o n of t h e e y eli d t h at aff e ct s t h e e y el a s h e s or t e ar pr o d u cti o n Di a g n o sti c w or k -u p: A s p er 1 0. 0
Gr a di n g
M a n a g e m e nt
N o f or m al gr a di n g s y st e m
W a r m c o m pr e s s e s a n d l u bri c ati o n dr o p s
C o nti n u e t h er a p y u nl e s s p er si st e nt a n d s eri o u s
All r e c o m m e n d ati o n s ar e e x p ert c o n s e n s u s b a s e d, wit h b e n e ﬁt s o ut w ei g hi n g h ar m s, a n d str e n gt h of 
r e c o m m e n d ati o n s ar e m o d er at e.
A b br e vi ati o n s: I C Pi, i m m u n e c h e c k p oi nt i n hi bit o r; G, Gr a d e ; ir A E, i m m u n e-r el at e d a d v er s e e v e nt; I V, i ntr a v e n o u s, 
T N F, t u m or n e cr o si s f a ct or.
D oc u me nt N o.
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 2 /1 5 9
A p pe n di x 6 A d verse 
E ve nts: 
Defi niti o ns 
a n d Pr oce d ures f or Rec or di n g, 
E v al u ati n g, F oll o w -u p, a n d Re p orti n g
Defi niti o ns
A d verse E ve nt
A n A E is a n y u nt o war d me dical occ urre nce i n a partici pa nt a d mi nistere d a p har mace utical pr o d uct, 
re gar dless of ca usal relati o ns hi p wit h t his treat me nt. T heref ore, a n A E ca n be a ny u nfa v ora ble a n d 
u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g), s ym pt o m, or disease te m p orally 
ass ociate d wit h t he use of a me dici nal pr o d uct, re gar dless if it is c o nsi dere d relate d t o t he me dici nal 
pr o d uct.
F or s ur gical or dia g n ostic pr oce d ures, t he c o n diti o n/ill ness lea di n g t o s uc h a pr oce d ure is 
c o nsi dere d as t he A E r at her t ha n t he pr oce d ure itself.
C o m pare d t o baseli ne ( Scree ni n g or t he W ee k 1, D a y 1 visit), me dical c o n diti o ns t hat d o n ot 
w orse n i n se verity or fre q ue nc y duri n g t he st u d y are defi ne d as baseli ne me dical c o n diti o ns a n d 
are N O T t o be c o nsi dere d as A Es. 
A ll ne wl y  dia g n ose d or w orse ni n g pre -e xisti n g c o n diti o ns (cli nicall y si g nifica nt c ha n ges i n 
fre q ue nc y, a n d/ or i nte nsit y), si g ns, a n d s y m pt o ms o bser ve d fr o m baseli ne ( Scree ni n g or t he Wee k 
1, D a y 1 visit), w het her relate d t o st u d y  i nter ve nti o n or n ot, are t o be re p orte d as A Es.
Pr o gressi o n of t he ca ncer u n der st u d y is n ot c o nsi dere d a n A E.
T he I n vesti gat or is re q uire d t o gra de t he se verit y or t o xicit y  of eac h A E.
I n vesti gat ors will refere nce t he Nati o nal Ca ncer I nstit ute - C o m m o n Ter mi n ol o g y  Criteria f or A Es 
( C T C A E), versi o n 5. 0 ( p u blicati o n date: 2 7 N o v e m ber 2 0 1 7 ), a descri pti ve ter mi n ol o g y that ca n 
be use d f or A E t o xicit y gra de re p orti n g.
A ge neral gra di n g (se verit y/i nte nsit y; hereafter referre d t o as se verity) scale is pr o vi de d at t he 
be gi n ni n g of t he a b o ve refere nce d d oc u me nt, a n d s pecific e ve nt gra des are als o pr o vi de d.
If t he se verit y for a n A E is n ot s pecificall y gra de d b y NCI -C T C A E, t he I n vesti gat or is t o use t he 
ge neral N CI -C T C A E defi niti o ns of Gra de 1 t hr o u g h Gra de 5, usi n g his or her best me dical 
j u dg me nt.
T he 5 ge neral gra des are:
Gra de 1 or Mil d
Gra de 2 or M o derate
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 3 /1 5 9
Gra de 3 or Se vere 
Gra de 4 or L ife-t hreate ni n g 
Gra de 5 or Deat h 
A n y  cli nical A E wit h se verit y of Gra de 4 or 5 m ust als o be re p orte d as a n S A E. H o we ver, a 
la b orat or y ab n or malit y o f Gra de 4, s uc h as a ne mia or ne utr o pe nia, is c o nsi dere d seri o us o nl y  if t he 
c o n diti o n meets o ne of t he seri o us criteria s pecifie d bel o w.
If deat h occ urs, t he pri mar y  ca use of deat h or e ve nt lea di n g t o deat h s h o ul d be rec or de d a n d 
re p orte d as a n S A E. “ Fatal” will be rec or de d as t he o utc o me of t his s pecific e ve nt a n d deat h will 
n ot be rec or de d as se parate e ve nt. O nl y, if n o ca use of deat h ca n be re p orte d (e. g, s u d de n deat h, 
u ne x plai ne d deat h), t he deat h per se mi g ht t he n be re p orte d as a n S A E.
I n vesti gat ors m ust also s yste maticall y assess t he ca usal relati o ns hi p of A Es t o st u d y inter ve nti o n 
(i ncl u di n g a n y ot her n o n st u d y inter ve nti o ns, ra diati o n t hera p y, etc.) usi n g t he f oll o wi n g 
defi niti o ns. Decisi ve fact ors f or t he assess me nt of ca usal relati o ns hi p of a n A E t o t he st u d y 
i nter ve nti o n i ncl u de, b ut ma y  not be li mite d t o, te m p oral relati o ns hi p bet wee n t he A E a n d t he st u d y 
i nter ve nti o n, k n o w n si de effects of st u d y inter ve nti o n, me dical hist or y , c o nc o mita nt me dicati o n, 
c o urse of t he u n derl yi n g disease, a n d st u d y  pr oce d ures.
U nrel ate d: N ot 
reas o na bly relate d t o t he st u d y inter ve nti o n. A E 
c o ul d n ot me dicall y 
( p har mac ol o gically/ cli nicall y) be attri b ute d t o t he st u d y inter ve nti o n u n der st u d y in t his cli nical 
st u d y pr ot oc ol. A reas o na ble alter nati ve e x pla nati o n m ust be a vaila ble.
Rel ate d:
Reas o na bl y 
relate d 
t o 
t he 
st u d y 
inter ve nti o n. 
A E 
c o ul d 
me dicall y 
( p har mac ol o gically/ cli nicall y) be attri b ute d t o t he st u d y inter ve nti o n u n der st u d y in t his cli nical 
st u d y pr ot oc ol. 
A b n or m al L a b or at or y Fi n di n gs a n d Ot her A b n or m al I n vesti g ati o n al Fi n di n gs
A b n or mal la b orat or y  fi n di n gs a n d ot her a b n or mal i n vesti gati o nal fi n di n gs (e. g, o n a n E C G trace) 
s h o ul d n ot be re p orte d as A Es u nless t he y are ass ociate d wit h cli nical si g ns a n d s y m pt o ms, lea d t o 
st u d y inter ve nti o n disc o nti n uati o n or are c o nsi dered ot her wise me dicall y  im p orta nt b y  the 
I n vesti gat or. If a la b orat or y ab n or malit y  fulfills t hese criteria, t he i de ntifie d me dical c o n diti o n (e. g,
a ne mia or i ncrease d A L T) m ust be re p orte d as t he A E rat her t ha n t he a b n or mal val ue itself.
Seri o us A d verse E ve n ts
A n S A E is a n y  u nt o war d me dical occ urre nce t hat at a n y d ose:

Res ults i n deat h

Is life-t hreate ni n g. Life-t hreate ni n g refers t o a n e ve nt i n w hic h t he partici pa nt is at ris k of deat h 
at t he ti me of t he e ve nt, n ot a n e ve nt t hat h y p ot heticall y mi g ht ha ve ca use d deat h if it was m ore 
se vere.

Re q uires i n patie nt h os pitalizati o n or pr ol o n gs a n e xisti n g h os pitalizati o n
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 4 /1 5 9

Res ults i n persiste nt or si g nifica nt disa bilit y  or i nca pacity

Is a c o n ge nital a n o maly or birt h defect

Is ot her wise c o nsi dere d t o be me dicall y  im p orta nt. I mp orta nt me dical e ve nts t hat ma y  not res ult 
i n deat h, be life-t hreate ni n g, or re q uire h os pitalizati o n ma y  be c o nsi dere d as S A Es w he n, base d 
u p o n a p pr o priate me dical j u d g me nt, t he y ma y je o par dize t he partici pa nt or ma y  re q uire me dical 
or s ur gical inter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d a b o ve. E xa m ples of s uc h e ve nts 
i ncl u de aller gic br o nc h os pas m re q uiri n g i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me, 
bl o o d d y scrasias or c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt h os pitalizati o n, o r t he 
de vel o p me nt of dr u g de pe n de nc y  or dr u g a b use.
F or t he p ur p oses of re p orti n g, a n y s us pecte d tra ns missi o n of a n i nfecti o us a ge nt via a st u d y 
i nter ve nti o n is als o c o nsi dere d a n S A E, as s pecifie d bel o w f or re p orti n g S A Es.
E ve nts t h at D o N ot Meet t he Defi niti o n of a n S A E
Electi ve h os pitalizati o ns t o a d mi nister, or t o si m plif y st u d y inter ve nti o n or pr oce d ures (e. g, a n 
o ver ni g ht sta y to facilitate c he m ot hera p y a n d relate d h y drati o n t hera py a p plicati o n) are n ot 
c o nsi dere d S A Es. H o we ver, all e ve nts lea di n g t o u n pla n ne d h os pitalizati o ns or u n pla n ne d 
pr ol o n gati o n of a n electi ve h os pitalizati o n ( i.e, u n desira ble effects of a ny a d mi nistere d treat me nt) 
m ust be d oc u me nte d a n d re p orte d as S A Es.
E ve nts N ot t o Be C o nsi dere d as A Es/ S A Es
Me dical c o n diti o ns prese nt at t he i nitial st u d y visit t hat d o n ot w orse n i n se verity or fre q ue nc y 
d uri n g t he st u d y are defi ne d as baseli ne me dical c o n diti o ns a n d are n ot t o be c o nsi dere d A Es.
A E/ S A Es O bser ve d i n Ass oci ati o n wit h Dise ase Pr o gressi o n
Pr o gressi o n of t he disease/ dis or der bei n g st u die d assesse d b y  
meas ure me nt of lesi o ns o n 
ra di o gra p hs or ot her met h o ds as well as ass ociate d cli nical si g ns or s ym pt o ms (i ncl u di n g 
la b orat or y ab n or malities) s h o ul d n ot be re p orte d as a n ( S) A E, u nless t he patie nt’s ge neral 
c o n diti o n is m ore se vere t ha n e x pecte d f or t he partici pa nt’s c o n diti o n a n d/ or u nless t he o utc o me 
is fatal wit hi n t he a d verse e ve nt re p orti n g peri o d, as defi ne d i n Secti o n 8. 3. 2 ( Met h o d of Detecti n g 
A d verse E ve nts a n d Seri o us A d verse E ve nts).
A d verse E ve nts of S peci al I nterest ( A E SI)
C ate g ories of A E SIs relate d t o M 7 8 2 4 i ncl u de:

I nf usi o n-relate d reacti o ns i ncl u di n g i m me diate h y perse nsiti vit y

I m m u ne-relate d a d verse e ve nts

T G F β i n hi biti o n me diate d s ki n reacti o ns

A ne mia 

Blee di n g a d verse e ve nt s
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
Rec or di n g a n d F oll o w -U p of A E a n d/ or S A E
It is i m p orta nt t hat eac h A E re p ort i ncl u de a descri pti o n of t he e ve nt, its d urati o n ( o nset a n d 
res ol uti o n dates a n d als o o nset a n d res ol uti o n ti mes, w he n it is i m p orta nt t o assess t he ti me of A E 
o nset relati ve t o t he rec or de d st u d y inter ve nti o n a d mi nistrati o n ti me), its se verit y, its ca usal 
relati o ns hi p wit h t he st u d y i nter ve nti o n, a n y ot her p ote ntial ca usal fact ors, a n y treat me nt gi ve n or 
ot her acti o n ta ke n, i ncl u di n g d ose m o dificati o n or disc o nti n uati o n of t he st u d y inter ve nti o n, a n d 
its o utc o me. I n a d diti on, seri o us cases s h o ul d be i de ntifie d, a n d t he a p pr o priate seri o us ness criteria 
d oc u me nte d.
S pecific g ui da nce is i n t he C R F C o m pleti o n a n d M o nit ori n g C o n ve nti o ns pr o vi de d b y  the S p o ns or.
Re p orti n g Seri o us A d verse E ve nts
Seri o us A d verse E ve nts
I n t he e ve nt of a n y ne w S A E occ urri n g d uri n g t he re p orti n g peri o d, t he I n vesti gat or m ust 
i m me diatel y (wit hi n a ma xi m u m of 2 4 H O U R S after bec o mi n g a ware of t he e ve nt) i nf or m t he 
S p o ns or or its desi g nee usi n g t he S A E re p ort f or m i n t he e C R F f oll o wi n g s pecific c o m pleti o n 
i nstr ucti o ns.
Re p orti n g of S A Es via pa per re p ort f or m is re q uire d as a bac k -u p met h o d o nl y  i n t he case of E D C 
fail ure. Na mes, a d dresses, a n d tele p h o ne a n d fa x n u m bers will be i ncl u de d o n t he pa per re p ort 
f or m. All i nf or mati o n re p orte d via pa pe r f or m m ust be tra nscri be d i nt o t he e C R F as s o o n as t he 
s yste m bec o mes a vaila ble.
I n e xce pti o nal circ u msta nces, a n S A E ( or f oll o w- u p i nf or mati o n) m a y  be re p orte d b y  tele p h o ne; 
i n t hese cases, a n S A E re p ort f or m m ust be c o m plete d i m me diatel y t hereafter i n the e C R F . 
Rele va nt pa ges fr o m t he e C R F ma y  be pr o vi de d i n parallel (e. g, me dical hist or y , c o nc o mita nt 
dr u gs). A d diti o nal d oc u me nts m a y  be pr o vi de d b y  the I n vesti gat or, if a vaila ble (e. g, la b orat or y 
res ults, h os pital re p ort, a ut o ps y re p ort). 
T he I n vesti gator m ust 
res p o n d t o a n y re q uest f or f oll o w- u p i nf or mati o n (e. g, a d diti o nal 
i nf or mati o n, o utc o me, fi nal e val uati o n, ot her rec or ds w here nee de d) or t o a n y questi o n t he 
S p o ns or/ desi g nee m a y  h ave o n t he A E wit hi n t he sa me ti meli nes as t h ose n ote d a b o ve f or i nitial 
re p orts. T his is necessar y  to e ns ure pr o m pt assess me nt of t he e ve nt b y  the S p o ns or or desi g nee a n d 
(as a p plica ble) t o all o w t he S p o ns or t o meet strict re g ulat or y ti meli nes ass ociate d wit h e x pe dite d 
safety re p orti n g o bli gati o ns.
Re q uests f or f oll o w - u p will us uall y  be ma de via t he res p o nsi ble M o nit or, alt h o u g h i n e xce pti o nal 
circ u msta nces t he dr u g safety de part me nt m a y  co ntact t he I n vesti gat or directl y  to o btai n f urt her 
i nf or mati o n or t o disc uss t he e ve nt.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
A p pe n di x 7
Cli nic al L a b or at or y Tests
T a ble 1 6
Pr ot oc ol -Re q uire d Cli nic al L a b or at or y Assess me nts
L a b or at or y  
A s s e s s m e nt s
a
P ar a m et er s
H e m at ol o g y b
Pl at el et C o u nt
R B C C o u nt
H e m o gl o bi n
H e m at o crit
R B C I n di c e s :

M C V

M C H

M C H C

R D W

%r eti c ul o c yt e s 
W B C C o u nt wit h Diff er e nti al :

n e utr o p hil s ( A N C)

l y m p h o c yt e s ( a b s ol ut e c o u nt)

m o n o c yt e s

e o si n o p hil s

b a s o p hil s
H e m o st a s e ol o g y
Pr ot hr o m bi n ti m e
I N R
a P T T
F ull Cli ni c al 
C h e mi str y 
P a n el A b
Li v er 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 , 
G G T, t ot al a n d 
i n dir e ct/ dir e ct bilir u bi n, 
al b u mi n, t ot al pr ot ei n, 
a n d cr e ati n e ki n a s e
S er u m El e ctr ol yt e s:
s o di u m p ot a s si u m , 
c al ci u m, m a g n e si u m, 
c hl ori d e, p h o s p h or u s/ 
p h o s p h at e s
R e n al P a n el : B U N/t ot al 
ur e a, cr e ati ni n e, 
e sti m at e d G F R, uri c a ci d
P a n cr e ati c P a n el :
a m yl a s e, li p a s e
Gl u c o s e
F ull Cli ni c al 
C h e mi str y 
P a n el B c
Ir o n P a n el: TI B C a n d/ or 
tr a n sf erri n, ir o n, f erriti n, 
s er u m f ol at e/ B 1 2
T S T , Q u a nti F E R O N-
T B -G ol d, or T -S P O T
(if p o siti v e hi st or y of 
t u b er c ul o si s 
e x p o s ur e)
d
Vir ol o g y : H B V a n d H C V 
s er ol o g y (r e p e at a s p er 
S e cti o n  1. 3 if p arti ci p a nt 
wit h i nf e cti o n hi st or y)
C R P
C or e C h e mi str y
Li v er 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, 
G G T, t ot al a n d 
i n dir e ct/ dir e ct bilir u bi n, 
al b u mi n, t ot al pr ot ei n, 
a n d cr e ati n e ki n a s e
S er u m El e ctr ol yt e s : 
s o di u m, p ot a s si u m, 
c al ci u m, m a g n e si u m, 
c hl ori d e, p h o s p h or u s/ 
p h o s p h at e s
R e n al P a n el : B U N/t ot al 
ur e a, cr e ati ni n e, 
e sti m at e d G F R, uri c a ci d
Gl u c o s e
T h yr oi d P a n el

T 4 , T S H
R o uti n e 
Uri n al y si s e

S p e cifi c gr a vit y , p h y si c al a p p e ar a n c e, c ol or

p H, gl u c o s e, pr ot ei n, bl o o d, k et o n e s, bilir u bi n, ur o bili n o g e n, nitrit e, l e u k o c yt e e st er a s e b y 
di p sti c k

Mi cr o s c o pi c e x a mi n ati o n
Ot h er S cr e e ni n g 
T e st s

F olli cl e - sti m ul ati n g h or m o n e a n d e str a di ol ( a s n e e d e d i n w o m e n of n o n- c hil d b e ari n g p ot e nti al 
o nl y )

S er u m o r hi g hl y s e n siti v e uri n e β- h C G pr e g n a n c y t e st ( a s n e e d e d f or w o m e n of c hil d b e ari n g 
p ot e nti al) b . 
A L T = al a ni n e a mi n otr a n sf er a s e ; A N C = a b s ol ut e n e utr o p hil c o u nt; a P T T = a cti v at e d p arti al t hr o m b o pl a sti n ti m e;
A S T = a s p art at e a mi n otr a n sf er a s e ; β-h C G = b et a -h u m a n c h ori o ni c g o n a d otr o pi n; B U N = bl o o d ur e a nitr o g e n ;
C R P = C- r e a cti v e pr ot ei n; G F R = gl o m er ul ar filtr ati o n r at e; G G T = g a m m a -gl ut a m yltr a n sf er a s 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 N R = i nt er n ati o n al n or m ali z e d r ati o; M C H = m e a n c o r p u s c ul ar h e m o gl o bi n; M C H C
= m e a n 
c or p u s c ul ar h e m o gl o bi n c o n c e ntr ati o n ; M C V
= m e a n c or p u s c ul ar v ol u m e;
R B C = r e d bl o o d c ell; R D W = r e d c ell 
di stri b uti o n wi dt h; T 4 = fr e e t h yr o xi n e; TI B C = t ot al ir o n-bi n di n g c a p a cit y; T S H = t h yr oi d-sti m ul ati n g h or m o n e ;
T S T = t u b er c uli n s ki n t e st; WB C = w hit e bl o o d c ell .
a
P erf or m e d a s i n di c at e d i n S e cti o n  1. 3 ( S c h e d ul e of A cti viti e s).
b 
S a m pl e s m u st b e dr a w n a n d r e s ult s f or c or e c h e mi str y, h e m at ol o g y, a n d pr e g n a n c y t e st r e vi e w e d pri or t o d o s e 
a d mi ni str ati o n.
c
P erf or m e d at S cr e e ni n g o nl y.
d
Di s c u s s wit h M e di c al M o nit or if a n ot h er t e st n ot li st e d i s st a n d ar d of c ar e f or y o ur i n stit uti o n .
e
R o uti n e uri n al y si s p erf or m e d at S cr e e ni n g a n d a s cli ni c all y i n di c at e d t h er e aft er.
D oc u me nt N o.
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 7 /1 5 9
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 8 /1 5 9
A p pe n di x 9
Pr ot oc ol A me n d me nt 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. 
Pr ot oc ol Versi o n 3. 1 ( 0 6 M a y 2 0 2 0)
O ver all R ati o n ale f or t he A me n d me nt
T he pri mar y p ur p ose of t his re gi o n-s pecific a me n d me nt is t o u p date t he Be nefit/ Ris k assess me nt 
wit h a d diti o nal i nf or mati o n o n t he
 assa y f or c o u ntries i n t he E ur o pea n U ni o n.
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
D o c u m e nt H e a d er a n d 
t hr o u g h o ut d o c u m e nt
C orr e ct e d s p elli n g of bi ntr af u s p a n d 
c orr e ct e d ot h er t y p o gr a p hi c al a n d 
f or m atti n g i s s u e s 
A d mi ni str ati v e u p d at e
2. 3   B e n efit/ Ri s k A s s e s s m e nt
Pr ot oc ol Versi o n 3. 0 ( 1 0 Fe br u ar y 2 0 2 0)
T his a me n d me nt is s u bsta ntial base d o n t he criteria i n Article 1 0(a) of Directi ve 2 0 0 1/ 2 0/ E C of 
t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n.
O ver all R ati o n ale f or t he A me n d me nt
T he pri mar y  pur p ose of t his gl o bal a me n d me nt is t o c ha n ge t he desi g n t o a n a da pti ve P hase III 
trial wit h sa m ple size a dj ust me nts base d o n pres pecifie d decisi o n r ules at t he first i nteri m a nal ys is
as e val uate d b y  the I n de pe n de nt Data M o nit ori n g C o m mittee , in de pe n de nt of t he st u d y tea m. I n 
a d diti o n, e n d p oi nts were c ha n ge d a n d pre me dicati o n f or i nf usi o n -relate d reacti o n was c ha n ge d t o 
o pti o nal. T he ke y  c ha n ges are liste d bel o w.
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
Titl e p a g e
St u d y titl e w a s r e vi s e d
T o r efl e ct t h e c h a n g e t o a n a d a pti v e 
st u d y d e si g n
Titl e p a g e
A m e n d m e nt n u m b er a d d e d
A d mi ni str ati v e u p d at e
Titl e p a g e
St u d y p h a s e a d d e d
A d mi ni str ati v e u p d at e
Titl e p a g e
St u d y p h a s e c h a n g e d fr o m II t o III
A d mi ni str ati v e u p d at e
Titl e p a g e
S p o n s or n a m e a n d l e g al r e gi st er e d 
a d dr e s s
A d mi ni str ati v e u p d at e
Titl e p a g e
Pr ot o c ol v er si o n c h a n g e d
A d mi ni str ati v e u p d at e
Titl e p a g e
R e pl a c e s v er si o n a d d e d
A d mi ni str ati v e u p d at e
Titl e p a g e
A p pr o v al d at e a d d e d
A d mi ni str ati v e u p d at e
1. 1 S y n o p si s
1. 2 S c h e m a,
2 I ntr o d u cti o n
3 O bj e cti v e s a n d E n d p oi nt s
4 St u d y D e si g n
C h a n g e d st u d y d e si g n fr o m P h a s e 
II t o a n a d a pti v e P h a s e III d e si g n 
wit h a d a pt ati o n r ul e b a s e d o n O R
T h e s e c h a n g e s ar e t o all o w s a m pl e 
si z e a dj u st m e nt b a s e d o n pr e d efi n e d 
crit eri o n a n d a d e q u at el y p o w er e d 
st u d y f or d u al pri m ar y e n d p oi nt s P F S 
a n d O S .
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
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
1. 2 S c h e m a
N e w fi g ur e w a s a d d e d f or s c h e m a 
N e w fi g ur e w a s a d d e d f or s c h e m a t o 
r efl e ct t h e n e w st u d y d e si g n.
1. 3 S c h e d ul e of A cti viti e s
T a bl e 1
Pr etr e at m e nt a n d M 7 8 2 4 dr u g 
a d mi ni str ati o n
O pti o n al w a s a d d e d f or 
pr e m e di c ati o n
T o s u b st a nti at e t h at pr e m e di c ati o n i s 
o pti o n al
1. 3 S c h e d ul e of A cti viti e s
T a bl e 1, T a bl e 2, T a bl e 3, a n d 
T a bl e 4
R e vi s e d s c h e d ul e of a cti viti e s f or 
h e m at ol o g y a n d h e m o st a s e ol o g y, 
c or e s er u m c h e mi str y, f ull s er u m 
c h e mi str y p a n el
T e xt i s m o difi e d f or r e q uir e m e nt s of 
s a m pl e c oll e cti o n pri or t o d o si n g a n d 
d el et e d t e xt o n t h e n e e d t o h a v e t h e 
r e s ult s r e vi e w e d wit hi n 3 d a y s pri or t o 
d o si n g
1. 3 S c h e d ul e of A cti viti e s
T a bl e 1, T a bl e 3, a n d T a bl e 4,
P R O q u e sti o n n air e s
Fr o m: If n e c e s s ar y, p arti ci p a nt s 
m a y c o m pl et e t h e P R O 
q u e sti o n n air e s o n a p a p er f or m, 
w hi c h will b e tr a n s cri b e d t o t h e 
el e ctr o ni c t a bl et b y sit e st aff
T o: If n e c e s s ar y, p arti ci p a nt s m a y 
c o m pl et e t h e P R O q u e sti o n n air e s 
o n a p a p er C R F ( e. g., if a n 
el e ctr o ni c t a bl et or sit e p a d i s n ot 
a v ail a bl e ), w hi c h will b e tr a n s cri b e d 
t o t h e el e ctr o ni c t a bl et b y t h e sit e 
st aff
R e vi s e d t e xt i s u p d at e d f or cl arit y a n d 
c o n si st e n c y.
2. 3 B e n e fit/ Ri s k a s s e s s m e nt
R ati o n al e w a s pr o vi d e d f or t h e 
c h a n g e i n st u d y d e si g n b a s e d o n 
f e e d b a c k fr o m h e alt h a ut h oriti e s
1. 1 S y n o p si s
2 I ntr o d u cti o n
3 O bj e cti v e s a n d E n d p oi nt s
4 St u d y D e si g n
R e vi s e d P ri m ar y E n d p oi nt s fr o m 
P F S a n d O R t o P F S a n d O S
B a s e d o n h e alt h a ut h orit y 
r e c o m m e n d ati o n. 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
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
4. 2. 3 O p e n -L a b el D e si g n
A d diti o n of t e xt: A c c e s s t o 
a g gr e g at e d a n al y s e s p er tr e at m e nt 
ar m will b e r e stri ct e d t o I D M C a n d 
Fir e w all T e a m a s p er 
c orr e s p o n di n g c h art er s.
T o pr e s er v e d at a i nt e grit y
4. 2. 6 A d a pti v e P h a s e III 
D e si g n
A d d e d t e xt t o cl arif y c h a n g e s o n 
t h e s t u d y d e si g n
A d d e d t e xt t o cl arif y c h a n g e s o n t h e 
st u d y d e si g n a n d a d e q u at el y p o w er e d 
st u d y f or d u al pri m ar y e n d p oi nt s P F S 
a n d O S .
4. 4 E n d of St u d y D efi niti o n  
R e vi s e d d efi niti o n of e n d of s t u d y
T e xt i s u p d at e d f or c o n si st e n c y wit h 
c urr e nt S p o n s or st a n d ar d
5. 2 E x cl u si o n Crit eri a
E x cl u si o n crit eri a # 4 w a s m o difi e d: 
Fr o m: T h e s e i m a gi n g s c a n s s h o ul d 
b ot h b e o bt ai n e d at l e a st 4 w e e k s 
a p art a n d s h o w n o e vi d e n c e of 
i ntr a cr a ni al pr e s s ur e.
T o: T h e s e i m a gi n g s c a n s s h o ul d 
b ot h b e o bt ai n e d at l e a st 2 w e e k s 
a p art a n d s h o w n o e vi d e n c e of 
i ntr a cr a ni al pr e s s ur e.
T e xt i s u p d at e d t o s u b st a nti at e t h e 
d e si g n
5. 2 E x cl u si o n Crit eri a
U p d at e d Bl e e di n g l a n g u a g e 
A d diti o n of n e w l a n g u a g e a s p er 
f e e d b a c k fr o m I D M C 
6. 3. 1 St u d y I nt er v e nti o n 
A s si g n m e nt
I V R S c h a n g e d t o I WR S
A s p er t h e n e w i nt er v e nti o n 
a s si g n m e nt m et h o d
6. 8. 1 I nf u si o n -r el at e d 
R e a cti o n s I n cl u di n g I m m e di at e 
H y p er s e n siti vit y
U p d at e d pr e m e di c ati o n 
r e q uir e m e nt s
T o s u b st a nti at e t h at pr e m e di c ati o n i s 
o pti o n al
6. 8. 4 A n e mi a
T a bl e 1 0 E v al u ati o n G ui d a n c e of 
S u s p e ct e d Tr e at m e nt -r el at e d 
A n e mi a A d v er s e E v e nt s i s r e vi s e d
B ett er u n d er st a n d a bl e a n d m or e 
u s ef ul f or cli ni c al pr a cti c e
6. 8. 5 M a n a g e m e nt of Bl e e di n g
E v e nt s
A d diti o n of t e xt: L o w gr a d e m u c o s al 
N e w t e xt f or m a n a g e m e nt of Gr a d e 2 
n o n -t u m or bl e e di n g
7. 2 P arti ci p a nt 
Di s c o nti n u ati o n/ Wi t h dr a w al 
fr o m t h e St u d y
8. 2 S af et y A s s e s s m e nt s a n d 
Pr o c e d ur e s
D el eti o n of t e xt
U p d at e d l a n g u a g e a s p er n e w 
t e m pl at e
8. 3. 5 Pr e g n a n c y
A d diti o n of n e w t e xt
U p d at e d l a n g u a g e a s p er n e w 
t e m pl at e.
9. 3 P o p ul ati o n s f or A n al y s e s
Pri m ar y a n al y si s p o p ul ati o n r e vi s e d 
t o f ull a n al y si s s et, w hi c h i n cl u d e s 
all p arti ci p a nt s r a n d o mi z e d 
a c c or di n g t o t h e i nt e nti o n t o tr e at 
(I T T) pri n ci pl e
T o b e c o m pli a nt wit h h e alt h a ut h orit y 
f e e d b a c k a n d ali g n wit h n e w st u d y 
d e si g n
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
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
9. 4 . 1 Effi c a c y A n al y s e s
R e vi si o n of t e xt t o ali g n w it h 
m o difi c ati o n of st u d y d e si g n
T h e s e c h a n g e s ar e t o all o w s a m pl e 
si z e a dj u st m e nt b a s e d o n pr e d efi n e d 
crit eri o n a n d a d e q u at el y p o w er e d 
st u d y f or d u al pri m ar y e n d p oi nt s P F S 
a n d O S .
1 0 R ef er e n c e s
A d diti o n of r ef er e n c e “ C h e n C, 
A n d er s o n K, M e hr otr a D V, et a l. A 
2- i n- 1 a d a pti v e p h a s e 2/ 3 d e si g n 
f or e x p e dit e d o n c ol o g y dr u g 
d e v el o p m e nt. C o nt e m p Cli n Tri al s. 
2 0 1 8; 6 4: 2 3 8 -4 2.
“ Rit c hi e G, G a s p er H, M a n J, et al. 
D efi ni n g t h e m o st a p pr o pri at e 
pri m ar y e n d p oi nt i n p h a s e 2 tri al s 
of i m m u n e c h e c k p oi nt i n hi bit or s f or 
a d v a n c e d s oli d c a n c er s. J A M A 
O n c ol. 2 0 1 8; 4( 4): 5 2 2 -2 8.”
“ Yi ni n g Y e, Ai Li, Li n g y u n Li u a n d 
Bi n Y a o. A gr o u p s e q u e nti al H ol m 
pr o c e d ur e wit h
m ulti pl e pri m ar y e n d p oi nt s. 
St ati sti c s i n M e di ci n e, 2 0 1 2. 
1 0. 1 0 0 2/ si m. 5 7 0 0”
D el eti o n of r ef er e n c e “ H o m m el G 1, 
Br et z F, M a ur er W . P o w erf ul s h ort-
c ut s f or m ulti pl e t e sti n g pr o c e d ur e s 
wit h s p e ci al r ef er e n c e t o 
g at e k e e pi n g str at e gi e s. St at M e d. 
2 0 0 7 S e p 3 0; 2 6( 2 2): 4 0 6 3 -7 3.”
R ef er e n c e s f or t h e F W E R c o ntr ol i n 
t h e n e w a d a pti v e p h a s e III d e si g n
A p p e n di x 5 T h e 
R e c o m m e n d ati o n s f or ir A E 
M a n a g e m e nt
i n A c c or d a n c e 
wit h t h e J oi nt A m eri c a n 
S o ci et y of Cli ni c al O n c ol o g y 
Cli ni c al Pr a cti c e G ui d eli n e s 
a n d N ati o n al C o m pr e h e n si v e 
C a n c er N et w or k
R e vi s e d t h e r e c o m m e n d ati o n s f or 
i m m u n e-r el at e d a d v er s e e v e nt s 
(ir A E) m a n a g e m e nt
R e vi s e d t o u p d at e ir A E m a n a g e m e nt 
g ui d eli n e s a n d F D A r e c o m m e n d ati o n s.  
I n str u cti o n s i n cl u d e t h e r e q uir e m e nt 
t h at tr e at m e nt m u st b e p er m a n e ntl y 
di s c o nti n u e d f or c ert ai n Gr a d e 4 ir A E 
t o xi citi e s. 
T hr o u g h o ut
Mi n or e dit ori al a n d d o c u m e nt 
f or m attin g r e vi si o n s
Mi n or t e xt r e vi si o n s ar e m a d e f or 
cl arit y, r e a d a bilit y, c o n si st e n c y of 
l a n g u a g e a cr o s s t h e d e v el o p m e nt 
pr o gr a m, a n d c o m pli a n c e wit h c urr e nt 
S p o n s or g ui d eli n e s.
Pr ot oc ol Versi o n 2. 1 ( 0 9 Se pte m ber 2 0 1 9)
T his a me n d me nt is n o n s u bsta ntial base d o n t he criteria i n Article 1 0(a) of Directi ve 2 0 0 1/ 2 0/ E C 
of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n .
O verall Rati o nale f or t he A me n d me nt
T he pr ot oc ol was a me n de d base d o n fee d bac k fr o m t he re g ulat or y age ncies of c o u ntries i n t he 
E ur o pea n U ni o n partici pati n g i n t he V H P.
D oc u me nt N o. 
O bject N o.
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9
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
Titl e p a g e
Pr ot o c ol v er si o n n u m b er i s 
u p d at e d 
T o r efl e ct c urr e nt a m e n d m e nt
S e cti o n 4. 2. 2
P e m br oli z u m a b a s 
C o m p ar at or
T h e r e s ult s fr o m K N-0 4 2 ar e 
d el et e d. I n a d diti o n, it i s s p e cifi e d 
t h at f or p e m br oli z u m a b i n p ati e nt s 
wit h St a g e 3 N S C L C, t h e E M A 
a s s e s s m e nt i s still o n g oi n g.
T o cl arif y t h e a p pr o v al st at u s of 
p e m br oli z u m a b i n E U.
S e cti o n 6. 9. 5
M a n a g e m e nt of Bl e e di n g 
E v e nt s
“F or Gr a d e 2 n o n -t u m or bl e e di n g, 
s e e S e cti o n  6. 8. 2 f or g e n er al 
m a n a g e m e nt of Gr a d e 2 A D R s. ” I s 
a d d e d
T o cl arif y t h e m a n a g e m e nt f or Gr a d e 2 
n o n -t u m or bl e e di n g e v e nt s . 
S e cti o n 9. 4. 1
Effi c a c y A n al y s e s
“I nt e nti o n-t o-Tr e at ( mI T T) ” i s 
c h a n g e d t o “ mI T T”
T hi s s h o ul d b e m o difi e d I nt e nti o n-t o-Tr e at , 
a s mI T T i s d efi n e d i n S e cti o n  4. 1 , 
t h er ef or e “ mI T T” i s u s e d.
A p p e n di x 9 1 0 , 1 1 , 1 2
Pr ot o c ol v er si o n n u m b er a n d 
a m e n d m e nt hi st or y i s u p d at e d
T o r efl e ct c urr e nt a m e n d m e nt
Pr ot oc ol Versi o n 2. 0 ( 0 8 J ul y 2 0 1 9)
T his a me n d me nt is s u bsta ntial base d o n t he criteria i n Article 1 0(a) of Directi ve 2 0 0 1/ 2 0/ E C of 
t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n.
O verall Rati o nale f or t he A me n d me nt
T he pr ot oc ol was a me n de d t o i nc or p orate fee d bac k o n i m m u ne-relate d a d verse e ve nt ma na ge me nt 
g ui deli nes fr o m t he F D A.
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
Titl e P a g e,
2 I ntr o d u cti o n,
4. 3 J u stifi c ati o n f or D o s e,
5. 1 I n cl u si o n Crit eri a,
8. 3. 4 R e g ul at or y R e p orti n g 
R e q uir e m e nt s f or S eri o u s 
A d v er s e E v e nt s,
A p p e n di x 2 St u d y 
G o v er n a n c e,
A p p e n di x 3 C o ntr a c e pti o n,
A p p e n di x 5 T h e 
R e c o m m e n d ati o n s f or ir A E 
M a n a g e m e nt
T e xt r e vi s e d t o cl arif y pr o c e d ur e s 
f or sit e s b a s e d i n J a p a n, p er 
Pr ot o c ol A m e n d m e nt 1. 1
T o b e c o m pli a nt wit h J a p a n r e g ul at or y 
r e q uir e m e nt a n d l o c al l a w
1. 3, S c h e d ul e of A cti viti e s ,
3 O bj e cti v e s a n d E n d p oi nt s,
8. 1 0 P ati e nt -R e p ort e d 
O ut c o m e s
1. 3, S c h e d ul e of A cti viti e s
1. 3, S c h e d ul e of A cti viti e s; 
D oc u me nt N o. 
O bject N o. 
C CI
C CI C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 3 /1 5 9
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
4. 2. 2 P e m br oli z u m a b a s 
C o m p ar at or
A d d e d m o st r e c e nt a p pr o v al f or 
P e m br oli z u m a b t h er a p y
T o i n cl u d e m o st r e c e nt d at a
4. 3 J u stifi c ati o n f or D o s e
A m e n d e d P h a s e I s af et y, 
, a n d pr eli mi n ar y effi c a c y 
a n al y si s i nf or m ati o n
T o i n cl u d e m o st r e c e nt d at a
5. 1 I n cl u si o n Crit eri a,
A p p e n di x 3
R e vi s e d crit eri a f or c o ntr a c e pti o n
T e xt i s u p d at e d f or c o n si st e n c y wit h 
c urr e nt S p o n s or st a n d ar d s a n d 
c o n si st e n c y a cr o s s t h e d e v el o p m e nt 
pr o gr a m.
5. 2 E x cl u si o n Crit eri a
E x cl u si o n Crit eri o n 1 w a s u p d at e d 
t o cl arif y d et ail s of m ol e c ul ar 
alt er ati o n s
E x cl u si o n Crit eri o n 7 w a s m o difi e d 
t o cl arif y e x cl u d e d h y p er s e n siti vit y 
r e a cti o n s. 
E x cl u si o n Crit eri o n 1 1 w a s 
u p d at e d t o e x cl u d e m aj or bl e e di n g 
e v e nt s
E x cl u si o n Crit eri o n 1 7 u p d at e d 
p arti ci p a nt s c a n n ot b e e nr oll e d if 
p arti ci p at e d i n a n ot h er cli ni c al 
st u d y wit hi n 4 w e e k s of fir st d o s e
T o cl arif y a n d pr o vi d e f urt h er i nf or m ati o n
T e xt i s u p d at e d i n li n e wit h ot h er st u d y 
r e q uir e m e nt s.
T hi s c h a n g e i s t o c o m pl et e t h e e x cl u si o n 
crit eri o n b y i n cl u di n g e x ci pi e nt s i n 
i n v e sti g ati o n al pr o d u ct ( M 7 8 2 4 or 
p e m br oli z u m a b).
T o e x cl u d e p arti ci p a nt s wit h hi st or y of 
bl e e di n g di at h e s e s or r e c e nt m aj or 
bl e e di n g e v e nt s
T o ali g n wit h M 7 8 2 4 pr o gr a m
5. 4 S cr e e n F ail ur e s
A d d e d t e xt t o s p e cif y c o n diti o n s 
w hi c h a p arti ci p a nt c a n b e 
r e s cr e e n e d
T o cl arif y r e -s cr e e ni n g pr o c e d ur e s
6. 3. 1 St u d y I nt er v e nti o n 
A s si g n m e nt
R e m o v e d r ef er e n c e t o I W R S
T o cl arif y st u d y will u s e I V R S
6. 4 St u d y I nt er v e nti o n 
C o m pli a n c e
A m e n d e d t e xt o n n o n a d h er e n c e
T o cl arif y crit eri o n f or n o n a d h er e n c e t o 
st u d y tr e at m e nt
6. 5. 2 Pr o hi bit e d M e di ci n e s, 
A p p e n di x 4
A d d e d t e xt cl arif yi n g u s e of 
tr a diti o n al C hi n e s e m e di ci n e s a n d 
a li st of pr o hi bit e d m e di ci n e s. 
T hi s c h a n g e i s t o i n di c at e tr a diti o n al 
C hi n e s e m e di ci n e s wit h a nti c a n c er 
pr o p erti e s ar e pr o hi bit e d. 
6. 6 D o s e S el e cti o n a n d 
M o difi c ati o n
A d d e d t e xt r e g ar di n g d o s e d el a y 
b e y o n d tr e at m e nt wi n d o w
T o cl arif y d o s e c a n n ot b e d el a y e d b e y o n d 
tr e at m e nt wi n d o w a n d s h o ul d b e s ki p p e d if 
mi s s e d
6. 8. 2 I m m u n e -r el at e d A d v er s e 
E v e nt s
A d d e d t e xt r e g ar di n g Gr a d e 4 
e v e nt s r e q uiri n g p er m a n e nt 
tr e at m e nt di s c o nti n u ati o n
T hi s c h a n g e i s m a d e f or c o n si st e n c y wit h 
c urr e nt ri s k i nf or m ati o n.
6. 8. 3 P ot e nti al 
T G F β- m e di at e d S ki n A d v er s e 
E v e nt s
U p d at e d t e xt f or m a n a g e m e nt of 
p ot e nti al T G F β- m e di at e d s ki n 
e v e nt s
T o u p d at e i n li n e wit h s ki n t o xi cit y 
g ui d eli n e s
6. 8. 5 M a n a g e m e nt of 
Bl e e di n g E v e nt s
A d d e d t e xt t o d e s cri b e 
m a n a g e m e nt of bl e e di n g e v e nt s
R e vi s e d t o u p d at e ir A E m a n a g e m e nt 
g ui d eli n e s a n d F D A r e c o m m e n d ati o n s.  
I n str u cti o n s i n cl u d e t h e r e q uir e m e nt t h at 
tr e at m e nt m u st b e p er m a n e ntl y 
di s c o nti n u e d f or c ert ai n Gr a d e 4 ir A E 
t o xi citi e s.
6. 9. 1. 2 P ot e nti al Ri s k s
A d d e d t e xt t o d e s cri b e m u c o s al 
T hi s c h a n g e i s m a d e f or c o n si st e n c y wit h 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 4 /1 5 9
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
bl e e di n g e v e nt s
c urr e nt ri s k i nf or m ati o n.
6. 9. 2 A d v er s e Dr u g R e a cti o n s 
R e q uiri n g Tr e at m e nt 
Di s c o nti n u ati o n
A d d e d t e xt t o d e s cri b e 
m a n a g e m e nt of bl e e di n g e v e nt s
T hi s c h a n g e i s m a d e f or c o n si st e n c y wit h 
c urr e nt ri s k i nf or m ati o n.
6. 9. 2 A d v er s e Dr u g R e a cti o n s 
R e q uiri n g Tr e at m e nt 
Di s c o nti n u ati o n
I n cl u d e d m a n a g e m e nt of bl e e di n g 
e v e nt s
T o pr o vi d e ri s k m a n a g e m e nt f or bl e e di n g 
e v e nt s.
8. 1 Effi c a c y A s s e s s m e nt s a n d 
Pr o c e d ur e s
A d d e d t e xt t o d e s cri b e all o w a n c e s 
f or C T s c a n
T o cl arif y pr o c e d ur e s f or C T s c a n
9. 3 P o p ul ati o n s f or A n al y s e s
A p p e n di x 5 T h e 
R e c o m m e n d ati o n s f or ir A E 
M a n a g e m e nt
A p p e n di x 6
M o difi e d n o n s eri o u s A E SI 
r e p orti n g
Di s c o nti n u e d e x p e dit e d r e p orti n g of 
n o n s eri o u s A E SI s
T hr o u g h o ut
Mi n or e dit ori al a n d d o c u m e nt 
f or m atti n g r e vi si o n s
Mi n or t e xt r e vi si o n s ar e m a d e f or cl arit y, 
r e a d a bilit y, c o n si st e n c y of l a n g u a g e a cr o s s 
t h e d e v el o p m e nt pr o gr a m, a n d c o m pli a n c e 
wit h c urr e nt S p o n s or g ui d eli n e s.
Pr ot oc ol Versi o n 1. 3 ( 0 1 Se pte m ber 2 0 1 8)
O verall Rati o nale f or t he A me n d me nt
T he pr ot oc ol was a me n de d f or c o m plia nce wit h l ocal re q uire me nts.
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 e cti o n 1. 3, 
S c h e d ul e of 
A cti viti e s; 
T a bl e 1 a n d 
T a bl e 3
S e cti o n 5. 2, 
E x cl u si o n 
Crit eri a
E x cl u si o n Crit eri o n 7 w a s m o difi e d t o 
cl arif y e x cl u d e d h y p er s e n siti vit y 
r e a cti o n s.
T hi s c h a n g e i s t o cl arif y t h e e x cl u si o n crit eri o n b y 
i n cl u di n g e x ci pi e nt s i n i n v e sti g ati o n al pr o d u ct 
( M 7 8 2 4 or p e m br oli z u m a b) c o n si st e nt wit h t h e 
p e m br oli z u m a b l a b el i n C hi n a.
D oc u me nt N o. 
O bject N o.
C CI
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 5 /1 5 9
Pr ot oc ol Versi o n 1. 2 ( 2 5 J ul y 2 0 1 8)
T his a me n d me nt is n o ns u bsta ntial base d o n t he criteria i n Article 1 0(a) of Directi ve 2 0 0 1/ 2 0/ E C 
of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n .
O verall Rati o nale f or t he A me n d me nt
T he pr ot oc ol was a me n de d base d o n fee d bac k fr o m t he re g ulat or y age ncies of c o u ntries i n t he 
E ur o pea n U ni o n partici pati n g i n t he V H P.
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 e cti o n 5. 2, 
E x cl u si o n 
Crit eri a
E x cl u si o n Crit eri o n 7 w a s m o difi e d t o 
cl arif y e x cl u d e d h y p er s e n siti vit y 
r e a cti o n s.
T hi s c h a n g e i s t o c o m pl et e t h e e x cl u si o n crit eri o n 
b y i n cl u di n g e x ci pi e nt s i n i n v e sti g ati o n al pr o d u ct 
( M 7 8 2 4 or p e m br oli z u m a b).
S e cti o n 9. 2, 
S a m pl e Si z e 
D et er mi n ati o n, 
T a bl e 1 3
A f o ot n ot e w a s a d d e d t o cl arif y t h e st u d y 
o p er ati n g c h ar a ct eri sti c s.
T hi s c h a n g e i s t o cl arif y t h e s a m pl e si z e 
c al c ul ati o n s.
Pr ot oc ol Versi o n 1. 1 -J P N ( 0 2 A u g ust 2 0 1 8)
T his a me n d me nt is n o ns u bsta ntial base d o n t he criteria i n Article 1 0(a) of Directi ve 2 0 0 1/ 2 0/ E C 
of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n beca use it neit her si g nifica ntl y 
i m pacts t he safet y or p hysical/ me ntal i nte grit y of partici pa nts n or t he scie ntific val ue of t he st u d y.
O verall Rati o nale f or t he A me n d me nt
T he rati o nale f or c ha n ge is t o ali g n Ja pa n -G C P a n d l ocal re g ulat or y  re q uire me nts i n Ja pa n.
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
Titl e P a g e,
S p o n s or N a m e a n d L e g al 
R e gi st er e d A d dr e s s
A d d e d t h e S p o n s or n a m e a n d 
a d dr e s s i n J a p a n
T o b e c o m pli a nt wit h J a p a n 
r e g ul at or y r e q uir e m e nt
2
I ntr o d u cti o n
A d d e d a n ot e t o a n i n di c ati o n w hi c h 
i s n ot a p pr o v e d i n J a p a n
T o b e c o m pli a nt wit h J a p a n 
r e g ul at or y r e q uir e m e nt
4. 3
J u stifi c ati o n f or D o s e
A d d e d a s e nt e n c e a b o ut t h e 
fi n di n g s r e g ar di n g e x p o s ur e i n 
A si a n a n d n o n -A si a n s u bj e ct s
T o pr o vi d e t h e i nf or m ati o n 
s u p p orti n g t h e d o s e r ati o n al e i n 
J a p a n e s e.
5. 1
I n cl u si o n Crit eri a
A d d e d a n ot e f or t h e c o n s e nt w h e n 
a p ati e nt i s < 2 0 y e ar s of a g e
A p er s o n n e e d s t o b e 2 0 y e ar s or 
o v er t o b e r e c o g ni z e d a s a n a d ult 
u n d er t h e J a p a n e s e l a w.
5. 2
E x cl u si o n Crit eri a
E x cl u si o n Crit eri o n 7 w a s m o difi e d 
t o cl arif y e x cl u d e d h y p er s e n siti vit y 
r e a cti o n s.
T hi s c h a n g e i s t o c o m pl et e t h e 
e x cl u si o n crit eri o n b y i n cl u di n g 
e x ci pi e nt s i n i n v e sti g ati o n al pr o d u ct 
( M 7 8 2 4 or p e m br oli z u m a b) t o b e 
c o m pli a nt wit h J a p a n e s e 
p e m br oli z u m a b l a b el .
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 6 /1 5 9
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
8. 3. 4
R e g ul at or y R e p orti n g 
R e q uir e m e nt s f or S eri o u s A d v er s e 
E v e nt s
R e pl a c e d t h e m a n d at or y t e xt t o t h e 
o n e f or st u di e s t o b e c o n d u ct e d i n 
J a p a n
T o b e c o m pli a nt wit h J a p a n 
r e g ul at or y r e q uir e m e nt
A p p e n di x 2
St u d y G o v er n a n c e,
St u d y A d mi ni str ati v e
A d d e d t h e S p o n s or n a m e i n J a p a n
A d d e d t h e J a p a n e s e mi ni st eri al 
or di n a n c e o n G C P
A d d e d a r ef er e n c e t o a s u p p orti n g 
d o c u m e nt
T o b e c o m pli a nt wit h J a p a n 
r e g ul at or y r e q uir e m e nt
T o cl arif y w h er e t o fi n d t h e 
or g a ni z ati o n a n d sit e i nf or m ati o n i n
J a p a n.
A p p e n di x 2
St u d y G o v er n a n c e,
R e g ul at or y a n d Et hi c al 
C o n si d er ati o n s
A d d e d t h e m a n d at or y t e xt f or 
st u di e s t o b e c o n d u ct e d i n J a p a n
T o b e c o m pli a nt wit h J a p a n 
r e g ul at or y r e q uir e m e nt
A p p e n di x 2
St u d y G o v er n a n c e,
Cli ni c al St u d y I n s ur a n c e a n d 
C o m p e n s a ti o n t o P arti ci p a nt s
A d d e d t h e m a n d at or y t e xt f or 
st u di e s t o b e c o n d u ct e d i n J a p a n
T o b e c o m pli a nt wit h J a p a n 
r e g ul at or y r e q uir e m e nt
A p p e n di x 2
St u d y G o v er n a n c e,
S o ur c e D o c u m e nt s
R e pl a c e d t h e m a n d at or y t e xt t o t h e 
o n e f or st u di e s t o b e c o n d u ct e d i n 
J a p a n
T o b e c o m pli a nt wit h J a p a n 
r e g ul at or y r e q uir e m e nt
A p p e n di x 3
C o ntr a c e pti o n
A d d e d a n ot e t o c o ntr a c e pti o n
w hi c h i s n ot a p pr o v e d i n J a p a n
T o b e c o m pli a nt wit h J a p a n 
r e g ul at or y r e q uir e m e nt
T a bl e A 2
M a n a g e m e nt of GI 
ir A E s i n P ati e nt s Tr e at e d Wit h 
I C Pi s
A d d e d a n ot e t o a m e di c ati o n w hi c h 
i s n ot a p pr o v e d i n J a p a n
T o b e c o m pli a nt wit h J a p a n 
r e g ul at or y r e q uir e m e nt
D oc u me nt N o. 
O bject N o. 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 7 /1 5 9
A p pe n di x 1 0
S p o ns or Si g n at ure P a ge
St u d y Title:
A n A da pti ve P hase III, M ultice nter, Ra n d o mize d, O pe n -
La bel , C o ntr olle d St u d y  of M 7 8 2 4 ( bi ntraf us p alfa) vers us 
Pe m br oliz u ma b as a First -li ne Treat me nt i n Patie nts wit h 
P D -L 1  E x pressi n g 
A d va nce d 
N o n -s mall
Cell 
L u n g 
Ca ncer
Re g ul at or y 
A ge nc y 
I de ntif yi n g 
N u m bers:
E u dra C T 2 0 1 8- 0 0 1 5 1 7- 3 2
Cli nic al St u d y Pr ot oc ol Versi o n:
2 2 J u ne 2 0 2 1/ Versi o n 4. 0
I a p pr o ve t he desi g n of t he cli nical st u d y :
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g nat ure
Date of Si g nat ure
N a me, ac a de mic de gree:
F u ncti o n/ Title:
I nstit uti o n:
E M D Ser o n o Researc h & 
De vel o p me nt 
I nstit ute, I nc., a n 
affiliate of Merc k K Ga A
A d dress:
4 5 A Mi d dlese x T ur n pi ke
Billerica, M A 0 1 8 2 1, U S A 
Tele p h o ne n u m ber:
F a x n u m ber:
E -m ail a d dress:
D oc u me nt N o.
O bject N o.
C CI
C CI
P P D
P P D
P P D
P P D
C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 8 /1 5 9
A p pe n di x 1 1
C o or di n ati n g I n vesti g at or Si g n at ure P a ge
St u d y Title:
A n A da pti ve P hase III, M ultice nter, Ra n d o mize d, O pe n -
La bel , C o ntr olle d St u d y  of M 7 8 2 4 ( bi ntraf us p alfa) vers us 
Pe m br oliz u ma b as a First -li ne Treat me nt i n Patie nts wit h 
P D -L 1  E x pressi n g 
A d va nce d 
N o n -s mall
Cell 
L u n g 
Ca ncer
Re g ul at or y 
A ge nc y 
I de ntif yi n g 
N u m bers:
E u dra C T 2 0 1 8- 0 0 1 5 1 7- 3 2
Cli nic al St u d y Pr ot oc ol Versi o n:
2 2 J u ne 2 0 2 1/ Versi o n 4. 0
Site N u m ber:
I a p pr o ve t he desi g n of t he cli nical st u d y , a m res p o nsi ble f or t he c o n d uct of t he st u d y at t his site, 
a n d u n dersta n d a n d will c o n d uct it per t he cli nical st u d y pr ot oc ol, a n y ap pr o ve d pr ot oc ol 
a me n d me nts, I nter 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.
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Si g nat ure
Date of Si g nat ure
N a me, ac a de mic de gree:
 
F u ncti o n/ Title:
C o or di nati n g I n vesti gat or
I nstit uti o n:
A d dress:
Tele p h o ne n u m ber:
F a x n u m ber:
E- m ail a d dress:
D oc u me nt N o. 
O bject N o. 
C CI
C CI
P P D
P P D
P P D
P P D
P P D
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C CI


Bi ntr af us p alf a ( M 7 8 2 4)
1 L N S C L C A d a pti ve P h ase III R C T M 7 8 2 4 vs Pe m br oliz u m a b
M S 2 0 0 6 4 7- 0 0 3 7
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 9 /1 5 9
A p pe n di x 1 2
Pri nci p al I n vesti g at or Si g n at ure P a ge
St u d y Title:
A n A da pti ve P hase III, M ultice nter, Ra n d o mize d, O pe n -
La bel , C o ntr olle d St u d y  of M 7 8 2 4 ( bi ntraf us p alfa) vers us 
Pe m br oliz u ma b as a First -li ne Treat me nt i n Patie nts wit h 
P D -L 1  E x pressi n g 
A d va nce d 
N o n -s mall
Cell 
L u n g 
Ca ncer
Re g ul at or y 
A ge nc y 
I de ntif yi n g 
N u m bers:
E u dra C T 2 0 1 8- 0 0 1 5 1 7- 3 2
Cli nic al St u d y Pr ot oc ol Versi o n:
2 2 J u ne 2 0 2 1/ Versi o n 4. 0
Si te N u m ber:
I a m res p o nsi ble f or t he c o n d uct of t he st u d y at t his site, a n d u n dersta n d a n d will c o n d uct it per t he 
cli nical st u d y pr ot oc ol, a n y ap pr o ve d pr ot oc ol a me n d me nts, I nter 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 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 st u dies 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 n vesti 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 
c o m pl yi n g wit h t he re g ulat or y re q uire me nts. T heref ore, I a gree t o s u p pl y the 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 m y  sp 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  to meet 
Healt h 
A ut h orit y 
re q uire me nts.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g nat ure
Date of Si g nat ure
N a me, ac a de mic de gree :
[Insert Na me a n d hi g hest de gree or f or a si n gle ce nter st u d y, 
i nsert fr o m Title Pa ge]
F u ncti o n/ Title:
I nstit uti o n:
[Insert Na me of I nstit uti o n or f or a si n gle ce nter st u d y, i nsert 
fr o m Title Pa ge]
A d dress:
[Insert F ull Maili n g A d dress (e g, Street, Cit y , p ostal c o de, a n d 
C o u ntr y )]
Tele p h o ne n u m ber:
[Insert F ull n u m ber, i ncl u di n g c o u ntr y c o de]
F a x n u m ber:
[Insert F ull n u m ber, i ncl u di n g c o u ntr y c o de]
E- m ail a d dress:
D oc u me nt N o.
O bject N o.
C CI
C CI
C CI

SAP_001.pdf: 
Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 4  
 
 
 
I nte gr ate d A n al ysis Pl a n 
Cli nic al St u d y  Pr ot oc ol 
I de ntific ati o n N o. 
M S 2 0 0 6 4 7- 0 0 3 7  
Title  
A n  A da pti ve  P hase  I II,  M ultice nter,  Ra n d o mize d,  O pe n-L a bel, 
C o ntr olle d  
St u d y  
of  
M 7 8 2 4   ( bi ntraf us p 
alfa)  
vers us 
Pe m br oliz u ma b  as  a  First -li ne Treat me nt  i n  Patie nts  wit h  P D -L 1 
E x pressi n g A d va nce d N o n -s mall Cell L u n g Ca ncer 
Tri al P h ase  
P hase I II  
I n vesti g ati o n al 
Me dici n al Pr o d uct(s)  
Bi ntraf us p alfa   
Cli nic al St u d y  Pr ot oc ol 
Versi o n  
1 0 Fe br u ar y 2 0 2 0/ Versi o n 3. 0 
I nte gr ate d A n al ysis 
Pl a n A ut h or  
C o or di n ati n g A ut h or  
 
, M er c k 
 
F u n cti o n  
A ut h or( s) / D at a A n al y st( s)  
 
 
 
I nte gr ate d A n al ysis 
Pl a n  
D ate a n d Versi o n  
1 4 J ul y 2 0 2 1  / Versi o n 5. 0 
Inte gr ate d A n al ysis 
Pl a n Re vie wers  
 
 
 
 
 
 
 
 
F u n cti o n  
N a m e  
 M er c k 
 M er c k 
, M er c k  
 M er c k 
, M er c k 
, M er c k 
 M er c k 
 M er c k 
, M er c k 
, M er c k 
 M er ck  
, M er c k 
C o nfi de nti al  
T his d o c u me nt is t h e pr o p ert y of Merc k K Ga A, Dar msta dt, Ger ma n y, or o n e of its affiliate d c o m p a nies.  
It is i nte n d e d f or restricte d use o nl y a n d ma y n ot - i n f ull or p art - be p asse d o n, re pr o d u ce d, p u blis h e d or use d wit h o ut 
e x press p er missi o n of Merc k K Ga A, Dar msta dt, Ger ma n y or its affiliate.  
C o p y ri g ht © 2 0 1 9 b y Merc k K G a A, D a r mst a dt, Ger m a n y o r its affili ate. All ri g hts reser v e d.  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI
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P P D
P P D
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P P D
P P D
P P D
P P D
P P D
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P P D
P P D
P P D
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Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 4  
 
 
A p pr o v al  P a ge   
 
I nte gr ate d A n al ysis Pl a n: M S 2 0 0 6 4 7- 0 0 3 7 
A n  A da pti ve  P hase III,  M ultice nter,  Ra n d o mize d,  O pe n-La b el,  C o ntr olle d  St u d y  of  M 7 8 2 4  
( bi ntraf us p  alfa) v ers us  Pe m br oliz u ma b  as a  First-li ne  Treat me nt  i n  Patie nts  wit h  P D-L 1 
E x pressi n g A d va nce d 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 D ata A n al ysis Res p o nsi ble is d oc u me nte d wit hi n C A R A . Wit h 
t he a p pr o val wit hi n C A R A , 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 m e nts are a d dresse d a de q u atel y. 
 
Merc k D at a A n al ysis R es p o nsi ble 
D ate  
Si g n at ure  
 
Via C A R A  a p pr o val pr o cess  
 
 
 
 
 
 
 
 
Gl o bal Versi o n I D:
Gl o bal Versi o n I D: C CI
P P D


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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1  
T a ble of C o nte nts  
I nte grate d A nal ysis Pla n ...................................................................................................... 1 
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 I nte grate d A nal ysis Pla n ............................................. 1 3  
5  
O bjecti ves a n d E n d p oi nts ................................................................... 1 4  
6  
O ver vie w of Pla n ne d A n al yses  ........................................................... 1 7 
6. 1  
Peri o dic I D M C Safet y E val uati o ns .................................................... 2 0  
6. 2  
O R I nteri m A nal ysis  ........................................................................... 2 1 
6. 3  
P F S I nteri m A nal ysis  .......................................................................... 2 1 
6. 4  
P F S Pri mar y A nal ysis a n d O S I nteri m A nal ysis  ................................ 2 2 
6. 5  
O S Pri mar y A nal ysis ( Fi nal a nal ysis) ................................................. 2 3 
6. 6  
O ver vie w of Pla n ne d A n al yses after Tri al Disc o nti n uati o n ............... 2 4  
7  
C ha n ges t o t he Pla n ne d A nal yses i n t he Cli nical St u d y Pr ot oc ol ...... 2 5  
7. 1  
C O VI D -1 9 I m pact  .............................................................................. 2 5 
8  
Pr ot oc ol De viati o ns a n d A nal ysis Sets ............................................... 2 6  
8. 1  
Defi niti o n of Pr ot oc ol De viati o ns a n d A nal ysis Sets ......................... 2 6  
8. 2  
Defi niti o n of A nal ysis Sets a n d S u b gr o u ps ........................................ 2 6  
9  
Ge ner al S pecificati o ns f or Data A n al yses  .......................................... 3 1 
1 0  
St u d y Partici pa nts ............................................................................... 3 8  
1 0. 1  
Dis p ositi o n of Partici pa nts a n d Disc o nti n uati o ns ............................... 3 8  
1 0. 2  
Pr ot oc ol De viati o ns ............................................................................ 4 1  
1 1  
De m o gra p hics a n d Ot her Baseli ne C haracteristics  ............................. 4 1 
1 1. 1  
De m o gra p hics ..................................................................................... 4 1  
1 1. 2  
Me dical Hist or y  .................................................................................. 4 2 
1 1. 3  
Ot her Baseli ne C haracteristics  ............................................................ 4 2 
1 1. 3. 1  
Vital Si g ns at Baseli ne  ........................................................................ 4 2 
1 1. 3. 2  
Disease Hist or y  ................................................................................... 4 3 
1 1. 3. 3  
E C O G Perf or ma n ce stat us  .................................................................. 4 3 
1 1. 3. 4  
S ki n Stat us Hist or y  ............................................................................. 4 4 
Gl o bal Versi o n I D: 
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Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
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I N F O R M A T I O N 
4/ 9 4  
1 1. 3. 5  
Nic oti ne C o ns u m pti o n ........................................................................ 4 4  
1 1. 3. 6  
T u m or Bi o ps y ..................................................................................... 4 4  
1 1. 3. 7  
P D -L 1 Test  .......................................................................................... 4 4 
1 2  
Pre vi o us or C o nc o mita nt Me dicati o ns/ Pr oce d ures ............................. 4 5  
1 2. 1  
C o nc o mita nt Me dicati o ns ................................................................... 4 5  
1 2. 2  
Pre me dicati o ns  .................................................................................... 4 6 
1 2. 3  
C o nc o mita nt Pr oce d ures ..................................................................... 4 6  
1 2. 4  
Pre vi o us A ntica ncer Treat me nts a n d Pr oce d ures ............................... 4 6  
1 2. 5  
A ntica ncer Treat me nt aft er Disc o nti n uati o n  ...................................... 4 7 
1 3  
Treat me nt C o m plia nce a n d E x p os ure ................................................. 4 8  
1 4  
Efficac y A nal yses  ............................................................................... 5 0 
1 4. 1  
Best O v erall Res p o nse A cc or di n g t o R E CI S T 1. 1 as Assesse d b y 
I R C ( Sec o n dar y E n d poi nt) ................................................................. 5 0  
1 4. 1. 1  
Se nsiti vit y A nal ysis B O R  ................................................................... 5 2 
1 4. 1. 2  
S u b gr o u p A nal ysis f or B O R ............................................................... 5 4  
1 4. 4  
Pr o gressi o n Fr ee S ur vi val Acc or di n g t o R E CI S T 1. 1 as assesse d 
b y I R C ( Pri mar y E n d p oi nt) ................................................................ 5 7  
1 4. 4. 1  
Se nsiti vit y A nal yses f or P F S .............................................................. 5 9  
1 4. 4. 2  
S u b gr o u p A nal ysis f or P F S ................................................................ 6 0  
1 4. 4. 3  
Ti me t o F oll o w - u p f or P F S ................................................................. 6 1 
1 4. 8  
D urati o n of Res p o nse ( S ec o n dar y E n d p oi nt) ..................................... 6 3  
1 4. 8. 1  
Se nsiti vit y A nal yses f or D O R ............................................................ 6 3  
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Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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1 4. 1 1  
O verall S ur vi val ( Pri mar y E n d p oi nt) .................................................. 6 4  
1 4. 1 1. 1  
S u b gr o u p A nal ysis f or O S .................................................................. 6 6  
1 4. 1 1. 2  
F oll o w- u p ti me si nce ra n d o mizati o n  .................................................. 6 6 
1 5  
Safet y A nal yses  .................................................................................. 6 6 
1 5. 1  
A d verse E v e nts  ................................................................................... 6 6 
1 5. 1. 1  
All A d verse E v e nts  ............................................................................. 6 7 
1 5. 1. 2  
A d verse E v e nts Lea di n g t o Treat me nt Disc o nti n uati o n ..................... 7 0  
1 5. 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  ................................................................................... 7 0 
1 5. 2. 1  
Deat hs  ................................................................................................. 7 0 
1 5. 2. 2  
Seri o us A d verse E v e nts ...................................................................... 7 1  
1 5. 2. 3  
A d verse E v e nts of S peci al I nt erest  ..................................................... 7 1 
1 5. 2. 4  
Blee di n g e ve nts ................................................................................... 7 4  
1 5. 2. 5  
T hree - Tier A p pr oac h t o S u m marizi n g a n d A nal yzi n g A Es ............... 7 4 
1 5. 3  
Cli nical La b orat or y E val uati o n ........................................................... 7 7  
1 5. 4  
Vital Si g ns  .......................................................................................... 7 9 
1 5. 5  
Ot her Safet y or T olera bilit y E val uati o ns ............................................ 8 1  
1 6  
A nal yses of Ot her E n d p oi nts .............................................................. 8 3  
1 6. 2  
P har mac o ki netics  ................................................................................ 8 7 
1 6. 2. 1  
Missi n g/ n o n- q ua ntifia ble P K Data Ha n dli n g ..................................... 8 7  
1 6. 2. 2  
Descri pti ve P K A nal ysis ..................................................................... 8 8  
1 6. 4  
Patie nt -Re p orte d O utc o mes  ................................................................ 9 0 
1 7  
Refere n ces  ........................................................................................... 9 2 
1 8  
A p pe n dices ......................................................................................... 9 4  
1 8. 1  
I A P _ M S 2 0 0 6 4 7- 0 0 3 7 List of o ut p uts ................................................ 9 4 
1 8. 2  
T o xicit y gra di n g f or la b orat or y para meters acc or di n g t o N CI-
C T C A E v. 5  ........................................................................................ 9 4 
1 8. 3  
I m p ort a nt Pr ot oc ol De viati o ns ............................................................ 9 4 
1 8. 4  
A da ptati o n Pla n .................................................................................. 9 4  
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Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
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Literat ure ( S A P te m plate)  ................................................................... 9 4 
 
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M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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2  
L ist of A b bre vi ati o ns a n d Defi niti o n of Ter ms 
A E  
A d verse e ve nt  
A E SI  
A d verse e ve nts of s pecial i nterest  
A L K  
A na plastic l y m p h o ma ki nase  
A L P  
Al kali ne p h os p hatase  
A L T  
Ala ni ne a mi n otra nsf eras e  
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  
B O R  
Best o verall res p o nse  
C e oi 
T he c o nce ntrati o n o bser v e 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  
C O VI D -1 9  
C or o na vir us Disease 2 0 1 9  
C S R  
Cli nical St u d y Re p ort  
C R  
C o m plete res p o nse  
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 vers e E ve nts  
C tr o u g h 
T he c o nce ntrati o n o bser v e d i m me diatel y bef ore ne xt d osi n g  
D C R  
Disease C o ntr ol Rate  
D O R  
D urati o n of Res p o nse  
DI  
D ose I nte nsit y  
E C G  
E lectr ocar di o gra m 
E C O G P S  
Easter n C o o per ati ve O nc ol o g y Gr o u p Perf or ma n ce Stat us  
e C R F 
Electr o nic case r e p ort f or m  
E G F R  
E pi der mal gr o wt h f act or rece pt or  
E O R T C Q L Q -
C 3 0  
E ur o pea n Or ga nizati o n f or Researc h a n d Treat m e nt of Ca ncer -Q ualit y of Life 
Q uesti o n naire C ore -3 0  
E Q -5 D -5 L  
E ur o pea n Q u alit y of Life 5 -di me nsi o ns 5 -le vel q u esti o n naire 
F A S  
F ull a nal ysis set 
F T 4  
F ree t h yr o xi ne 
1 L  
First -li ne 
Ge o Mea n  
Ge o metric Mea n  
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Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
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H B V  
He patitis B vir us  
H C V  
He patitis C vir us  
H L T  
Hi g h -le vel Ter m 
H L G T  
Hi g h -le vel Gr o u p T er m 
H R  
Hazar d rati o  
I A P 
I nte grate d A nal ysis Pla n 
I C H 
I nter nati o nal C o u ncil f or Har m o nizati o n  
I H C 
I m m u n o hist oc he mical 
I D M C 
I n d e pe n de nt Data M o nit ori n g C o m mittee 
I L-2 9  
Ite m List-2 9  
I M P 
In v esti gati o nal Me dici nal Pr o d uct  
I N R 
I nter nati o nal n or malize d rati o 
ir A E 
I m m u ne-relat e d A E 
I R C 
I n d e pe n de nt Re vi e w C o m mittee 
I R R 
I nf usi o n-relat e d reacti o ns  
IR T  
I nteracti ve Res p o nse Tec h n ol o g y  
Me d D R A  
Me dical Dicti o nar y f or R e g ulat or y Acti vities  
N C  
N ot Calc ulate d  
N CI  
Nati o nal Ca ncer I nstit ute  
N S C L C  
N o n -s mall cell l u n g ca n cer  
N S C L C -S A Q  
N o n -s mall cell l u n g ca n cer s y m pt o m assess me nt q uesti o n naire 
O R  
O bjecti ve Res p o nse  
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 -L 1  
Pr o gra m me d deat h -li ga n d 1  
P F S  
Pr o gressi o n -fr ee s ur vi val  
Gl o bal Versi o n I D: 
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C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 4  
 
 
P F S 2  
Pr o gressi o n -fr ee s ur vi val after n e xt a ntica ncer treat me nt  
P GI C  
Patie nt Gl o bal I m pr essi o n of C ha n ge  
P GI S  
Patie nt Gl o bal I m pr essi o n of Se verit y  
P K  
P har mac o ki netic  
P R  
Partial res p o nse  
P R E S C R  
Prescree ni n g a nal ysis set 
P R O  
Patie nt -re p orte d  o utc o m es (it  ma y  refer  als o  t o  patie nt-re p orte d  o utc o mes 
a nal ysis set) 
P T  
Pr eferre d Ter m  
R DI  
Relati ve D ose I nte nsit y 
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  
Seri o us a d verse e ve nt  
S A F  
Safet y a nal ysis set 
S C R  
Scree ni n g a n al ysis set 
S D  
Sta ble disease  
S D T M  
St u d y Data Ta b ulati o n M o del  
S M Q  
Sta n dar dise d  Me d D R A Q ueries  
S O C  
S yste m Or ga n Class  
St D  
Sta n dar d De viati o n  
2 L  
Sec o n d -li ne  
T E A E  
Treat me nt E mer g e nt A d v erse E ve nts  
T G F β  
Tra nsf or mi n g gr o wt h fact or β  
T S H  
T h yr oi d -sti m ulati n g h or m o ne 
U L N  
U p per li mit of n or mal  
V A S  
Vis ual a nal o g scal e  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
3  
M o dific ati o n Hist or y  
U ni q u e  
I d e ntifi er f or 
V er si o n  
D at e of  
I 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  
0 6 F e br u ar y 2 0 1 9  
N A  
2. 0  
3 0  M ar c h  2 0 2 0  
•  
C h a n g e d dr u g n a m e fr o m M 7 8 2 4 t o 
bi ntr af u s p alf a  
•  
A d d e d P R O s: I L -2 9, P GI S a n d P GI C i n t h e 
li st of a b br e vi ati o n s, “ O bj e cti v e s a n d 
E n d p oi nt s” a n d “ O v er vi e w of Pl a n n e d 
A n al y s e s” s e cti o n s  
•  
St u d y o bj e cti v e s ( a c c or di n g t o pr ot o c ol v. 
3. 0)  
•  
C h a n g e s i n o v er vi e w of pl a n n e d  a n al y s e s 
a n d effi c a c y a n al y s e s ( a c c or di n g t o gl o b al 
pr ot o c ol a m e n d m e nt, pr ot o c ol v. 3. 0)  
•  
R e pl a c e d s u bj e ct wit h p arti ci p a nt  
•  
R e n a m e d I T T a n al y si s s et a s F A S a n al y si s 
s et  
 
 
•  
M er g e d I D M C S A P v. 1. 1 wit h t h e c urr e nt I A P  
•  
A d d e d cl arifi c ati o n i n t h e d efi niti o n of 
b a s eli n e f or s af et y a n al y s e s  
•  
A d d e d cl arifi c ati o n i n t h e d efi niti o n of o n -
tr e at m e nt p eri o d 
•  
A d d e d i m p ut ati o n r ul e s f or pr e vi o u s a n d 
c o n c o mit a nt m e di c ati o n s, st art d at e of 
s u b s e q u e nt a nti c a n c er t h er a pi e s, d e at h 
d at e s  
•   
Ad d e d h a n dli n g r ul e s f or t u m or a s s e s s m e nt s  
•  
U p d at e s i n p arti ci p a nt di s p o siti o n t a bl e  
•  
R e n a m e d I V R S wit h I R T  
•  
A d d e d li sti n g of p arti ci p a nt s f or w hi c h st u d y 
tr e at m e nt h a s b e e n r ei niti at e d 
•  
E C O G P erf or m a n c e st at u s m o v e d i n “ Ot h er 
B a s eli n e C h ar a ct eri sti c s” s e cti o n  
•  
C h a n g e s i n Ni c oti n e C o n s u m pti o n t a bl e  
•  
C h a n g e s i n P D -L 1 t a bl e  
•  
A d d e d d et ail s r e g ar di n g h a n dli n g of d at a 
aft er tr e at m e nt r ei niti ati o n  
•  
R e n a m e d a d mi ni str ati o n wit h i nt er v e nti o n  
•  
A d d e d a n al y si s “ F oll o w -u p Ti m e si n c e 
R a n d o mi z ati o n”  
•  
A d d e d a n al y s e s f or t h e e v al u ati o n of 
p ot e nti al eff e ct of A D A o n bi ntr af u s p alf a 
s af et y, effi c a c y a n d P K  
•  
A d d e d li sti n g of A E s o c c urri n g aft er  
tr e at m e nt r ei niti ati o n 
•  
Cl arifi c ati o n s o n s af et y s e cti o n a n d c h a n g e s 
i n I m m u n e-r el at e d A d v er s e E v e nt s d efi niti o n 
•  
A d d e d “ Bl e e di n g e v e nt s” s e cti o n  
•  
A d d e d cl arifi c ati o n o n tr e at m e nt d ur ati o n 
p eri o d  r e g ar di n g r ei niti ati o n 
 
 
 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: 
C CI
C CI
P P D


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 4  
 
 
U ni q u e  
I d e ntifi er f or 
V er si o n  
D at e of  
I 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  
•  
A d d e d e DI S H pl ot f or A S T v al u e s  
•  
R e m o v e d s e cti o n o n P R O, it will b e pr o vi d e d 
i n a s e p ar at e A p p e n di x of t h e I A P 
•  
C h a n g e d t e sti n g str at e g y: H ol m gr o u p 
s e q u e nti al d e si g n pr o vi d e d  
 
 
  
•  
Pr o vi d e d n e w w or di n g f or c e n s ori n g r e a s o n s  
( a d mi ni str ati v e c e n s ori n g) 
 
 
 
 
 
 
•  
Pr o vi d e d n e w w or di n g f or T hr e e - Ti er 
a p pr o a c h a n al y si s  
•  
A d d e d d et ail s f or W B C diff er e nti al c o u nt s 
a n d c al ci u m i n t h e “ Cli ni c al L a b or at or y 
E v al u ati o n” s e cti o n  
•  
S p e cifi e d t y p e of a n al y s e s p erf or m e d o n 
c o a g ul ati o n p ar a m et er s  
3 . 0 
2 3  N o v e m b er  
2 0 2 0  
 
•  
A d d e d C O VI D -1 9 a b br e vi ati o n  
•  
R e m o v e d s e c o n d ar y o bj e cti v e s of O R R a n d 
P F S a s s e s s e d b y I n v e sti g at or a s p er 
pr ot o c ol v. 3. 0  a n d a d d e d  t h e s e a n al y s e s a s 
s e n siti vit y a n al y s e s f or B O R a n d P F S i n t h e 
Effi c a c y A n al y s e s s e cti o n  
•  
U p d at e d o v er vi e w of pl a n n e d a n al y s e s f or 
P F S I A a s p er M er c k r e q u e st: a d d e d f or e st  
pl ot of H R b y s u b gr o u p s, r e m o v e d a n al y s e s 
o n P R O q u e sti o n n air e s, r e m o v e d O R b y P D -
L 1 st at u s a n d A E S I b y P D-L 1 st at u s  
•  
A d d e d s e cti o n 7. 1 C O VI D -1 9 I m p a ct  
•  
A d d e d m or e d et ail e d  d efi niti o n of b a s eli n e 
a n d a d d e d d efi niti o n of st u d y d a y/ st u d y 
tr e at m e nt d a y 
•  
S e cti o n G e n er al S p e cifi c ati o n s f or D at a 
A n al y s e s: a d d e d d efi niti o n of pr e, d uri n g, 
p o st p a n d e mi c p eri o d f or C O VI D-1 9 i m p a ct 
a s s e s s m e nt.  
•  
U p d at e d s e cti o n s “ Di s p o siti o n of p arti ci p a nt s 
a n d Di s c o nti n u ati o n s”, “ Pr ot o c ol D e vi ati o n s”  
“ A d v er s e E v e nt s” i n cl u di n g C OVI D- 1 9 
a n al y s e s d et ail s  
•  
U p d at e d l o st t o f oll o w -u p d efi niti o n r e pl a ci n g 
“ c e n s ori n g” d at e wit h “l a st k n o w n ali v e” d at e  
•  
U p d at e d d efi niti o n of I m m u n e -r el at e d 
A d v er s e E v e nt s  
•  
A d d e d “ Li p s q u a m o u s c ell c ar ci n o m a” a n d 
“B o w e n ’s di s e a s e ” i n t h e br o a d d efi niti o n of 
p ot e nti al T G F b et a -m e di at e d s ki n A E s  
•  
A d d e d s e cti o n “ A n e mi a a d v er s e e v e nt s”  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
P P D


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 4  
 
 
U ni q u e  
I d e ntifi er f or 
V er si o n  
D at e of  
I 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  
•  
R e m o v e d u n n e c e s s ar y f or m ul a f or c al ci u m 
d eri v a ti o n 
•  
A d d e d Cr e ati ni n e Cl e ar a n c e d eri v ati o n  
4. 0  
2 2 A pril 2 0 2 1 
 
•  
A d d e d s e cti o n 1 6. 2 “ P h ar m a c o ki n eti c s”  
 
 
•  
A d d e d t h e c o m p ut ati o n d e s cri pti o n f or t h e 
d ur ati o n of ni c oti n e c o n s u m pti o n  
•  
Ni c oti n e c o n s u m pti o n: y e ar s si n c e q uitti n g, 
cl arifi c ati o n s a d d e d i n t h e c o m p ut ati o n 
d e s cri pti o n  
•  
A d d e d i m p ut ati o n r ul e s f or d at e s of ni c oti n e 
c o n s u m pti o n  
•  
A d d e d s u m m ar y t a bl e s f or i m p ort a nt/ n o n -
i m p ort a nt C O VI D-1 9 r el at e d P D s  
•  
A d d e d li sti n g of c o n c o mit a nt C O VI D -1 9 
v a c ci n ati o n s  
•  
R e m o v e d pr e vi o u s m e di c ati o n s t e xt a s t hi s 
s e cti o n h a s b e e n r e m o v e d fr o m e -crf a s it 
w a s o ut of st u d y o bj e cti v e s  
•   
A dd e d a n al y s e s of p ot e nti al eff e ct of n -A B o n 
s af et y  
•  
U p d at e s a p pli e d t o s e cti o n “ T hr e e -Ti er 
A p pr o a c h t o S u m m ari zi n g a n d A n al y zi n g 
A E s”  
•  
A d d e d s e cti o n “ O v er vi e w of Pl a n n e d 
A n al y s e s aft er Tri al Di s c o nti n u ati o n”  
•  
D efi niti o n of o n -tr e at m e nt p eri o d: a d d e d 
r ef er e n c e t o e x p a n d e d o n-tr e at m e nt p eri o d 
f or ir A E s 
•  
A d d e d fl a g v ari a bl e f or bl e e di n g e v e nt s i n 
A E s li sti n g s  
•  
A d d e d fl a g v ari a bl e of p o s si bl e H y’ s l a w 
c a s e s i n t h e li sti n g of t ot al bilir u bi n , A L T, A S T 
a n d A L P v al u e s  d uri n g o n -tr e at m e nt p eri o d 
•  
R e m o v e d A p p e n di x “ R ul e s f or t h e 
i d e ntifi c ati o n of pr e vi o u s, c o n c o mit a nt a nd 
b ot h pr e vi o u s a n d c o n c o mit a nt 
m e di c ati o n s/ pr o c e d ur e s”, n ot a p pli c a bl e d u e 
t o t h e pr e vi o u s m e di c ati o n s s e cti o n r e m o v al 
5. 0  
1 4 J ul y 2 0 2 1  
 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
P P D
P P D


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
U ni q u e  
I d e ntifi er f or 
V er si o n  
D at e of  
I 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  
•  
A D A: c h a n g e d t h e c at e g or y n a m e i n 
T a bl e 1 1 fr o m “ Tr e at m e nt e m er g e nt 
( b a s eli n e n o n-p o siti v e)” t o “ Tr e at m e nt 
e m er g e nt ( b a s eli n e i n d u c e d)”  
•  
A D A a n d N a b: r e m o v e d s e nt e n c e 
r e g ar di n g c e n s ori n g f or s u bj e ct s still o n 
tr e at m e nt at d at a c ut-off a n d p o siti v e 
a s s e s s m e nt at t h eir l a st a s s e s s m e nt 
b ef or e c ut -off  
•   
n-A B: m o difi e d “ S u bj e ct at Ri s k 
( D e n o mi n at or f or I n ci d e n c e)” i n T a bl e 
1 3.  
•   
n-A B: r e m o v e d a n al y s e s o n tit er v al u e s  
4  
P ur p ose of t he I nte gr ate d A n al ysis Pl a n 
T he  p ur p ose  of  t his I nt e grate d  A nal ysis  Pla n  (I A P) is  t o  d oc u me nt  t ec h nical  a n d  detaile d 
s pecificati o ns f or t he a n al yses at peri o dic safet y e v al uati o n b y I D M C , i nteri m a n d pri mar y a nal yses 
of data c ollect e d f or pr ot oc ol M S 2 0 0 6 4 7- 0 0 3 7 . Res ults of t he a nal yses des cri be d i n t his I A P will 
b e 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 i nteri m a n d pri mar y 
a nal yses i de ntifie d i n t his I A P will be i ncl u de d i n re g ulat or y s u b missi o ns or f ut ure ma n uscri pts. 
A n y p ost -h oc, or u n pl a n n e d a nal yses p erf or me d t o pr o vi de res ults f or i ncl usi o n i n t he C S R b ut n ot 
i de ntifie d i n t his pr os pecti ve I A P will be clearl y i de ntifie d i n t he C S R. T he I A P is base d u p o n 
S ecti o n 9 ( Statistical C o nsi derati o ns)  of  t he st u d y pr ot oc ol a n d is pre pare d i n c o m plia nce wit h 
I nter nati o nal C o u ncil f or Har m o nizati o n (I C H) G ui deli ne E 9 .  
 
 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 4  
 
 
5  
O bjecti ves a n d E n d p oi nts   
 
T he o bjecti ves a n d e n d p oi nts are defi ne d i n T a ble 1 .  
T a ble 1 
St u d y O bjecti ves a n d E n d p oi nts  
O bj e cti v e s  
E n d p oi nt s ( O ut c o m e M e a s ur e s)  
I A P S e cti o n 
Pri m ar y  
 
 
T o d e m o n str at e i m pr o v e m e nt i n P F S 
wit h bi ntr af u s p alf a  c o m p ar e d wit h  
p e m br oli z u m a b  
 
T o d e m o n str at e i m pr o v e m e nt i n O S wit h 
bi ntr af u s p alf a  c o m p ar e d wit h  
p e m br oli z u m a b  
P F S a c c or di n g t o R E CI S T 1. 1 
a s s e s s e d b y I R C  
 
 
O S  
Effi c a c y  A n al y s e s ,  s e cti o n s 1 4. 4 , 
1 4. 1 1  
S e c o n d ar y  
 
 
•  
S af et y  
T o e v al u at e t h e s af et y a n d 
t ol er a bilit y of bi ntr af u s p alf a  
c o m p ar e d wit h p e m br oli z u m a b  
 
•  
O c c urr e n c e of T E A E s a n d 
tr e at m e nt-r el at e d A E s  
S af et y A n al y s e s, s e cti o n  1 5  
•  
Effi c a c y  
T o e v al u at e t h e effi c a c y i n o bj e cti v e 
r e s p o n s e of bi ntr af u s p alf a  
c o m p ar e d wit h p e m br oli z u m a b  
 
•  
O bj e cti v e r e s p o n s e  a c c or di n g 
t o R E CI S T 1. 1 a s s e s s e d b y 
I R C 
Effi c a c y A n al y s e s , s e cti o n 1 4. 1  
- D O R  
•  
D O R a s s e s s e d fr o m C R or P R 
a c c or di n g t o R E CI S T 1. 1 
a s s e s s e d b y I R C u ntil P D, 
d e at h, or l a st t u m or 
a s s e s s m e nt  
Effi c a c y A n al y s e s , s e cti o n 1 4. 8  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: 
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
O bj e cti v e s  
E n d p oi nt s ( O ut c o m e M e a s ur e s)  
I A P S e cti o n 
L o n g -t er m f oll o w-u p of s ur vi v al f or 5 y e ar s aft er t h e l a st d o s e of bi ntr af u s p alf a  or p e m br oli z u m a b i n a p arti ci p a nt 
u nl e s s r e p ort e d a s l o st t o f oll o w -u p, h a d di e d, or t h e st u d y i s t er mi n at e d.  
A D A  = a nti -dr u g a nti b o di e s; A E  = a d v er s e e v e nt; C e oi  = c o n c e ntr ati o n at e n d of i nf u si o n; C tr o u g h = c o n c e ntr ati o n at 
t h e e n d of t h e d o si n g i nt er v al; C R = c o m pl et e r e s p o n s e; D O R  = d ur ati o n of r e s p o n s e; E O R T C Q L Q -
C 3 0  = E ur o p e a n Or g a ni z ati o n f or R e s e ar c h a n d Tr e at m e nt of C a n c er -Q u alit y of Lif e Q u e sti o n n air e C or e -3 0; 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; I H C = i m m u n o hi st o c h e mi str y; I L-2 9  = It e m 
Li st -2 9 ;I R C = I n d e p e n d e nt R e vi e w C o m mitt e e; 
 
 N S C L C = n o n -s m all c ell l u n g c a n c er; 
N S C L C - S A Q = n o n -s m all c ell l u n g c a n c er s y m pt o m a s s e s s m e nt q u e sti o n n air e; O R =  o bj e cti v e r e s p o n s e; 
O R R  = o bj e cti v e r e s p o n s e r at e; O S  = o v er all s ur vi v al; P A  = pri m ar y a n al y si s; P D  = pr o gr e s si v e di s e a s e; 
 1; P F S = pr o gr e s si o n -fr e e s ur vi v al; s ur vi v al; 
 
 P GI C  = P ati e nt Gl o b al I m pr e s si o n of C h a n g e ; P GI S  = P ati e nt Gl o b al I m pr e s si o n of S e v erit y ; 
P K = p h ar m a c o ki n eti c; P R  = p arti al r e s p o n s e; P R O  = p ati e nt -r e p ort e d o ut c o m e; R E CI S T = R e s p o n s e E v al u ati o n 
Crit eri a i n  S oli d T u m or s; T E A E  = tr e at m e nt-e m er g e nt a d v er s e e v e nt; T M B  = t u m or m ut ati o n b ur d e n. 
 
 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
6  
O ver vie w of Pl a n ne d A n al yses  
T he f oll o wi n g a nal yses are descri be d i n t his I A P: 
•  Peri o dic I nde pe n d e nt D at a M o nit ori n g C o m mittee ( I D M C) Safet y E v al uati o ns  
•  O bjecti ve  Res p o nse I nt eri m a nal ysis ( O R I A) 
•  Pr o gressi o n- Fr ee S ur vi val I nteri m a nal ysis ( P F S I A)  
•  P F S Pri mar y a nal ysis ( P F S P A)  
•  O verall S ur vi val I nteri m A nal ysis ( O S I A)  
•  O verall S ur vi val P ri mar y A nal ysis ( O S P A)  
Details  of  o ut p uts  bel o n gi n g  t o  eac h  of  t he  a nal yses  liste d  a b o ve are  pr o vi de d  i n  a  se p arat e 
d oc u me nt (“I A P _ M S 2 0 0 6 4 7- 0 0 3 7 List of o ut p uts”) pr o vi de d i n A p p e n di x t o t his I A P.  
A n al ysis f or peri o dic I D M C s afet y e v al u ati o ns 
T he I D M C will peri o dicall y re vie w acc u m ulati n g s afet y data.  T he I D M C will e val uate q ualit y a n d 
c o m plete ness of saf et y d ata bas e d o n t he pr o vi de d st u d y data. M ore o ver , t he I D M C will pr o vi d e 
rec o m me n dati o ns  re gar di n g m o dificati o n  a n d/ or  c o nti n uati o n  of  t he  st u d y,  i ncl u di n g  a n y 
a d diti o nal  safet y  m o nit ori n g  or  ris k  miti gati o n  pr oce d ures  t o e ns ure  partici pa nt  safet y  a n d  t he 
vali dit y a n d scie ntific merit of t he st u d y.  
T he  first  I D M C  safet y  data  re vie w  meeti n g t o o k place  w he n  t he first  6 0  partici pa nts  ha ve 
c o m plete d 6 wee ks of f oll o w u p p ost  ra n d o mizati o n. T he f oll o wi n g I D M C safet y meeti n gs will be 
hel d  e ver y  6  m o nt hs  f oll o wi n g  t he  i nitial  I D M C  meeti n g.  F urt h er  a d -h oc  meeti n gs  ma y  be 
sc he d ule d b y t he I D M C as nee d e d. F or eac h I D M C meeti n g, all data will be i ncl u de d u p t o a n 
a d mi nistrati ve c ut off dat e.  
A d a pti ve P h ase III Tri al Desi g n  a n d a n al yses bef ore/ after a d a pt ati o n decisi o n 
I n pr ot oc ol versi o n 3. 0, t he st u d y desi g n was m o difie d t o a n a da pti ve tri al desi g n t o per mit sa m ple 
size a d a ptati o n base d o n pres pecifi e d a d a ptati o n r ules e val uati n g t h e o bjecti ve res p o nse at a pre -
pla n ne d i nteri m a nal ysis.  
A n al ysis f or a d a pt ati o n decisi o n ( O R I A) 
T he st u d y’s I D M C will e val uate t he res ults fr o m t he pre -defi n e d  i nteri m a n al ysis ( O R I A) base d 
o n o bjecti ve r es p o nse as assesse d b y t h e I R C o n t he 7 3 -1 0 P D -L 1 hi g h a n al ysis set restrict e d t o 
partici pa nts ra n d o mize d at least 6 m o nt hs bef ore t he data c ut off date w hic h is pla n ne d at 6 m o nt hs 
after t he r a n d o mizati o n of t he 1 0 0t h partici pa n t teste d 7 3-1 0 P D -L 1 hi g h. I n t his a nal ysis, t he I D M C 
will deci de, base d o n O R R differe nce bet wee n treat me nt ar ms per st u d y desi g n, t o eit her kee p t he 
st u d y r u n ni n g at t he i nitial sa m ple size ( N = 3 0 0), or e x pa n d t h e sa m ple size ( N = 5 8 4), or st o p f or 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
f utilit y. T he O R R criteri o n f or e x pa nsi o n is pres p ecifie d i n t h e c orres p o n di n g c o nfi de ntial I D M C  
c harter a p pe n di x . T he st u d y is st o p pe d f or f utilit y ( n o n -bi n di n g) at t he O R I A, if Δ O R R ≤0  (i.e. 
t he res p o nse r ate i n t he bi ntraf us p alfa ar m is n ot hi g her t ha n i n t he p e m br oliz u ma b ar m).  
A n al yses after a d a pt ati o n decisi o n ( P F S a n d O S I A a n d P A) 
If I D M C will deci d e t o k ee p t he st u d y r u n ni n g , eit her at t he i nitial sa m ple size or at a n e x p a n de d  
sa m ple size, t he P F S a n d O S i nteri m a n d pri mar y a nal yses will be pr o vi de d at t he c ut-off d ates 
deter mi ne d b y a pre -s p ecifie d n u m ber of o bser v e d e ve nts. The n u m ber of e ve nts tri g geri n g t he 
a nal yses diff er acc or di n g t o t he t otal sa m ple size a n d are dis pla ye d i n t he t a ble bel o w ( Ta bl e 2 ). 
T a ble 2 
C ut off d ates f o r t he pl a n ne d P F S a n d O S I A a n d P A  a n al yses  
A n al y si s  
D at a c ut off d at e  
 
I niti al S a m pl e Si z e ( N = 3 0 0) 
E x p a n d e d S a m pl e Si z e ( N = 5 8 4)  
P F S I A  
W h e n 1 4 0 Pr o gr e s si o n -fr e e s ur vi v al ( P F S) 
e v e nt s h a v e b e e n r e a c h e d  
W h e n 1 4 0  Pr o gr e s si o n -fr e e s ur vi v al ( P F S) 
e v e nt s h a v e b e e n r e a c h e d  
P F S P A * 
W h e n 2 2 4  Pr o gr e s si o n -fr e e s ur vi v al ( P F S) 
e v e nt s h a v e b e e n r e a c h e d  
W h e n 3 8 6  Pr o gr e s si o n -fr e e s ur vi v al ( P F S) 
e v e nt s h a v e b e e n r e a c h e d 
O S I A * 
W h e n 1 6 9  O v er all s ur vi v al ( O S ) e v e nt s h a v e 
b e e n r e a c h e d  
W h e n 2 7 0  O v er all s ur vi v al ( O S ) e v e nt s h a v e 
b e e n r e a c h e d  
O S P A 
W h e n 1 9 7 O v er all s ur vi v al ( O S ) e v e nt s h a v e 
b e e n r e a c h e d  
W h e n 3 3 9  O v er all s ur vi v al ( O S ) e v e nt s h a v e 
b e e n r e a c h e d  
* O n discreti o n of t h e s p o ns or t h e sa me c ut off ca n b e use d f or O S I A a n d P F S P A f or o p erati o n al reas o ns if t h e n u m b er of e ve nts 
f or P F S P A is reac h e d a n d at t h e sa me ti me t h e n u m b er of O S e v e nts is i n t h e ra n g e of ± 5 % of t h e pla n n e d e v e nt size f or O S IA. 
A La n -De Mets O' Brie n -Fle mi n g a p pr o xi mati o n s p e n di n g  f u n cti o n will b e use d f or calc ulati o n of efficac y bo u n ds f or P F S a n d O S 
at c orres p o n di n g a n al yses . Efficac y  b o u n d aries will b e recalc ulate d o n t h e b asis of t h e act u al n u m ber of e v e nts reac h e d at c ut-off 
date.  
Testi n g str ate g y f o r P F S a n d O S  
T he 2 pri mar y e n d p oi nts of t his st u d y are P F S  acc or di n g t o R E CI S T  1. 1 assesse d b y I R C a n d O S . 
T he  st u d y  will  be  c o nsi dere d  p ositi ve  if  eit her  t he O S  a nal ysis  res ults  a n d/ or  t he  P F S  a nal ysis 
res ults are statisticall y si g nifica nt. 
T he f oll o wi n g effi cac y a nal yses  are pl a n ne d: P F S I A, P F S P A, O S I A, O S P A.  
Gl o bal Versi o n I D:
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
•  Pri m ar y e n d p oi nt  P F S  
T he f oll o wi n g n ull h y p ot hesis will be teste d:  
𝐻𝐻0
𝑃𝑃𝑃𝑃𝑃𝑃: 𝜆𝜆𝑀𝑀
𝑃𝑃𝑃𝑃𝑃𝑃(𝑡𝑡) = 𝜃𝜃𝜆𝜆𝑃𝑃
𝑃𝑃𝑃𝑃𝑃𝑃(𝑡𝑡),𝜃𝜃≥1  vers us 𝐻𝐻1
𝑃𝑃𝑃𝑃𝑃𝑃: 𝜆𝜆𝑀𝑀
𝑃𝑃𝑃𝑃𝑃𝑃(𝑡𝑡) = 𝜃𝜃𝜆𝜆𝑃𝑃
𝑃𝑃𝑃𝑃𝑃𝑃(𝑡𝑡),𝜃𝜃< 1  
W here 𝜆𝜆⋅
𝑃𝑃𝑃𝑃𝑃𝑃(𝑡𝑡) r e pres e nts t he hazar d at ti me 𝑡𝑡 a n d  𝜃𝜃 t he u n k n o w n c o nsta nt of pr o p orti o nalit y of 
hazar ds i n t he tr eat me nt gr o u ps M  ( M 7 8 2 4/ bi ntraf us p alfa) a n d P  ( pe m br oli z u ma b). 
•  Pri m ar y e n d p oi nt O S  
T he f oll o wi n g n ull h y p ot hesis will be teste d:  
𝐻𝐻0
𝑂𝑂𝑃𝑃: 𝜆𝜆𝑀𝑀
𝑂𝑂𝑃𝑃(𝑡𝑡) = 𝜃𝜃𝜆𝜆𝑃𝑃
𝑂𝑂𝑃𝑃(𝑡𝑡),𝜃𝜃≥1  vers us 𝐻𝐻1
𝑂𝑂𝑃𝑃: 𝜆𝜆𝑀𝑀
𝑂𝑂𝑃𝑃(𝑡𝑡) = 𝜃𝜃𝜆𝜆𝑃𝑃
𝑂𝑂𝑃𝑃(𝑡𝑡),𝜃𝜃< 1  
W here 𝜆𝜆⋅
𝑂𝑂𝑃𝑃(𝑡𝑡) re prese nts t he h azar d at ti me 𝑡𝑡 a n d 𝜃𝜃 t he u n k n o w n c o nsta nt of pr o p orti o nalit y of 
hazar ds i n t he tr eat me nt gr o u ps M  ( M 7 8 2 4/ bi ntraf us p alfa) a n d P  ( pe m br oli z u ma b). 
T he t y pe I err or is strictl y c o ntr olle d at a l e vel of 2. 5 % o ne-si de d b ase d o n w or k b y C he n et al. 
(C he n 2 0 1 8 ). B o nferr o ni me t h o d is use d t o s plit t he al p ha of 2. 5 % a n d use 0. 5 % f or testi n g 𝐻𝐻0
𝑃𝑃𝑃𝑃𝑃𝑃 
a n d 2 % f or testi n g 𝐻𝐻0
𝑂𝑂𝑃𝑃 (all o ne-si de d).  
Gr o u p se q ue ntial b o u n d aries f or P F S a n d O S e n d p oi nts will be deri ve d fr o m t he al p ha-s p e n di n g 
f u ncti o n acc or di n g t o La n-De Mets ( O’ Bria n -Fle mi n g b o u n daries ) at l ocal si g nifica nce le v els α P F S  
f or P F S a n d αO S  f or O S, r es pecti vel y (all o ne si de d). 
T he H ol m gr o u p s e q ue ntial desi g n will be use d  ( Ye et al 2 0 1 3): m o nit or P F S e n d p oi nt usi n g its 
l ocal αP F S  a n d its s pecific gr o u p se q ue ntial b o u n d ar y cP F S  a n d m o nit or O S e n d p oi nt usi n g its l ocal 
α O S  a n d its s pecific gr o u p se q ue ntial b o u n dar y cO S . If  eit her  of t he t w o e n d p oi nts ( P F S or O S) 
cr osse d  its c orr es p o n di n g b o u n dar y at s o me s pecific l o o k (eit her P F S I A or P F S P A or O S I A or 
O S P A)  t he n its l ocal t y p e I err or ca n be reall ocate d t o t he ot h er e n d p oi nt s o t hat t he ot her e n d p oi nt 
ca n be teste d usi n g t he f ull le vel al p ha b o u n d ar y (i.e α = 2. 5 %) ta ki n g i nt o acc o u nt t he gr o u p-
se q ue ntial testi n g pr oce d ure. 
T he fa mil y -wise err or rate is c o ntr olle d at 2. 5 % ( o ne -si de d) f or t he descri be d testi n g pr oce d ure. 
A n  a p pe n di x  t o  t his  I A P,  “ A da ptati o n  Pla n”,  i ncl u des  si m ulati o n  res ults,  w hic h  s h o w  t hat  t his 
h ol ds tr ue u n der br o a d variati o n of ass u m pti o ns. 
T he m ulti ple pri mar y res ults will be c o nsi dere d statisticall y si g nifica nt o nl y if eit her of t he t w o 
i n di vi d ual  h y p ot heses  𝐻𝐻0
𝑃𝑃𝑃𝑃𝑃𝑃 or 𝐻𝐻0
𝑂𝑂𝑃𝑃 are rejecte d  b y  t he  cl ose d  test  at  a n y  l o o k. O perati n g 
c haracteristics of t he st u d y desi g n are d etaile d i n  T a ble  3 bel o w: 
T a ble  3 
O per ati n g St u d y C h ar acteristi cs f or P h ase II/III Desi g n  
A n al y si s  
I niti al S a m pl e Si z e ( N = 3 0 0) 
E x p a n d e d S a m pl e Si z e ( N = 5 8 4)  
 
 
Pl a n n e d  
E v e nt s 
Criti c al V al u e s  
L o c al 
P o w er 
Pl a n n e d  
E v e nt s 
Criti c al V al u e s  
L o c al 
P o w er 
 
 
H R  
p- v al u e  
H R  
p- v al u e  
P F S 
I A 
1 4 0  
0. 5 7  
0. 0 0 0 3 8  
1 7 %  
1 4 0  
0. 4 7  
3. 1 5* 1 0 - 6 
  2 %  
 
P A  
2 2 4  
0. 7 1  
0. 0 0 4 8 7  
5 0 %  
3 8 6  
0. 7 7  
0. 0 0 5 0 0  
9 0 %  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI


Bintrafusp alfa (M7824) 1L NSCLC Adaptive Phase III RCT M7824 versus Pembrolizumab
MS200647-0037 - Version 5.0 
C O N F I D E N T I A L
I N F O R M A T I O N
20/94
Analysis 
Initial Sample Size (N=300)
Expanded Sample Size (N=584)
Planned 
Events 
Critical Values
Local 
Power 
Planned 
Events 
Critical Values
Local 
Power 
HR
p-value
HR
p-value
OS
IA  
169
0.71
0.01201
52%
270
0.75
0.00914
71%
PA  
197
0.74
0.01658
14%
339
0.80
0.01731
18%
HR = hazard ratio; IA = interim analysis, OS = overall survival, PA = primary analysis, PFS = progression-free survival.  Hazard 
ratio is an expected one based on the assumption of exponential distribution. The decision will be based on the p-value. Alpha is 
distributed to the PFS and OS analyses based on Bonferroni’s method.
Unblinding
The study team is blinded for all analyses conducted by treatment arm until the IDMC recommends 
unblinding.  
Until the unblinding is recommended, the analyses will be performed by an independent statistical 
provider for the IDMC and they will be transmitted from this group to the IDMC only. 
After the prospectively determined data cutoff date is reached (displayed in Table 2) the data center 
statistician will prepare the outputs (using programs prepared by the blinded team based on dummy
treatment arms) in agreement with the IDMC charter and transmit the analyses, tabulations, and 
listings to the IDMC for the meeting. The data center statistician will be available at the IDMC 
meeting should any questions from the IDMC members arise regarding the data and/or analyses. 
Periodic IDMC Safety Evaluations
Periodic IDMC safety evaluations will be taken every 6 months following the initial IDMC 
meeting (performed when the first 60 participants have completed 6 weeks post randomization) 
and will evaluate:
•
Participant disposition
•
Important protocol deviations 
•
Enrollment details (participants randomized by region and country, randomized by strata) 
•
Demographics and other baseline characteristics (height, weight and BMI at baseline, disease 
history)  
•
Treatment compliance and exposure (duration of therapy) 
•
Safety analyses (overview of treatment-emergent adverse events (TEAEs), serious TEAEs 
(SAE), treatment-related TEAEs, adverse events of special interest (AESI), Bleeding events, 
clinical laboratory evaluations, vital signs) 
Further details can be found in the IDMC Charter.
Global Version ID: 
Global Version ID: CCI


Bintrafusp alfa (M7824) 1L NSCLC Adaptive Phase III RCT M7824 versus Pembrolizumab
MS200647-0037 - Version 5.0 
C O N F I D E N T I A L
I N F O R M A T I O N
21/94
OR Interim Analysis
The OR interim analysis will be triggered at 6 months after the randomization of the 100th
participant tested 73-10 PD-L1 high and will evaluate:
•
Unconfirmed best overall response per RECIST 1.1 as assessed by IRC (Difference in ORR, 
see Section 14 for details) and reasons for non-evaluable unconfirmed best overall response. 
•
Duration of response 
Participant disposition, important protocol deviations, enrollment details (participants randomized 
by region and country, randomized by strata), demographics and other baseline characteristics 
(height, weight and BMI at baseline, disease history, PD-L1 assays concordance), duration of 
therapy and safety analyses (overview of treatment-emergent adverse events (TEAEs), serious 
TEAEs (SAE), treatment-related TEAEs, adverse events of special interest (AESI), Bleeding 
events, clinical laboratory evaluations, vital signs) will also be described at the time of BOR 
interim analysis. Further evaluations on PD-L1 assays may be included in this analysis (on request 
of the IDMC) e.g. unconfirmed OR by PD-L1 assays status and/or TEAEs and AESI by PD-L1 
assays status (as described in sections 14.1.1 and 15.5). Additionally descriptive statistics of 
demographics and baseline characteristics in subjects with and without bleeding events may be 
included on IDMC request (as described in section 15.2.4).
PFS Interim Analysis
The PFS Interim analysis will be triggered by the data cutoff date displayed in Table 2 and will 
describe:
•
Best overall response per RECIST 1.1 as assessed by IRC
•
Best overall response per RECIST 1.1 as assessed by Investigator 
•
PFS per RECIST 1.1 as assessed by IRC (𝐻𝐻0
𝑃𝑃𝑃𝑃𝑃𝑃tested see Section 14 for details)
•
PFS per RECIST 1.1 as assessed by Investigator
•
PFS per RECIST 1.1 as assessed by IRC subgroup analyses: forest plot of HR and its 
corresponding 95% confidence interval (CI)  by subgroups 
•
Duration of response 
Participant disposition, important protocol deviations, enrollment details (participants randomized 
by region and country, randomized by strata), demographics and other baseline characteristics 
(height, weight and BMI at baseline, disease history, PD-L1 assays concordance), duration of 
therapy, cumulative dose, dose intensity and relative dose intensity, safety analyses (overview of 
treatment-emergent adverse events (TEAEs), serious TEAEs (SAE), treatment-related TEAEs, 
adverse events of special interest (AESI), bleeding events, clinical laboratory evaluations, vital 
signs) will also be described at the time of PFS interim analysis. Additional descriptive statistics 
Global Version ID: 
Global Version ID: CCI


Bintrafusp alfa (M7824) 1L NSCLC Adaptive Phase III RCT M7824 versus Pembrolizumab
MS200647-0037 - Version 5.0 
C O N F I D E N T I A L
I N F O R M A T I O N
22/94
of demographics and baseline characteristics in subjects with and without bleeding events may be 
included on IDMC request (as described in section 15.2.4).
PFS Primary Analysis and OS Interim Analysis
The PFS primary analysis and OS Interim analysis will be triggered by the data cutoff dates 
displayed in Table 2 and will include the following sections of this IAP:
•
Participant disposition 
•
Important protocol deviations 
•
Enrollment details (participants randomized by region and country, randomized by strata) 
•
Demographics, medical history and other baseline characteristics (height, weight and BMI at 
baseline, disease history, skin status history, nicotine consumption, tumor biopsy, PD-L1 
assays concordance) 
•
Previous and concomitant medications and procedures 
•
Treatment exposure and compliance (e.g. duration of treatment, number of infusions and dose 
intensity)
•
Efficacy analyses: 
o
PFS per RECIST 1.1 as assessed by IRC (𝐻𝐻0
𝑃𝑃𝑃𝑃𝑃𝑃tested, see Section 14 for details)
o
PFS per RECIST 1.1 as assessed by Investigator
o
PFS per irRECIST as assessed by IRC
o
BOR per RECIST 1.1 as assessed by IRC
o
BOR per RECIST 1.1 as assessed by Investigator 
o
BOR per irRECIST as assessed by IRC
o
Change from baseline and Maximum shrinkage in sum of diameter of target lesions 
according to RECIST 1.1 assessed by IRC 
o
Time to response 
o
Duration of response 
o
Overall survival (OS) (𝐻𝐻0
𝑂𝑂𝑃𝑃tested, see Section 14 for details). Alpha re-allocation is 
possible if 𝐻𝐻0
𝑃𝑃𝑃𝑃𝑃𝑃is rejected previously 
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•
Safety analyses (overview of treatment-emergent adverse events (TEAEs), serious TEAEs 
(SAE), treatment-related TEAEs, adverse events of special interest (AESI), Bleeding events, 
ECOG PS, vital signs, clinical laboratory evaluations, and electrocardiograms [ECG]) 
•
Analyses on Patient-Reported Outcomes (PRO) (EORTC-QLQ-C30, NSCLC-SAQ, EQ-5D-
5L, PGIS, PGIC and IL-29). See section 16.4
•
Further evaluations on PD-L1 assays may be included in this analysis (on request of the IDMC)
e.g. OR by PD-L1 status and/or TEAEs and AESI by PD-L1 assays status (as described in 
sections 14.1.1 and 15.5)
•
Additionally descriptive statistics of demographics and baseline characteristics in subjects with 
and without bleeding events may be included on IDMC request (as described in section 15.2.4).
OS Primary Analysis (Final analysis)
The following analyses will be described in the OS primary analysis, triggered by the data cutoff 
point displayed in Table 2:
•
Participant disposition 
•
Important protocol deviations 
•
Enrollment details (participants randomized by region and country, randomized by strata) 
•
Demographics, medical history and other baseline characteristics (height, weight and BMI at 
baseline, disease history, skin status history, nicotine consumption, tumor biopsy, PD-L1 
assays concordance) 
•
Previous and concomitant medications, procedures, follow-up treatments
•
Treatment exposure and compliance (e.g. duration of treatment, number of infusions, and dose 
intensity)
•
Efficacy analyses: 
o
PFS per RECIST 1.1 as assessed by IRC (𝐻𝐻0
𝑃𝑃𝑃𝑃𝑃𝑃tested, see Section 14 for details). 
Hypothesis tested only if not rejected in previous analyses and alpha re-allocation is 
possible if 𝐻𝐻0
𝑂𝑂𝑃𝑃is rejected 
o
Overall survival (OS) Overall survival (OS) (𝐻𝐻0
𝑂𝑂𝑃𝑃tested, see Section 14 for details). 
Alpha re-allocation is possible if 𝐻𝐻0
𝑃𝑃𝑃𝑃𝑃𝑃is rejected previously 
o
BOR on the subsequent line of therapy, 
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CCI
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Bintrafusp alfa (M7824) 1L NSCLC Adaptive Phase III RCT M7824 versus Pembrolizumab
MS200647-0037 - Version 5.0 
24/94
•
Safety analyses (overview of treatment-emergent adverse events (TEAEs), serious TEAEs 
(SAE), treatment-related TEAEs, adverse events of special interest (AESI), Bleeding events, 
ECOG PS, vital signs, clinical laboratory evaluations, and ECG) 
•
Analyses on PRO (EORTC-QLQ-C30, NSCLC-SAQ,EQ-5D-5L, PGIS, PGIC and IL-29). See 
section 16.4
•
Further evaluations on PD-L1 assays may be included in this analysis e.g. TEAEs and AESI 
by PD-L1 assays status (as described in section 15.5)
•
Additionally descriptive statistics of demographics and baseline characteristics in subjects with 
and without bleeding events may be included (as described in section 15.2.4).
Overview of Planned Analyses after Trial Discontinuation
At the time of the PFS IA the IDMC recommended to terminate the study. Based on this 
recommendation, the Sponsor decided to discontinue the clinical study MS200647-0037 as the 
study was unlikely to meet the primary endpoints. Therefore, the analyses described in Sections 
6.1 - 6.5 will not be performed as planned, but one primary analysis will be performed for reporting 
purpose. The analyses considered relevant for this purpose are listed  below:  
•
Participant disposition 
•
Important protocol deviations 
•
Enrollment details (participants randomized by region and country, randomized by strata) 
•
Demographics, medical history and other baseline characteristics (height, weight and BMI at 
baseline, disease history, ECOG at baseline, skin status history, nicotine consumption)  
•
Demographics and baseline characteristics in subjects with and without bleeding events 
•
Previous and concomitant medications, procedures, follow-up treatments
•
Treatment exposure and compliance (e.g. duration of treatment, number of infusions and dose 
intensity)
•
Efficacy analyses: 
o
PFS per RECIST 1.1 as assessed by IRC
o
PFS per RECIST 1.1 as assessed by Investigator
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Bintrafusp alfa (M7824) 1L NSCLC Adaptive Phase III RCT M7824 versus Pembrolizumab
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I N F O R M A T I O N
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o
BOR per RECIST 1.1 as assessed by IRC
o
Duration of response 
o
Overall survival (OS)  
•
Safety analyses (overview of treatment-emergent adverse events (TEAEs), serious TEAEs 
(SAE), treatment-related TEAEs, adverse events of special interest (AESI), Bleeding events, 
ECOG PS, vital signs, clinical laboratory evaluations) 
7
Changes to the Planned Analyses in the Clinical Study Protocol
The statistical methods as described in the protocol will be adopted. There are no changes to the 
planned analyses, except additional outputs that will be generated to assess the potential impact of 
COVID-19 pandemic and described in the Section 7.1 below. 
COVID-19 Impact
No changes to the planned analysis of the efficacy endpoints will be performed due to the impact 
of COVID-19 outbreak. Instead, additional outputs (summary tables and listings) will be generated 
to assess potential impacts of COVID-19 to this study. 
•
An overview table of the impact by COVID-19  
•
An overview table of participants who started the treatment pre/during COVID-19 study 
period 
•
A listing of  COVID-19 impact  
•
A listing of COVID-19 related protocol deviations 
•
A table of treatment-emergent adverse events associated to COVID-19 
•
A listing of AEs related to COVID-19. 
•
A listing of COVID-19 vaccinations. 
Details of the categorization of participants for COVID-19 impact assessment is provided in 
Section 9 and details of the analyses are provided in Sections 10.1, 10.2, 15.1.1, 12.1.
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Bintrafusp alfa (M7824) 1L NSCLC Adaptive Phase III RCT M7824 versus Pembrolizumab
MS200647-0037 - Version 5.0 
C O N F I D E N T I A L
I N F O R M A T I O N
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8
Protocol Deviations and Analysis Sets
Definition of Protocol Deviations and Analysis Sets
Important protocol deviations are protocol deviations that might significantly affect the 
completeness, accuracy, and/or reliability of the study data or that might significantly affect a 
participant's rights, safety, or well-being.  
Important protocol deviations will be identified and confirmed prior to or at each Cross-Functional 
Data Review Meetings and will include: 
• Deviations from the inclusion and exclusion criteria 
• Deviations post inclusion 
Important protocol deviations are listed in a specific document (Merck template 
CS_TP_MS_PD001), deviations to be checked programmatically are identified in this list.
Important protocol deviations list is provided in Appendix 18.3 of this IAP.
All important protocol deviations will be documented in SDTM datasets whether identified 
through site monitoring, medical review or programming. 
Further considerations for PK analysis:
Examples of protocol deviations or important events for PK analysis and PK result interpretation 
may include, but may not be limited to, the following: 
• Dose delayed outside the allowed window 
• Actual dosing time not recorded 
• Dose change or missed dose 
• Pre-dose sample collected after the actual start of infusion
• End-of-infusion sample collected before the actual end of infusion 
• Sample processing errors that may lead to inaccurate bioanalytical results
For the above protocol deviations or important events for PK, the relevant PK data will be excluded 
from summaries based on the PK analysis set (PKAS).
Refer to Section 16.2 for more details of protocol deviations and handling relevant to PK. 
Definition of Analysis Sets and Subgroups
Prescreening Analysis Set (PRESCR)
The prescreening analysis set includes all participants who signed the prescreening informed 
consent. 
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M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
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Scree ni n g A n al ysis Set ( S C R)  
T he scr ee ni n g a nal ysis set i ncl u des all p artici pa nt s wh o si g ne d  t he mai n  i nf or me d c o ns e nt a n d w h o 
are n ot pre-s cree ni n g fail ures, re gar dless of t he partici pa nt ’s ra n d o mizati o n a n d st u d y  i nter ve nti o n 
stat us i n t he st u d y. 
F ull A n al ysis Set  (F A S )  
T he f ull a nal ysis set (F A S ) will i ncl u de all partici pa nt s w h o were ra n d o mi ze d t o eit her bi ntraf us p 
alfa or pe m br oliz u m a b ar m. A nal yses p erf or me d o n t he F A S  set will ta ke i nt o acc o u nt partici p a nt s’ 
all ocati o n t o treat me nt ar ms as ra n d o mize d.  
F ull A n al ysis Set wit h 6 m o nt hs f oll o w -u p ( F A S wit h 6 m f -u p)  
T he F A S wit h 6 m f - u p a nal ysis set will i ncl u de all partici pa nts ra n d o mize d at least 6 m o nt hs bef ore 
c ut-off date w hic h is pla n ne d  at 6 m o nt hs after e nr olli n g t he 1 0 0 t h partici pa nt teste d 7 3- 1 0 P D -L 1  
hi g h. 
S afet y A n al ysis Set ( S A F)   
T he safet y set will i ncl u de all partici pa nt s w h o were a d mi nistere d a n y d ose of a n y I n vesti gati o nal 
Me dici nal Pr o d uct ( I M P, bi ntraf us p alf a  or pe m br oliz u ma b). A nal ys es perf or me d o n t he safet y set 
will  c o nsi der partici pa nt s  as  treate d. Partici pa nts  will  be  classifie d  acc or di n g  t o  t he  treat me nt 
recei v e d at  ra n d o mizati o n  u nless  t he  i nc orrect  treat me nt(s)  was/ were  recei ve d  t hr o u g h o ut  t h e 
d osi n g p eri o d i n w hic h case partici pa nts will be classifie d acc or di n g t o t he first  I M P i nter ve nti o n 
recei v e d. 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
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Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
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 /9 4  
 
 
Ta ble 4  dis pla ys t he use of t he a nal ysis sets i n t he differe nt a nal yses: 
T a ble 4 
O ver vie w of t he A n al ysis Set U se d i n t he A n al yses 
A n al y s e s  
A L L  
F A S  
F A S 
wit h 6 m 
f-u p  
S A F  
P R O  
P K A S  
P arti ci p a nt di s p o siti o n  
 
 
 
 
 
 
I m p ort a nt Pr ot o c ol D e vi ati o n s 
 
 
 
 
 
 
E nr oll m e nt d et ail s  
 
 
 
 
 
 
D e m o gr a p hi c s  
 
 
 
 
 
 
B a s eli n e A s s e s s m e nt s  
 
 
 
* 
 
 
P a st a n d C o n c o mit a nt T h er a pi e s  
 
 
 
 
 
 
C o m pli a n c e a n d E x p o s ur e  
 
 
 
 
 
 
Effi c a c y: Pri m ar y  
 
 
 
 
 
 
Effi c a c y: S e c o n d ar y , O R I A  
 
 
 
 
 
 
Effi c a c y: S e c o n d ar y , O R I A 
s e n siti vit y a n al y s e s  
 
 
 
 
 
 
Effi c a c y: S e c o n d ar y  
 
 
 
 
 
 
S af et y a n d T ol er a bilit y  
 
 
 
 
 
 
P R O q u e sti o n n air e s  
 
 
 
 
 
 
*O nl y t h e f oll o wi n g t a bl e s: Di s e a s e hi st or y; H ei g h t, W ei g ht a n d B o d y M a s s I n d e x. 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI
C CI


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M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
F or i ncl u di n g baseli ne v aria bles i nt o C o x's pr o p orti o nal hazar ds m o del a n d l o gistic m o dels t he 
f oll o wi n g para meterizati o n is t o be use d. F or varia bles wit h m ore t ha n t w o cate g ories, a n i n dicat or 
varia ble will be d efi ne d f or eac h cate g or y e xce pt f or t he first cate g or y, w hic h al wa ys d efi nes t he 
refere nce. I n case of l o w n u m ber of partici pa nt s wit hi n a cate g or y (i.e. 2 0 partici pa nt s), cate g ories 
ma y be p o ole d. 
 
 
T he f oll o wi n g s u b gr o u ps will be defi ne d: 
A ge  
•  a ge < 6 5 y ears ( Ref ) 
•  a ge ≥ 6 5 years  
A ge 2: 
•  a ge < 7 5 y ears ( Ref ) 
•  a ge  ≥  7 5 years 
Se x  
•  Male ( Ref)  
•  Fe male  
Race  
•  Ca ucasia n  / W hite ( R ef)  
•  Asia n  
•  Ot her  
Et h nicit y  1: 
•  Ja pa nese  
•  N ot Ja pa nese  ( Ref) 
Et h nicit y 2: 
•  His pa nic or Lati n o  
•  N ot His pa nic or Lati n o ( Ref) 
E C O G P S  at baseli ne 
•  E C O G P S 0 ( Ref)  
•  E C O G P S 1  
N S C L C Hist ol o g y:  
•  S q ua m o us cell car ci n o ma ( Ref) 
•  N o n -s q ua m o us cell carci n o ma 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI
C CI


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M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
S m o ki n g stat us: 
•  N e ver s m o ker ( Ref) 
•  E ver s m o ker 
P D -L 1 test use d f or partici pa nt e nr oll me nt: 
•  2 2- C 3 1 
•  7 3- 1 0 ( Ref) 
Pri or ra di ot hera p y: 
•  Yes  
•  N o ( Ref)  
Pri or  c yt ot o xic t hera p y: 
•  Yes  
•  N o ( Ref)  
Brai n lesi o ns at baseli ne:  
•  Yes  
•  N o ( Ref)  
P o ole d Re gi o n: 
•  N ort h A merica  ( Ref) 
•  E ur o pe 
•  Asia  
•  Lati n A merica  
A D A stat us:  
•  E ver p ositi ve ( Ref) 
•  Ne ver p ositi ve 
 
1 E nr oll me nt b y l ocal 
 is p ossi ble o nl y if t he pre-scree ni n g 
i nf or me d c o nse nt was si g ne d u p u ntil a n d i ncl u di n g 2 3 Se pte m ber. Fr o m 2 4 Se pte m ber 2 0 1 9 o n war ds o nl y e nr oll me nt 
b y Ce ntral 7 3 -1 0 P D -L 1 ( D A K O) assa y was all o we d.  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
9  
Ge ner al S pecific ati o ns f or D at a A n al yses  
U nless ot her wis e i n dicat e d all a nal yses will be prese nte d se paratel y f or t he t w o treat me nt ar ms 
( bi ntraf us p alf a a n d pe m br oliz u ma b).  
F or  t he I D M C meeti n gs,  o pe n sessi o n ta bles will  be  prese nte d  wit h  treat me nt ar ms c o m bi ne d ( o nl y 
t otal c ol u m n will be dis pla ye d); cl ose d sessi o n ta bles will  i ncl u de se parat e c ol u m ns f or t he t w o 
treat me nt ar ms a n d a t otal c ol u m n w he n a p pr o pri ate. 
T he  s u m mar y  of  o ut p uts t o  be  pr o d uce d f or  o pe n  a n d/ or cl ose d sessi o n f or I D M C meeti n gs is 
prese nte d i n Ta bl e 5 . 
T a ble 5 
O ut p uts  t o  be  pr o d uce d  f or  o pe n  a n d/ or  cl ose d  sessi o ns  of  t he  I D M C 
m eeti n gs  
A n al y s e s  
I D M C m e eti n g o p e n 
s e s si o n  
I D M C m e eti n g 
cl o s e d s e s si o n  
P arti ci p a nt  di s p o siti o n  st at u s  
 
 
I m p ort a nt Pr ot o c ol D e vi ati o n s 
 
 
E nr oll m e nt d et ail s  
 
 
S u m m ar y of ti m eli n e s s/ cl e a nli n e s s of D at a  
 
 
D e m o gr a p hi c s  a n d ot h er b a s eli n e c h ar a ct eri sti c s  
 
 
Tr e at m e nt d ur ati o n  
 
 
Effi c a c y a n al y s e s*  
 
 
S af et y a n al y s e s  
 
 
* Effi c a c y a n al y si s will b e pr o vi d e d i n a d diti o n t o o ut p ut s f or r e g ul ar I D M C s af et y m e eti n g s o nl y f or effi c a c y a s s e s s m e nt s 
I D M C m e eti n g s. 
D at a h a n dli n g after c ut off d ate : 
Data  after  t he c ut off will  n ot  be  dis pla ye d  i n  a n y  listi n gs  or  use d  f or s u m mar y  statistics,  e. g. 
la b orat or y val ues of sa m ples ta ke n after data c ut off, A Es wit h o nset date after data c ut off, etc. will 
n ot be i ncl u de d i n a n y a n al ysis or listi n g.  
St o p dates are n ot affecte d b y t his r ule, e. g. a st o p date of A Es, w hic h starts pri or t o t he c ut off, b ut 
st o ppe d  after d ate of c ut off, will n ot be c ha n g e d. 
D ata c ut will occ ur bef or e t he a nal ysis data b ase creati o n pr ocess,   i.e. o n t h e S D T M i n i n p ut t o t he 
pr ocess f or t he A D A M cr eati o n.  
P o oli n g of ce nters:  
Beca use  of  t he  hi g h  n u m ber  of  partici pati n g  ce nters  a n d  t he  a ntici p ate d  s mall  n u m ber  of 
partici pa nt s r a n d o mize d i n eac h ce nt er d ata will be p o ole d acr oss ce nters, a n d t he fact or ce nter 
will n ot be c o nsi dere d i n statistical m o dels or f or s u b gr o u p a nal yses.  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI


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M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
U nsc he d ule d assess m e nts  
As per data b ase defi niti o n, t he u nsc he d ule d safet y assess me nts are al w a ys li n ke d t o a sc he d ule d 
ti me p oi nt (eac h u nsc he d ule d assess me nt is li n ke d t o t he pre vi o us sc he d ule d ti me p oi nt). Safet y 
data  retri e ve d  fr o m  a n  u nsc he d ule d  ti me  p oi nt  ( v ital si g ns,  E C G  a n d la b orat or y  data)  will  be 
a nal yze d acc or di n g t o t he f oll o wi n g sce nari o: 
•  F or s hift ta ble s, t he y will be ta ke n i nt o acc o u nt i n  t he defi niti o n of t he w orst assess me nt 
d uri n g t he st u d y 
•  F or des cri pti o n at eac h ti me p ost -baseli ne p oi nt, t he first a vaila ble res ult (i n c hr o n ol o gical 
or der) will be ta ke n i nt o acc o u nt i n t he a n al ysis i n case of m ulti ple val ues. 
F or d escri pti o n at bas eli ne, t he last a v aila ble res ult bef ore ra n d o mizati o n will be ta ke n i nt o acc o u nt 
i n t he a nal ysis i n case of m ulti ple val ues. 
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 descri pti ve statistics, i.e.  
•  n u m ber of partici p a nt s ( N), n u m ber of p artici pa nt s wit h missi n g val ues  
•  mea n, sta n dar d d e viati o n ( St D) 
•  me dia n, 2 5t h Perce ntile - 7 5t h Perce ntile ( Q 1 -Q 3),  
•  mi ni m u m a n d ma xi m u m . 
If t here ar e n o missi n g val ues t his s h o ul d be i n dicate d b y a 0. 
Q ualitati ve varia bles will be 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 be base d o n t he n u m ber of partici pa nt s 
of t he a nal ysis set of i nterest. T h eref ore,  c o u nts of missi n g o bser vati o ns will be i ncl u de d i n t h e 
de n o mi nat or a n d pr ese nt e d as a se p arat e cat e g or y.  
Defi niti o n of b aseli ne  a n d c h a n ge fr o m b aseli ne: 
T he last n o n -missi n g meas ure me nt pri or t o ra n d o mizati o n or pri or t o t he first d ose of I M P will 
ser ve as t h e baseli ne meas ure me nt, de pe n di n g of t he t y pe of a n al ysis. Details are gi ve n i n t he ta ble 
bel o w: 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
T a ble 6 
B aseli ne d ate t o be use d i n t he a n al yses  
A n al y si s  
D at e of r a n d o mi z ati o n*  
D at e of st art of fir st 
d o s e of I M P  
Di s p o siti o n  
 
 
Pr ot o c ol d e vi ati o n s  
 
 
D e m o gr a p hi c s a n d ot h er s b a s eli n e 
c h ar a ct eri sti c s  
 
 
M e di c al hi st or y  
 
 
C o n c o mit a nt m e di c ati o n s, Pr e vi o u s/ 
S u b s e q u e nt a nti c a n c er t h er a p y  
 
 
Tr e at m e nt e x p o s ur e a n d c o m pli a n c e  
 
 
Effi c a c y ( O S, P F S, B O R …)  
 
 
S af et y ( T E A E, S A E, A E SI …)  
 
 
L a b or at or y e v al u ati o n  
 
 
Vit al si g n s  
 
 
Ot h er s af et y ( E C G/ E C O G)  
 
 
P R O  
 
 
* If t h e l a st n o n-mi s si n g m e a s ur e m e nt pri or t o r a n d o mi z ati o n i s n ot a v ail a bl e, t h e l a st m e a s ur e m e nt pri or t o t h e fir st 
st u d y tr e at m e nt a d mi ni str ati o n will b e u s e d wit h t h e e x c e pti o n of pr e -r a n d o mi z ati o n a s s e s s m e nt s u s e d f or t h e d eri v ati o n 
of effi c a c y e n d p oi nt s ( e. g. t u m or a s s e s s m e nt at b a s eli n e, w hi c h will b e s et t o mi s si n g, if n ot d o n e pri or t o r a n d o mi z ati o n).  
 
F or t he p ur p os es of t he d escri pti o n of baseli ne c haracteristics o n t he f ull a n al ysis set, t he baseli ne 
val ue of saf et y par a meters s uc h as vital si g ns will be defi ne d as t he last n o n -missi n g 
meas ure me nt pri or t o ra n d o mizati o n. Si milarl y, s u b gr o u p classificati o n bas e d o n baseli ne val u es 
will be deri ve d usi n g t he last n o n- missi n g meas ure me nt pri or t o ra n d o mizati o n. 
If a n assess me nt t hat is pla n ne d t o be p erf or me d bef ore ra n d o mizati o n, or first d ose of I M P per 
pr ot oc ol is perf or me d o n t he sa me da y as  t he ra n d o mizati o n or start date  of  f irst d ose of  I M P, 
res pecti vel y, b ut t h e ass ess me nt ti me is n ot a vaila ble, it will be ass u me d t hat it was perf or me d 
pri or  a n d  will  be  c o nsi d ere d  f or  deri v ati o n  of  baseli ne.  If  a  sc he d ule d  pre -d ose  meas ure m e nt 
act uall y occ urre d p ost -d ose, t he n t he c orres p o n d i n g meas ure me nt will be a nal yze d si milar t o a n 
u nsc he d ule d p ost- d ose m eas ure m e nt.  
A bs ol ute a n d per ce nt c h a n ges fr o m baseli ne are d efi ne d as:   
a bs ol ute c ha n ge = ti me p oi nt val ue – baseli ne val u e  
perce nt c ha n ge = 1 0 0 * (ti me p oi nt val ue – baseli ne val ue) / bas eli ne val ue  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
St u d y D a y/ Tre at m e nt D a y 
St u d y da y 1 is relati ve t o ra n d o mizati o n a n d treat me nt da y 1 is relati ve t o first d ose of I M P, t he 
use of st u d y da y 1 or treat me nt da y 1 de pe n d o n t he t y pe of a nal ysis, as detaile d i n  Ta ble 6  of t his 
d oc u me nt. 
Defi niti o n of o n -tre at m e nt peri o d: 
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 I M P i nter v e nti o n t o  t he  last I M P 
i nter ve nti o n date + 3 0 d a ys O R t he earliest date of s u bse q ue nt a ntica n cer  t hera p y mi n us 1 da y, 
w hic he ver occ urs first, u nless ot her wise state d. Date s of s u bse q ue nt a ntica ncer t hera p y i ncl u de 
dates of s u bse q ue nt a ntica ncer dr u g t hera p y, dat es of s u bse q ue nt a ntica ncer ra di ot hera p y, dat es of 
s u bse q ue nt a ntica ncer s ur ger y. N ote t hat t he o n-treat me nt peri o d will i ncl u de t he i nitial treat me nt 
peri o d as well as t he rei nitiati o n of treat me nt peri o d, as a p plica ble . W het her a partici pa nt rei nitiates 
treat me nt (f oll o wi n g t he r ules as o utli ne d i n t he pr ot oc ol) or n ot, 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 I M P i nter ve nti o n  a d mi nistrati o n  t o  t he  last I M P  i nter ve nti o n 
a d mi nistrati o n date + 3 0 da ys or t he earliest date of s u bse q ue nt a ntica ncer dr u g (a ntica ncer t hera p y, 
a ntica ncer  s ur ger y  a n d  a ntica ncer  ra di ot hera p y)  t hera p y mi n us  1  da y,  w hic he ver  o cc urs  first, 
u nless ot her wise state d.  
F or a nal ys es o n i m m u ne -relate d a d v erse e v e nts a n e x pa n de d o n-treat me nt p eri o d will be use d. See 
secti o n 1 5. 2. 3. 2  f or details. 
Defi niti o n of d ur ati o n:  
D urati o n will be cal c ulat e d b y t he diff ere n ce of st art a n d st o p date + 1 (e. g. s ur vi val ti me ( d a ys) = 
date of deat h – date of ra n d o mizati o n + 1) (if n ot ot her wise s pecifie d). 
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 .   
Ti m e si nce i niti al c a ncer di a g n osis  
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 m e si nce d oc u m e nte d, l oc all y a d v a nce d, i n o per a ble or met ast atic dise ase  
Ti me si nce d oc u me nte d, l ocall y a d va nce d, i n o pera ble or met astatic disease ( m o nt hs) = ( dat e of 
ra n d o mizati o n – 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)/ 3 0. 4 3 7 5 
Nic oti ne c o ns u m pti o n: d ur ati o n of c o ns u m pti o n  
T he d urati o n of nic oti ne c o ns u m pti o n is c o m p ute d as f oll o ws:  
•  If a s u bject is a f or mer s m o ker, t he differe n ce i n years bet w ee n e n d date a n d start date of 
nic oti ne c o ns u m pti o n is c o m p ute d (e n d dat e of ni c oti ne c o ns u m pti o n – start date of 
nic oti ne c o ns u m pti o n + 1 ) / 3 6 5. 2 5 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
•  If a s u bject is a c urr e nt s m o ker, t he differe n ce i n years bet w ee n nic oti ne c o ns u m pti o n 
c ollecti o n date a n d start date of nic oti ne c o ns u m pti o n is c o m p ute d. ( nic oti ne c o ns u m pti o n 
c ollecti o n d ate – start dat e of nic oti ne c o ns u m pti o n + 1 ) / 3 6 5. 2 5 
Nic oti ne c o ns u m pti o n: ye ars si nce q uitti n g  
Years si nce q uitti n g is c o m p ute d f or f or mer s m o k ers o nl y as (c ollecti o n of nic oti ne c o ns u m pti o n 
dat e - e n d d ate of s m o ki n g + 1 )/ 3 6 5. 2 5. 
C o n versi o n f act ors: 
T he f oll o wi n g c o n v ersi o n fact ors will be us e d t o c o n vert da ys i nt o m o nt hs or years: 1 m o nt h = 
3 0. 4 3 7 5 da ys, 1 year = 3 6 5. 2 5 da ys. 
H a n dli n g of missi n g d at a: 
U nless ot her wise s pecifie d  i n t his I A P, missi n g data will n ot be i m p ute d .  
Missi n g statistics, e. g. w he n  t he y ca n n ot be calc ul ate d, s h o ul d be prese nte d as “ n d”.  F or e xa m ple, 
if n = 1, t he meas ur e of v aria bilit y (St D ) ca n n ot be c o m p ute d a n d s h o ul d be prese 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 dates ( d ate of i nf or me d c o nse nt, date of birt h ) f or t he calc ulati o n of a ge will be i m p ute d 
as f oll o ws:  
•  I n case of missi n g da y f or at least o ne d ate, b ut m o nt h a n d year a vaila ble f or b ot h dates:  
t he da y of i nf or me d c o ns e nt a n d t he da y of birt h will be set t o 1. 
•  I n case of missi n g m o nt h f or at least o ne date, b ut year a v aila ble f or b ot h dates, t h e d a y 
a n d t he m o nt h of i nf or me d c o nse nt a n d t he da y a n d m o nt h of birt h will be set t o 1. 
I n c o m plete dates f or disease hist or y ( date of i nitial ca ncer dia g n osis, date of d oc u me nte d, l ocall y 
a d va nce d, i n o pera bl e or me tastatic disease dia g n osis) a n d dates of nic oti ne c o ns u m pti o n: 
•  If t he da y is missi n g, it will be i m p ute d t o t he 1st da y of t he m o nt h.  
•  If b ot h da y a n d m o nt h ar e missi n g, t he m o nt h a n d da y will be i m p ute d as Ja 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.  
I n c o m plete dates f or c o n c o mita nt me dicati o ns will be i m p ute d as f oll o ws:  
F or start d ate of me dicati o n : 
•  If t he da y is missi n g, it will be i m p ute d t o t he 1st da y of t he m o nt h.  
•  If b ot h da y a n d m o nt h ar e missi n g, t he m o nt h a n d da y will be i m p ute d as Ja 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.  
Gl o bal Versi o n I D:
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
F or e n d d ate me dicati o n:  
•  If t he da y is missi n g, it will be i m p ute d t o t he last da y of t he m o nt h.  
•  If b ot h da y a n d m o nt h ar e missi n g, t he m o nt h a n d da y will be i m p ute d as Dece m b er 3 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. 
N ote: I n case t he i m p utati o n re s ults i n a d ate l ater t ha n t he dat e of patie nt's deat h, t he n t h e dat e of 
deat h will be use d t o i m p ute t he i nc o m plete st o p date. 
I n c o m plete  dates  f or  start  date  of  s u bse q ue nt  a ntica ncer  t hera p y  ( dr u g  t hera p y,  ra di ot hera p y, 
s ur ger y) will be i m p ute d as f oll o ws a n d will be us e d f or deter mi ni n g ce ns ori n g dates f or effi cac y 
a nal yses a n d i n t he d eri v ati o n of t he e n d of o n-treat me nt peri o d: 
•  If o nl y da 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 ntica n cer t hera p y is b ef ore t hat dat e. I n t hat case, t h e i nc o m plete a ntica ncer 
t hera p y start dat e will be i m p ute d as t he e n d date of t he a ntica n cer t hera p y. 
•  If b ot h da y a n d m o nt h ar e missi n g, n o i m p utati o n will be perf or me d.  
I n c o m plete s u bse q ue nt a ntica ncer t h era p y st o p dates will n ot be i m p ute d.  
I n c o m plete A E-relate d d ates will be i m p ute d as f oll o ws:  
•  I n case t h e o nset date is missi n g c o m pletel y or missi n g partiall y b ut t he o nset m o nt h a n d 
year, or t he o nset y ear ar e e q u al t o t he start of I M P t he n t he o ns et date will be re place d b y 
t he mi ni m u m of start of I M P a n d A E res ol uti o n date (if n ot missi n g).  
•  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. 
•  I n c o m plete st o p dates will be re place d b y t he last d a y of t he m o nt h (if da y is missi n g o nl y), 
if n ot res ulti n g i n a dat e l ater t ha n t h e date of p artici pa nt 's deat h. I n t he latter cas e t he d ate 
of deat 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.   
I n c o m plete date of deat h:  
F or t he p ur p ose of s ur vi v al a nal yses  ( P F S a n d O S), partiall y missi n g deat h dates will be i m p ute d 
as f oll o ws: 
•  If o nl y t he da y is missi n g, t he deat h date will be i m p ute d t o t he ma xi m u m bet wee n:   
 T he da y after t he last k n o w n ali ve date ( n o n-i m p ute d date) a n d  
 1 5t h da y of t he m o nt h 
•  Ot her wise it will n ot be i m p ute d  
  
O utsi de s ur vi val a nal yses n o deat h i m p utati o n is d o ne. 
I n c o m plete date of first d ose of I M Ps: 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
I n case t he date of first d ose of I M P is missi n g, it is ass u me d t hat t h e first d ose of I M P is gi ve n at 
t he ra n d o mizati o n date. T he r a n d o mizati o n date will re place i nc o m plete d ates of t h e first d os e of 
I M Ps. Partial  dates, w hi c h are n ot t o be i m p ute d acc or di n g t o t he I A P, will be prese nte d i n t he 
f or mat li ke “ _ _ _ _ _ Y Y Y Y”. If val u es are i m p ute d acc or di n g t o t he I A P, i m p ute d val ues will be 
prese nte d i n partici pa nt d ata listi n gs a n d i m p ute d i nf or mati o n will be fla g ge d. 
H a n dli n g r ules f or t u m or assess m e nts  
If  t here  are  m ulti ple  sca n  dates  ass ociate d  wit h  a n  e val uati o n,  t he  earli est  of  t he  sca n  dates 
ass ociate d wit h t he e v al u ati o n will be use d as t he date of assess m e nt.  
Pref erre d ter m f or a n al ysis of W H O - D D c o de d d at a: 
F or d ata c o de d acc or di n g t o W H O -D D (e. g., c o n c o mita nt me dicati o ns), s u m maries will be d o n e 
o n t he pref err e d ter m le v el w here t h e preferre d ter m is c orres p o n di n g t o c o des e n di n g i n 0 1 0 0 1. 
Wit h t his a p pr oac h, variati o ns of salt f or ms of acti ve i n gre die nts wi ll be a n al yze d u n der t he sa me 
ter m,  e. g.  di p he n h y dra mi ne  a n d  di p he n h y dra mi n e  h y dr oc hl ori de  will  be  a nal yze d  as  t he  sa me 
preferre d t er m di p he n h y dra mi ne.  
D at a c ollecte d aft er rei niti ate d tre at me nt:  
Data  c ollect e d  after  rei nitiati o n  of  treat me nt  will  be  i ncl u de d i n  t he  s u m mar y  statistics. Data 
listi n gs  will  i ncl u de  b ot h  data  c ollecte d  d uri n g  t he  first  peri o d  of  treat me nt,  a n d  d uri n g  t he 
rei nitiati o n  of  treat me nt  (e xce pt  f or  listi n gs  dis pla yi n g  para meters  deri ve d  d uri n g  t he  first 
treat me nt peri o d o nl y). D ata collecte d d uri n g t he rei nitiati o n of treat me nt will be fla g ge d.  
Re -scree ne d p arti ci p a nt s 
Re- scree ne d p artici pa nts will be o nl y c o u nte d o nce i n t he scree ni n g a nal ysis set, c o nsi deri n g t he 
latest scr ee ni n g (s cree ni n g wit h latest i nf or me d c o nse nt).  If a partici pa nt  is re-s cree ne d se veral 
ti mes,  t he n  he  will  be  c o u nte d o nl y  o nce  i n  t he  dis p ositi o n  ta ble i n  t he  n u m ber  of re-scree n e d 
partici pa nt s. 
Defi niti o n of P re-, D uri n g-, P ost-p a n de mic Ti me Peri o ds  
P artici pa nts will be cate g orize d bas e d o n t he C O VI D - 1 9 st u d y peri o d defi n e d as: 
•  Pre -pa n de mic ti me p eri o d: s u bjects w h o starte d t h e treat me nt b ef ore t he start of C O VI D - 1 9 
pa n de mic.  
•  D uri n g- pa n de mic ti me p eri o d: s u bjects w h o starte d t he treat me nt o n t he sa me date or after 
t he start of C O VI D- 1 9 pa n de mic 
•  P ost- pa n de mic ti me peri o d: t he e n d of pa n de mic is c o nsi dere d n ot yet reac he d a n y w here  at 
t he ti me of t his I A P versi o n re d acti o n, c o ns e q ue ntl y n o partici pa nt will be gr o u pe d i nt o t he 
p ost C O VI D - 1 9 st u d y peri o d f or t his st u d y a n d n o p ost-pa n de mic date will b e defi ne d.  
T he start of C O VI D -1 9 p a n de mic is defi ne d b y c o u ntr y as t he earliest date of eit her t he dat e of t he 
first deat h fr o m C O VI D-1 9 occ urre d i n eac h c o u ntr y acc or di n g t o t he p u blis he d data b y E ur o pea n 
Ce ntre  
f or  
Diseas e  
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 p a.e u/e n/ p u blicati o ns- data/ d o w nl oa d-t o da ys-data - g e o gra p hic-
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI


Bintrafusp alfa (M7824) 1L NSCLC Adaptive Phase III RCT M7824 versus Pembrolizumab
MS200647-0037 - Version 5.0 
C O N F I D E N T I A L
I N F O R M A T I O N
38/94
distribution-covid-19-cases-worldwide) or 11th March 2020 (when the WHO declared COVID-
19 pandemic). 
Software: 
All analyses will be performed using SAS 9.4 or higher in the SAS Grid environment. 
10
Study Participants 
The subsections in this section include specifications for reporting participant disposition and 
treatment/study discontinuations.  Additionally, procedures for reporting protocol deviations are 
provided (see Section 10.2).
Disposition of Participants and Discontinuations
Descriptive statistics will be used to summarize participant disposition and reason for 
discontinuation, based on the electronic case report form (eCRF) data. 
The following information will be reported: 
• Total number of participants prescreened
• Number of participants who did not continue beyond prescreening overall and grouped by 
reason (reason related to central testing, reason related to local testing, reason independent 
of local/central testing)
• Number of participants who completed the pre-screening (pre-screening ICF signed), but 
have not signed the main ICF yet
• Total number of screened participants 
• Total number of re-screened participants 
• Number of participants who did not continue beyond screening overall and grouped by 
reason (participant did not meet all eligibility criteria, withdrew informed consent, 
progressive disease, adverse event, lost to follow-up, death, other) 
• Number of participants who completed the screening (main ICF signed), but have not been 
randomized yet 
• Number of randomized participants overall and by treatment arm  
• Number of randomized participants who did not receive any treatment  
• Number of randomized participants with treatment on-going in each treatment arm 
• Number of randomized participants off treatment, grouped by treatment arm and main reason
• Number of randomized participants with treatment reinitiated
• Number of randomized participants with treatment on-going after reinitiation
• Number of randomized participants who discontinued treatment after reinitiation
Global Version ID: 
Global Version ID: CCI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
•  N u m ber of r a n d o mize d p artici pa nt s w h o disc o nti n ue d t he treat me nt b ut are still i n st u d y f or 
f oll o w- u p, gr o u pe d b y tr eat me nt ar m 
•  N u m ber of ra n d o mize d p artici pa nt s w h o disc o nti n ue d t he st u d y, gr o u pe d b y treat me nt ar m 
a n d mai n reas o n  (as r e p orte d o n “ St u d y ter mi nati o n” pa ge of t h e e C R F). 
I n  a d diti o n,  t he  n u m b er  of partici pa nt s  i n  eac h  a nal ysis  set  d efi ne d  i n  Secti o n 8. 2  will  b e 
s u m marize d. T he per ce nt a ge of partici pa nt s wit h perce nt a ge based o n t he n u m ber of partici pa nt s 
i n t he F A S p o p ulati o n will be prese nte d . T h e dis p ositi o n of partici pa nt s ma y  als o be pres e nte d 
wit h s o me P D -L 1 assa y i nf or mati o n i n a C O N S O R T dia gra m (e. g. P D-L 1 assa y test perf or me d 
f or  t he  i ncl usi o n; D a k o  7 3- 1 0, 
 res ults). T he  discre pa n cies  bet w ee n 
pla n ne d  a n d  treate d ar ms will  be  cr oss -ta b ulat e d  a n d  pr o vi de d  i n  a  listi n g. T he  n u m ber  of 
ra n d o mize d partici pa nts as per I nteracti ve Res p o nse Tec h n ol o g y ( I R T) b y re gi o n a n d c o u ntr y will 
be pr o vi de d, as w ell as t he n u m ber of p artici pa nt s b y ra n d o mizati o n strata (as per I R T). 
F or t he I D M C meeti n gs, t i meli ness a n d Clea nli ness  of t he data  will  be s u m marize d as f oll o ws: 
F or  partici pa nts w h o  ar e still o n treat me nt:  
•  N u m ber  of partici pa nt s wit h  last  o n-st u d y safet y i nf or mati o n ( A Es, La bs,  V S , Ot her  safet y 
e val uati o ns: E C G, E C O G) e nter e d i nt o t he data  e xtract  
•  Wit hi n  1 m o nt h pri or t o t he data  c ut off date  
•  Bet wee n  1 a n d 2 m o nt hs pri or t o t he data  c ut off date 
•  Bet wee n  2 a n d 3 m o nt hs pri or t o t he data  c ut off date 
•  M ore  t ha n 3 m o nt hs pri or t o t he data  c ut off date  
•  N o  i nf or mati o n 
F or  partici pa nts w h o  ha v e  ha d  t heir e n d of  treat me nt visit:   
•  N u m ber of partici pa nts i n t he f oll o w- u p p hase wit h  a n d wit h o ut f oll o w- u p i nf or mati o n 
•  A m o n g partici pa nt s wit h  f oll o w- u p i nf or mati o n, n u m ber of partici pa nts wit h o ut a deat h  re p ort 
i n t he f oll o w- u p p hase 
•  A m o n g partici pa nt s w it h f oll o w- u p i nf or mati o n a n d n o deat h  re p ort i n t he f oll o w- u p p hase,  
n u m ber of partici pa nt s wit h  last f oll o w- u p date  (fr o m t he Partici pa nt Stat us/ S ur vi val F oll o w-
U p  e C R F pa ge) 
•  Wit hi n  1 m o nt h pri or t o t he data  c ut off date  
•  Bet wee n  1 a n d 2 m o nt hs pri or t o t he data  c ut off date 
•  Bet wee n  2 a n d 3 m o nt hs pri or t o t he data  c ut off date 
•  M ore  t ha n 3 m o nt hs pri or t o t he data  c ut off date  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
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T he listi n g of partici pa nt  dis p ositi o n will i ncl u de all partici pa nt s (i.e. pre-scree n e d partici pa nts, 
pre -scree ni n g fail ures, p artici pa nt s i ncl u de d i n scree ni n g, scree ni n g fail ures, b ut n ot re-scree ne d 
partici pa nt s). T h e  listi n g  will  i ncl u de  t he  f oll o wi n g  i nf or mati o n  (if  a p plica ble):  pla n n e d  ar m 
(partici pa nt s  h a vi n g  act u al  ar m  differe nt  fr o m  pl a n ne d  ar m  will  b e  fl a g g e d a n d  dis pla ye d  i n  a 
se parat e  listi n g), partici p a nt  i de ntifier, d ate  of pre scree ni n g  i nf or m e d  c o nse nt,  i ncl u de d  i n  t h e 
scree ni n g p hase a n d reas o n f or e xcl usi o n, d ate of  mai n  i nf or m e d c o ns e nt, i ncl u de d i n t he st u d y, 
reas o n f or e xcl usi o n, ra n d o mizati o n date, first/last treat me nt date, reas o n off-treat me nt, date a n d 
reas o n  off-st u d y,  p o p ulati o n  fla gs. W he n  t he  reas o ns,  s uc h  as 
t he reas o n off -treat me nt  is 
cate g orize d  as “ Ot her, s p ecif y” or “ Wit h dre w c o nse nt fr o m treat me nt, s pecif y” , t he ver b ati m  te xt 
as e nter e d i n t he e C R F will  be prese nte d  i n t he listi n g. 
If a n y  r e-scree n e d partici pa nt s  will  be  o bser ve d,  t he  listi n g  of  re-scree ne d  partici pa nts  will  be 
pr o vi de d a n d will i ncl u d e t he f oll o wi n g i nf or m ati o n: pla n ne d ar m, p artici pa nt  i de ntifier, dat e of 
i nf or me d  c o ns e nt,  ra n d o mizati o n  date, p artici pa nt  i de ntifier  at  scree n  fail ure,  dat e  of  i nf or me d 
c o nse nt at scr ee n f ail ure, date of scr ee ni n g fail ure, reas o n of s cree ni n g fail ure.  
I n a d diti o n, a listi n g of partici pa nts f or w hic h st u d y treat me nt has b ee n rei nitiate d will be pr o vi de d 
wit h t he f oll o wi n g i nf or mati o n: par tici pa nt i de ntifier, date of ra n d o mizati o n, pla n ne d treat me nt,  
date  of  first I M P i nter v e nti o n,  date  of  last I M P  i nter ve nti o n, date  a n d  reas o n  f or  treat me nt 
ter mi nati o n (if treat me nt is disc o nti n ue d), as a p plica ble. 
F or t he I D M C meeti n gs, Ka pla n -M eier’s pl o ts of ti me t o treat me nt disc o nti n uati o n a n d ti me t o 
st u d y disc o nti n uati o n will be pr o vi de d (if m ore t ha n 1 0 e ve nts will be o bser ve d). 
I n  a d diti o n,  f or  t he  assess me nt  of  C O VI D-1 9  i m pact  o n  t his  st u d y, a n  o ver vie w  ta ble  will  be 
prese nte d b y tr eat me nt ar m wit h t he f oll o wi n g i nf or mati o n: 
•  S u bjects p ote ntiall y affecte d b y C O VI D -1 9 (i.e. s u bjects w h o st arte d treat me nt after start 
of  t he  C O VI D -1 9  p a n de mic,  or  w h o  starte d  treat me nt  pri or  t o  start  of  t he  C O VI D - 1 9 
pa n de mic a n d are still o n g oi n g after t he start of t he pa n de mic)  
•  S u bjects wit h at l east o ne C O VI D - 1 9 i m pact    
•  S u bjects wit h at least o ne C O VI D -1 9 i m pact i n t he f oll o wi n g cate g ories: a d verse e v e nts, 
deat h,  pr ot oc ol  de viati o ns,  misse d  dr u g  a d mi nistrati o n, 
treat me nt  a d mi nistrati o n 
m o dificati o ns, misse d t u m or assess me nts, dela ye d t u m or asse ss me nts, misse d visits, tele-
visits re placi n g o n-site visits, treat me nt disc o nti n uati o n, st u d y disc o nti n uati o n. 
•  N u m ber of s u bjects wit h misse d t u m or assess me nts, dela ye d t u m or assess me nts, misse d 
visits, tele - visits re placi n g o n-site visits ( 1 / 2 / 3 / > 3)  
T he fre q u e nc y distri b uti o n of p artici pa nts w h o starte d t he treat me nt bef ore  or  d uri n g t he pa n de mi c 
per c o u ntr y -s pecific start of C O VI D-1 9 st u d y peri o d (see Secti o n 9  f or details o n t he C O VI D - 1 9 
cate g orizati o n b y st u d y peri o d) will be als o dis pla ye d .  
Gl o bal Versi o n I D: 
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A listing of  COVID-19 impact will be provided with the following information: treatment arm, 
participant identifier, first and last date of treatment administration, date of the event, visit, 
category, event, event description/reason 
Protocol Deviations
Important protocol deviations will be determined for all participants by either medical review 
processes or programming based on the inclusion/exclusion criteria or other criteria presented in 
the protocol and documented in SDTM. The following summary tables and listings of important 
protocol deviations will be provided (separately for pre-/post inclusion deviations): 
•
Frequency table per reason of important protocol deviations 
•
Listing of important protocol deviations. 
Potential impact of COVID-19 pandemic in MS200647-0037 will be evaluated by an analysis of 
protocol deviations: 
•
The summary of important COVID-19 related PDs by category and type of PD will be 
provided 
•
The summary of non-important COVID-19 related PDs by category will be provided 
•
The listing of important protocol deviations will be enriched by the variable “COVID-19
Related Protocol Deviations” flagging all protocol deviations due to COVID-19. 
11
Demographics and Other Baseline Characteristics
Summaries will be presented for the FAS analysis set.  
Demographics
Demographic characteristics will be summarized as follows:  
Demographic characteristics (from “Demographics” e-CRF page)
• Sex: male, female 
• Ethnicity: Hispanic or Latino, not Hispanic or Latino; Japanese, not Japanese
• For participant reporting one race only: White, Black or African American, Asian, American 
Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, Not collected at the site, 
Other 
• For participants reporting several races, all combinations will be reported under ‘More than 
one race” category.  
• Age (years): summary statistics  
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•  Age categories:
o
< 65 years, ≥ 65 years 
o
65-74, 75-84 and ≥85 years
• Geographic Region:  
o
North America
o
Europe 
o
Asia and Pacific
o
Latin America
Specifications for computation: 
Age [years]: (date of given main informed consent - date of birth + 1) / 365.25 
Handling of incomplete dates of birth or informed consent is specified in Section 9 of this IAP, 
paragraph “Handling of incomplete dates”.  
Investigator site codes will be used for the determination of the participant’s geographic region. 
A listing of individual demographics will be also provided. 
Medical History
Relevant past and ongoing medical conditions at baseline will be summarized from the “Medical 
History Details” eCRF page, using the latest available version of Medical Dictionary for 
Regulatory Activities (MedDRA), preferred term as event category and MedDRA system organ 
class (SOC) body term as Body System category.  
Medical history will be displayed in terms of frequency tables: ordered by primary SOC and
preferred term (PT) in alphabetical order. Each participant will be counted only once within each 
PT or SOC.
The related listing will also be provided. 
Other Baseline Characteristics
Analyses of baseline characteristics with respect to ECGs and clinical laboratory evaluations are 
discussed in Section 15 (Safety Analyses).
11.3.1
Vital Signs at Baseline
The following vital signs at baseline will be collected from the “Vital signs” eCRF page and will 
be summarized:
Global Version ID: 
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Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
•  Hei g ht (c m)  
•  Wei g ht at baseli ne ( k g) 
•  B o d y mass i n de x ( B MI) ( k g/ m 2). 
B MI  ( k g/ m 2) will be c o m p ute d as  wei g ht( k g)/[ h ei g ht( m)]2 
1 1. 3. 2  
Dise ase H ist or y 
I nf or mati o n  o n disease  c haracteristics  c ollecte d  o n  t he  “ Dis ease  Hist or y ”  e C R F  p a ge  will  be 
s u m marize d as f oll o ws: 
•  T u m or  hist ol o g y:  a de n ocarci n o ma,  a d e n os q ua m o us  carci n o ma,  s q ua m o us  cell  carci n o ma, 
lar ge  cell  car ci n o ma,  sarc o mat oi d  carci n o ma,  n e ur oen d ocri ne  carci n o m a,  diff use  i di o patic 
carci n o ma, o t h er 
•  Ti me si nce i nitial ca ncer dia g n osis ( m o nt hs), c o m p utati o n details pr o vi de d i n Secti o n 9  
•  Ti me si nce  d oc u m e nte d, l ocall y  a d va n ce d,  i n o pera ble or  metast atic  disease  ( m o nt hs) , 
c o m p utati o n details pr o vi de d i n Secti o n  9  
•  T N M  classificati o n  at  i nitial  dia g n osis  a n d  at  st u d y  e ntr y :  eac h  T,  N,  M  cate g or y  will  be 
descri be d ( T X, T 0, N 1, etc.) 
•  M olec ular a b n or malities:  
o  E G F R  ( m utate d, wil d) 
o  A L K tra nsl ocati o n ( yes, n o) 
o  R O S 1 rearr a n ge me nt  ( y es, n o) 
o  B R A F V 6 0 0 E m utati o n ( yes, n o). 
Disease hist or y will als o be prese nt e d i n a de dicat e d listi n g. 
1 1. 3. 3  
E C O G Perf or m a nce st at us  
T he E C O G Perf or ma nce Stat us  will be deri ve d fr o m t he data c ollecte d o n t he “E C O G  Perf or ma n ce 
Stat us”  e C R F p a ge. It will be des cri be d at b aseli ne b y t he fre q ue n c y a n d p erce nta ge of partici pa nts 
i n eac h cate g or y:  
0: F ull y acti ve, a ble t o carr y o n all pre- disease p erf or ma nce wit h o ut restricti o n.  
1: Restricte d i n p h ysicall y stre n u o us acti vit y b ut a m b ulat or y a n d a ble t o carr y o ut w or k of a li g ht 
or se de ntar y n at ure, e. g., li g ht h o use w or k, office w or k. 
2: A m b ulat or y a n d ca pa ble of all selfcare b ut u na ble t o carr y o ut a n y w or k acti vities. U p a n d a b o ut 
m ore t ha n 5 0 % of wa ki n g h o urs. 
3: Ca pa ble of o nl y li mite d selfcar e, c o nfi ne d t o be d or c hair m ore t ha n 5 0 % of wa ki n g h o urs. 
4: C o m pletel y disa ble d. Ca n n ot carr y o n a n y selfcare. T otall y c o nfi ne d t o be d or c hair. 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
5: Dea d.  
1 1. 3. 4  
S ki n S t at us H ist or y 
S ki n stat us hist or y is c ollecte d o n t he “ S ki n Stat us  Hist or y” e C R F pa g e a n d will be s u m marize d  
b y t he fre q u e nc y a n d p er ce nta ge of partici pa nt s h a vi n g t he f oll o wi n g s ki n stat us hist or y: 
•  Pers o nal hist or y of fr e q u e nt s u n b ur n ( Yes, N o, U n k n o w n) 
•  Pers o nal hist or y of eas y s u n b ur n ( Yes, N o, U n k n o w n) 
•  Pers o nal hist or y of s ki n ca ncer ( Yes, N o, U n k n o w n) 
•  Pers o nal hist or y of si g nifica nt U V e x p os ure ( Y es, N o, U n k n o w n) 
•  Pers o nal hist or y of p h ot ose nsiti vit y d ue t o s ki n dis or der ( Yes, N o, U n k n o w n) 
•  Pers o nal hist or y of p h ot ose nsiti vit y d ue t o me dicati o n ( Yes, N o, U n k n o w n) 
•  Fa mil y  hist or y  of  s ki n  ca ncer  i n  first  de gree  relati ve  (i.e.  pare nts,  si bli n gs  a n d/ or  c hil dre n) 
( Yes, N o, U n k n o w n) 
•  N u m ber of partici pa nt s ha vi n g hist or y of t he s ki n c o n diti o ns a b o ve ( N o c o n diti o ns, 1 c o n diti o n, 
2 c o n diti o ns, 3 or m ore c o n diti o ns). 
1 1. 3. 5  
Nic oti ne C o ns u m pti o n  
T he nic oti ne c o ns u m pti o n i nf or mati o n will be c ollecte d fr o m t he “ Nic oti ne c o ns u m pti o n” e -C R F 
pa ge a n d it will be descri be d as f oll o ws: 
•  Nic oti ne  use:  Ne ver  us e r, E ver  us er  (i ncl u di n g  f urt her  brea k d o w n:  f or mer  /  c urre nt)  as 
c ollecte d i n 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 statistics 
•  Years  si nce 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 
A listi n g of nic oti ne c o ns u m pti o n,  i ncl u di n g treat me nt ar m, partici pa nt i de ntifier, a ge, se x, race, 
will  als o  be  pr o d uce d  wit h  t he  f oll o wi n g  data:  nic oti ne  use  stat us,  start/e n d  date  of  nic oti ne 
c o ns u m pti o n, a n d d urati o n of c o ns u m pti o n ( years). 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI
C CI


Bintrafusp alfa (M7824) 1L NSCLC Adaptive Phase III RCT M7824 versus Pembrolizumab
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12
Previous or Concomitant Medications/Procedures
Summaries will be presented for the FAS analysis set
Concomitant Medications
Concomitant medications are medications, other than IMPs and premedications for IMP, which 
are taken by participants any time on-treatment (see on-treatment definition in Section 9), 
medications taken on the first day of IMP will be considered on-treatment. In case the date values 
will not allow to unequivocally allocate a medication to concomitant medication the medication 
will be considered as concomitant medication. Medications started before the signing of the main 
informed consent and continue past the time of the signing will be categorized as concomitant 
medications.
Concomitant medications are reported on the “Concomitant medications details” eCRF page. 
Summaries on concomitant medications will present the number and percentage of participants by
drug class and preferred term according to the most recent available version of the WHO-DD 
dictionary. 
A participant will be counted only once within a given drug class and within a given drug name, 
even if he/she received the same medication at different times. The summary will be sorted by 
Drug Class and Preferred Term in alphabetical order. 
Concomitant medications will be presented in a listing. The listing will include treatment arm, 
participant identifier, age, sex, race, preferred term and medication name as provided by the 
investigator, start date, end date, dose, dose units, frequency, route, reason for the medication.  The 
listing will be sorted by treatment arm, participant identifier, start date, end date (note that missing 
end date are considered as ongoing and will be displayed after non-missing date in case of same 
start date) and preferred term.
A separate listing of concomitant COVID-19 vaccinations will be provided, this listing will include 
the same information as concomitant medications listing.
Global Version ID: 
Global Version ID: CCI
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Premedications
Premedications are medications administered per protocol on the same day as, but prior to, 
bintrafusp alfa  intervention. In the protocol v.3.0 bintrafusp alfa premedication is an optional 
procedure. 
The number of participants receiving premedication will be summarized for each treatment visit 
based on “Premedication details” eCRF page (participants for whom the question “Has the
participant received premedications before infusion?” is answered “Yes” at the corresponding 
visit).
Percentages will be calculated on the number of participants who actually received an infusion at 
the associated visit.  
Premedications will be presented in a listing from “Premedication Details” eCRF page. The listing 
will include participant identifier, age, sex, race, medication name, visit, date/time of intervention, 
dose, dose units, and route.  The listing will be sorted by participant identifier, premedication start 
date and medication name. 
Concomitant Procedures
All concomitant procedures, which were undertaken any time during on-treatment period are 
collected into the CRF page “Concomitant Procedures Details”. 
Concomitant procedures will be presented in a listing including treatment arm, participant
identifier, age, sex, race, name of procedure (as provided by the investigator), start date, end date, 
indication, and reason for procedure. A flag will be added to identify each procedure as prior to 
treatment and on-treatment. The listing will be sorted by treatment arm, participant indentifier, 
start date, end date (note that missing end date are considered as ongoing and will be displayed 
after non-missing date in case of same start date) and procedure name.
Previous Anticancer Treatments and Procedures
The previous anticancer treatments and procedures are collected under the “Prior Anticancer Drug 
Therapies Details”, “Prior Anticancer Radiotherapy Details”, and the “Prior Anticancer Surgeries 
Details” eCRF pages. 
The number of participants in each of the following anticancer treatment categories will be 
tabulated:
•
Participants with at least one previous anticancer treatment or procedure (i.e. drug therapy, 
radiotherapy or surgery) 
•
Participants with at least one previous anticancer drug therapy 
•
Participants with at least one previous anticancer radiotherapy 
•
Participants with at least one previous anticancer surgery. 
Global Version ID:
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Previous anticancer drug therapy will be summarized as follows:  
•
Type of previous anticancer therapy: Cytotoxic therapy/Endocrine therapy/Monoclonal 
antibodies therapy/Small molecules/Immunotherapy/ Other.
•
Intent of therapy: Neoadjuvant /Adjuvant  
•
Best response of last treatment regimen: complete response (CR)/partial response (PR)/stable 
disease (SD)/non-complete response/non-progressive disease (Non CR/Non PD), progressive 
disease (PD)/not evaluable/unknown.  
Previous anticancer drugs, previous radiotherapy, and previous anticancer surgery will be 
presented in separate listings as follows: 
The previous anticancer drug listing will contain treatment arm, participant identifier, age, sex, 
race, preferred term, medication name, start date, end date, type of therapy, intent of therapy, best 
response and criteria on the last treatment regimen, and date of progression on the regimen.  This 
listing will be sorted by treatment arm, participant identifier, anticancer drug start date, end date 
and preferred term  
The previous radiotherapy listing will contain treatment arm, participant identifier, age, sex, race, 
start date, end date, prior radiotherapy to bone for palliation only, site of therapy, total dose, 
number of fractions and best response on the treatment regimen.  This listing will be sorted by 
treatment arm, participant identifier, radiotherapy start date, radiotherapy end date and site of 
radiotherapy. 
The previous anticancer surgery listing will contain treatment arm, participant identifier, age, sex, 
race, date of surgery, name and site of surgery, curative intent of surgery (Y/N), and outcome of 
surgery.  This listing will be sorted by treatment arm, participant identifier, surgery date and name 
of surgery. 
Anticancer Treatment after Discontinuation
Anticancer treatment after discontinuation of IMP will be summarized according to the eCRF page 
“Anticancer Treatment After Discontinuation” for anticancer drug therapy, “Radiotherapy After 
Discontinuation” for anticancer radiotherapy and to “Surgery After Discontinuation” for 
anticancer surgery. 
The number of participants in each of the following anticancer treatment categories will be 
tabulated:
•
Participants with at least one subsequent anticancer treatment (i.e. drug therapy, radiotherapy 
or surgery)
•
Participants with at least one subsequent anticancer drug therapy 
•
Participants with at least one subsequent anticancer radiotherapy 
•
Participants with at least one subsequent anticancer surgery. 
The type of subsequent anticancer drug therapy as provided in the e-CRF (i.e. Cytotoxic therapy/ 
Endocrine therapy/ Monoclonal antibodies therapy/ Small molecules/ Immunotherapy/ Other) will 
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Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
be descri be d, as w ell as t he  i nte nt of t hera p y ( N e o a dj u va nt/ A dj u va nt) a n d t he best res p o ns e  (C R , 
P R , sta ble disease, P D , n o n-C R / n o n-P D , n ot e val ua ble, u n k n o w n).  
I n a d diti o n, t he a ntica ncer treat me nt after disc o nti n uati o n of I M P will be pr o vi de d i n a d ata listi n g 
i ncl u di n g t y pe of t hera p y, preferre d t er m/ me dicati o n na me, me dicati o n t y p e, re gi me n na m e, best 
res p o nse, start d ate, e n d date, ra di ot hera p y site a n d na me of s ur g er y/l ocati o n. 
1 3  
Tre at me nt C o m pli a nce a n d E x p os ure  
S u m maries will be perf or me d o n S A F a nal ysis set.  
Partici pa nts will be treate d wit h bi ntraf us p alfa or pe m br oliz u ma b at t he f oll o wi n g d oses: 
•  Bi ntraf us p alfa  at a d ose of 1 2 0 0 m g per i nf usi o n o nce e v er y 2 wee ks  
•  Pe m br oliz u ma b at a d ose of 2 0 0 m g per i nf usi o n o nce e v er y 3 wee ks. 
T hese d oses will be a d mi nistere d as “flat” d oses i n de pe n de nt of t he b o d y wei g ht. B ot h treat me nts 
will be a d mi nistere d u ntil P D per R E CI S T 1. 1, u n acce pta ble t o xicit y, or f or u p t o 2 4 m o nt hs. 
All d osi n g calc ulati o ns a n d s u m maries will be base d o n “ St u d y Treat me nt A d mi nistrati o n Details” 
e C R F pa ge. Data c ollecte d d uri n g t he treat me nt rei nitiati o n p hase will be i ncl u de d i n t he s u m mar y 
statistics. 
A d ose is re gar de d t o be a d mi nistere d, if t he act ual d ose recei ve d is > 0 
T he d urati o n of bi ntraf us p alfa treat me nt (i n wee ks) d uri n g t he st u d y is defi ne d as:  
d urati o n = �date of last d ose- date of first d ose + 1 4
7
� 
wit h “last d ose” bei n g t h e last d ose of r ei nitiati o n peri o d , if a p plica bl e. 
T he d urati o n of pe m br oliz u ma b treat me nt (i n wee ks) d uri n g t he st u d y is defi ne d as:  
d urati o n = �date of last d ose- date of first d ose + 2 1
7
� 
wit h “last d ose” bei n g t h e last d ose of r ei nitiati o n peri o d, if a p plica bl e. 
T he c u m ulati ve d os e of bi ntraf us p alf a  or p e m br oliz u ma b  per p artici pa nt  i n a ti me peri o d is t h e 
s u m  of  t he  act ual  d ose  le vels  t hat  t he part ici pa nt recei ve d  wit hi n  t hat  peri o d (i.e.  t otal  d ose 
a d mi nistere d ( m g)).  
T he d ose i nte nsit y ( DI) ( m g/c ycle) of bi ntraf us p alfa per 2- wee k p eri o d is defi ne d as :  
d ose i nte nsit y = �
C u m ulati ve d ose
( d urati o n of t hera p y (i n wee ks))/ 2� 
T he d ose i nte nsit y ( DI) ( m g/c ycle) of p e m br oliz u ma b per 3- w ee k p eri o d is defi ne d as : 
d ose i nte nsit y = �
C u m ulati ve d ose
( d urati o n of t hera p y (i n wee ks))/ 3� 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
T he r elati ve d os e i nte nsit y ( R DI) is defi n e d as t h e act ual d ose i nte nsit y di vi de d b y t he pla n ne d 
d ose per c y cle a n d e x presse d i n perce nt a ge.  
R DI ( %) = 1 0 0 * [ DI ( m g/c ycle)/( pla n n e d d ose p er c ycl e) ( m g)] 
F or  p artici pa nts  w h o  r ei nitiate  t he  treat me nt,  t he  var yi n g  d urati o n  of  c y cle  will  be  t a ke n  i nt o 
acc o u nt.  
T he f oll o wi n g s u m mar y ta bles will be pr o vi de d: 
•  D urati o n of t her a p y ( w ee ks) 
•  T otal n u m ber of i nf usi o ns recei v e d o verall  
•  C u m ulati ve d ose ( m g) 
•  D ose i nte nsit y ( m g/ c ycle )  
•  Relati ve d ose i nte nsit y ( %) . 
A listi n g of treat me nt e x p os ure will i ncl u de treat me nt ar m, partici pa nt  i d e ntifier, a g e, se x, race, 
visit, i nf usi o n start date a n d ti me, i nf usi o n e n d date a n d ti me, i nf usi o n rate ( m L/ hr), act u al d ose 
( m g), a d mi nistrati o n l ocati o n, a d mi nistrati o n m o dificati o n  a n d reas o n f or m o dificati o n, c ha n ge i n 
a d mi nistrati o n detail,  treat me nt  dela y  ( da ys). T his  listi n g  will  be  s orte d  b y  treat me nt  a r m, 
partici pa nt  i de ntifier, i nf usi o n start date a n d i nf usi o n e n d date. 
A n a d diti o nal  listi n g of tr eat me nt e x p os ure will i n cl u de treat me nt ar m, partici pa nt  i de ntifier, a ge, 
se x,  race, d urati o n  of  t h era 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 os e  of 
t hera p y ( m g), d ose i nte nsit y ( m g/c ycle), a n d relati ve d ose i nte nsit y ( %).  T his listi n g will be s orte d 
b y treat me nt ar m a n d partici pa nt  i de ntifier.  
T her a p y Del a ys  
Dela ys of t her a p y will be deri ve d b y i nf usi o n as f oll o ws:  
•  F or bi ntraf us p alfa i nter v e nti o ns as t he n o. of da ys si nce last i nf usi o n - 1 4 
•  F or pe m br oliz u m a b i nter ve nti o ns as t he n o. of da ys si nce t he start of last i nf usi o n – 2 1. 
If t he val ue a b o ve is > 0 da ys, t he n t his will be classe d as a dela y. A partici pa nt ma y ha ve m ore 
t ha n o ne treat me nt d ela y t hr o u g h o ut t he c o urse of treat me nt. 
T he f oll o wi n g will be s u m marize d i n a ta ble:  
•  N u m ber of partici pa nt s wit h dela ys  
•  L o n gest dela y  per p artici pa nt  ( n o dela y, 1- 2 d a ys, 3- 8 da ys, 9- 1 5 da ys, ≥1 6 da ys)  
•  N u m ber of del a ys per p artici pa nt  ( 0 dela y, 1 dela y, 2 dela ys, 3 dela ys, ≥ 4 d ela ys). 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI


Bintrafusp alfa (M7824) 1L NSCLC Adaptive Phase III RCT M7824 versus Pembrolizumab
MS200647-0037 - Version 5.0 
C O N F I D E N T I A L
I N F O R M A T I O N
50/94
Infusion Temporary Interruptions 
IMP infusion interrupted as recorded on the “Study Treatment Administration Details” page of the 
eCRF will be used for analysis. Number of participants with at least one IMP interruption, reason 
for infusion temporary interruptions, as well as a categorization of the number of IMP interruptions 
(1 / 2 / ≥3) will be summarized.  
Infusion Rate Reductions
Infusion rate reductions as recorded on the “Study Treatment Administration Details” page of the 
eCRF will be used for analysis. Number of participants with at least one infusion rate reduced to 
50%, reasons for infusion rate reduction, as well as a categorization of the number of infusion rate 
reductions (1 / 2 / ≥3) will be summarized.  
14
Efficacy Analyses
Best Overall Response efficacy analyses at OR interim analysis will be performed on 73-10 PD-
L1 High analysis set, if any Best Overall Response sensitivity analyses will be performed at OR 
interim analysis it will be based on FAS with 6m f-up analysis set. Remaining efficacy analyses 
will be presented for the FAS analysis set.  
A group sequential testing procedure will be used to test primary endpoints.
Best Overall Response According to RECIST 1.1 as Assessed by 
IRC (Secondary Endpoint)
Best overall response (BOR) will be assessed based on the tumor response at different evaluation 
time points from randomization until the first documented disease progression for RECIST 1.1 
criterion. Only tumor assessments performed before the start of any further anticancer treatment 
will be considered in the assessment of BOR. Clinical deterioration will not be considered as 
documented disease progression. 
The BOR according to RECIST 1.1 criteria as assessed by IRC can be CR, PR, Non-CR/Non-
PD, SD, PD, or NE.
The following rules will be applied to the derivation of BOR: 
•
CR = at least one determination of CR before disease progression
•
PR = at least one determination of PR before disease progression (and not qualifying for a CR)
•
SD = at least one SD assessment ≥ 6 weeks after start date and before disease progression (and
not qualifying for CR or PR)
•
As tumor lesions are evaluated by the IRC, it may happen that the independent reviewer
disagrees with the Investigator and does not assess any tumors as “measurable” at screening.
Global Version ID: 
Global Version ID: CCI
CCI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
I n t hat case, t he B O R c o ul d be rat e d as “ n o n- C R/ n o n-P D” (if n o “ C R” or “ P D” are pre vi o usl y 
re p orte d a n d if t he “ n o n- C R/ n o n-P D” assess me nt is ≥ 6 wee ks after start date).  
•  P D = pr o gressi o n ≤ 1 2 w ee ks aft er ra n d o mizati o n (a n d n ot q ualif yi n g f or C R, P R, S D  or n o n-
C R/ n o n- P D ) 
•  If a p artici pa nt  has  a missi n g baseli ne t u m or assess me nt a n d/ or n o ( or N E) t u m or assess me nts 
o n- treat me nt, B O R will be N ot E val ua ble ( N E). 
•  I n t h e cas e t he si n gle r es p o nse is S D, S D m ust ha ve bee n assesse d n o less t ha n 6 wee ks (at 
least 4 2 da ys) after r a n d o mizati on, ot her wise, t he best res p o nse will be N E. 
T he n u m ber a n d perce nt a ge of partici pa nt s wit h u nc o nfir me d B O R of C R, P R, N o n - C R/ n o n-P D, 
S D, P D, a n d N E will be ta b ulate d b y treat me nt ar m. 
A listi n g will be pr o vi de d wit h t he f oll o wi n g i nf or mati o n: treat me nt ar m, partici pa nt  i de ntifier, 
a ge,  se x ,  race, d ate  of  ra n d o mizati o n, first/last  d ose, u nc o nfir me d  B O R,  date  of  s u bse q ue nt 
a ntica ncer  t hera p y (i. e.  dr u g  t hera p y,  ra di ot hera p y  or  s ur ger y), d ate  of  deat h, visit,  date(s)  of 
i ma gi n g, lesi o n  t y pe  (tar get  lesi o n,  n o n-tar get  lesi o n,  ne w  lesi o n),  descri pti o n  of  tar get  lesi o ns 
(size, site, t y pe, met h o d, res p o nse), n o n-tar g et lesi o ns (stat us, site, t y pe, met h o d, res p o nse) a n d 
ne w lesi o ns (site, t y pe, met h o d), s u m of lesi o n dia meters, perce nt c h a n g e i n tar get lesi o ns fr o m 
baseli ne, a n d o verall res p o nse, s orte d b y treat me nt ar m, partici pa nt  i de ntifier, visit, date of i ma gi n g 
a n d lesi o n I D. 
A s u m mar y t a ble of t he reas o ns f or n o n -e v al ua bl e B O R as a dj u dicate d b y t he I R C b y treat me nt 
ar m will be pr o vi de d: 
•  N o baseli ne ass ess me nt  
•  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 do 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 o n -e val ua ble ’ 
•  Ne w a ntica ncer t her a p y starte d bef ore first e val ua ble p ost- baseli ne assess m e nt  
•  S D of i ns ufficie nt d urati o n ( < 6 wee ks after ra n do mizati o n  wit h o ut f urt her e v al ua ble t u m or 
assess me nt) . N ote: S p eci al a n d rare cases w h ere 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 i nt o t his cate g or y. 
•  N o n - C R/ n o n-P 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 ua ble t u m or ass ess 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 ra n d o mizati o n a n d t here w as 
n o e val ua ble t u m or ass ess me nt i n bet wee n )  
•  N o I R C re vi e w ma y als o be a d de d if re q uire d b y t he data 
•  If t he I R C is n ot a ble t o i de ntif y a n y diseas e at baseli ne (tar g et or n o n-tar g et lesi o ns), t he 
B O R ma y be rate d as “ N o Disease” ( N D ), “N o Disease” ma y cat e g or y ma y als o be a d de d 
if re q uire d b y t he d ata. 
Gl o bal Versi o n I D:
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
A  listi n g  of  reas o ns  f or n o n- e val ua ble B O R  will  als o  be  create d  i ncl u di n g:  treat me nt  ar m , 
partici pa nt  i de ntifier, a ge, se x, race, date of ra n d o mizati o n,  date of first a n d last d ose, date(s) of 
i ma gi n g, o verall r es p o nse, date of s u bse q u e nt a ntica ncer t hera p y (i. e. dr u g t hera p y, ra di ot hera p y 
or s ur ger y) a n d t he r eas o n f or u nc o nfir m e d B O R N E . 
T he O bjecti ve  Res p o nse  R at e  ( O R R)  is defi n e d as t he n u m ber of parti ci pa nt s ha vi n g  a B O R 
assess me nt of C R or P R, o ut of t he t otal n u m ber of partici pa nt s bel o n gi n g t o t he a nal ysis set of 
i nterest. 
T he Dise ase C o ntr ol R at e  (D C R)  is defi n e d as t he pr o p orti o n of partici pa nt s wit h B O R acc or di n g 
t o e val uati o n criteria of C R, P R, or S D  o ut of t he t otal n u m ber of partici pa nt s bel o n gi n g t o t he 
a nal ysis set of i nterest. 
T he u nc o nfir me d O R R will be calc ul ate d f or eac h treat me nt ar m wit h a 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 xact 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) . At O R I A, th e differe nce Δ O R R  will be esti mate d b y 
t he cr u de rate differe nce bet wee n bi n traf us p alfa a n d pe m br oliz u ma b ar ms a n d c o m ple me nte d b y  
a 9 5 % Mietti ne n -N ur mi n e n CI  ( c o m p ute d b y t he F R E Q pr oce d ure usi n g t h e RI S K DI F F( C L = M N) 
o pti o n).  
At P F S I A a n d f oll o wi n g a nal yses, t he differe nce i n O R R will be esti mate d base d o n C oc hra n -
Ma ntel -Hae nszel met h o d (ta ki n g i nt o acc o u nt t he ra n d o mizati o n strata ) a n d t he test statistics will 
be prese nt e d.  
T he o d ds rati o a dj uste d b y ra n d o mizati o n strata wit h ass ociate d 9 5 % CI will als o be prese nt e d. 
A d diti o nall y,  D C R  will  be  cal c ulate d  al o n g  wit h  t he  c orres p o n di n g  t w o -si de d  e x act  Cl o p per-
Pears o n 9 5 % CI per treat me nt ar m. 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
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 /9 4  
 
 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
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 /9 4  
 
 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
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 /9 4  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
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 /9 4  
 
 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: 
C CI
C CI


Bintrafusp alfa (M7824) 1L NSCLC Adaptive Phase III RCT M7824 versus Pembrolizumab
MS200647-0037 - Version 5.0 
C O N F I D E N T I A L
I N F O R M A T I O N
57/94
Progression Free Survival According to RECIST 1.1 as assessed by IRC 
(Primary Endpoint) 
A primary endpoint of this study is PFS time. The disease progression will be based on IRC 
assessment on imaging and classified according to RECIST version 1.1 criteria.   
Progression Free Survival (PFS) time is defined as the time from randomization to the date of 
the first documentation of objective PD as assessed by IRC or death due to any cause, whichever 
occurs first. Death will be considered as event if reported within: 
•
12 weeks (84 days) after the last tumor assessment without progression or the randomization 
(whichever occurs later) – during the first 18 months of follow-up  
•
24 weeks (168 days) after the last tumor assessment without progression or the randomization 
(whichever occurs later) - after 18 months of follow-up. 
The following censoring rules will be applied for the PFS computation: 
•
Any participant with neither assessment of tumor progression, nor death date within 12 weeks
after last tumor assessment (or 24 weeks after 18 months of follow-up) or randomization will 
be censored on the date of last evaluable tumor assessment or randomization whatever is later
•
If death without previously documented PD is observed after more than 84 days during the 
first 18 months of follow-up (or 168 days after the first 18 months of follow-up) of last tumor 
assessment, the participant will be censored at the date of the last evaluable tumor assessment  
•
Participants who do not have a baseline tumor assessment or who do not have any post-baseline 
tumor assessments will be censored at randomization unless death occurred on or before the 
time of the second planned tumor assessment (i.e. 12 weeks) in which case the death will be 
considered an event 
•
Participants who start new anticancer treatment prior to an event will be censored on the date 
of the last evaluable tumor assessment before anticancer therapy is given 
•
Participants with an event after two or more subsequent missing response assessments (i.e. no 
assessments in 84 days during the first 18 months of follow-up or 168 days after the first 
18months of follow-up) will be censored on the date of the last evaluable tumor assessment. 
Censoring rules are also summarized in Table 7.
Table 7 
Censoring Rules
PFS Event Status
Censoring
Date of event / censoring
Progressed or 
died
Within two subsequent scheduled 
tumor assessments after last 
response assessment of CR, PR or 
SD 
Event
Minimum (Date of PD, Date of death)
Otherwise
Censored
Date of last evaluable tumor 
assessment with outcome CR, PR or 
SD or date of randomization, 
whatever is later
Global Version ID: 
Global Version ID: CCI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
P F S E v e nt St at u s  
C e n s ori n g  
D at e of e v e nt / c e n s ori n g  
N eit h er pr o gr e s s e d n or di e d  
C e n s or e d  
D at e of l a st  e v al u a bl e  t u m or 
a s s e s s m e nt wit h o ut c o m e C R, P R or 
S D or d at e of r a n d o mi z ati o n, 
w h at e v er i s l at er  
T he last t u m or assess me nt date is defi ne d as t he  last a vaila ble a n d e v al ua ble t u m or assess me nt 
perf or me d pri or t o t he c ut off date ( or pri or t o e n d of st u d y, i.e. partici pa nt s l ost t o f oll o w-u p or 
w h o wit h dra w c o nse nt)  or pri or t o s u bse q ue nt a ntica ncer t hera p y (i. e. dr u g t hera p y, ra di ot hera p y 
or s ur ger y) . If n o e v al ua ble t u m or ass ess me nt is a v aila ble, t his date will be t he ra n d o mizati o n date. 
P F S = ( date of P D or deat h/ce ns ori n g – date of ra n d o mizati o n + 1)/  3 0. 4 3 7 5 ( m o nt hs).  
K a pl a n- Meier a n al ysis 
T he a n al ysis of P F S will be prese nt e d b y treat me nt ar m a n d will b e perf or me d wit h a K a pla n -
Meier  met h o d ( pr o d uct -li mit esti mates) a n d a s u m mar y of ass o ciate d statistics will be prese nte d 
i ncl u di n g 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 dia n will be calc ulate d acc or di n g 
t o Br o o k me yer a n d Cr o wle y ( 1 9 8 2)  a n d C Is f or t he s ur vi val f u n cti o n esti mates at M o nt h 3, 6, 9, 
1 2 a n d 2 4 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 bfleisc h a n d Pre ntice 
( 1 9 8 0) ( C O N F T Y P E =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 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 u la.  
Fre q u e nc y  ( n u m ber  a n d  perce nt a ge)  of partici pa nt s  wit h a n d  wit h o ut  a n  e ve nt,  o verall  a n d  per  
e ve nt t y pe ( P D or deat h) will be prese nte d b y treat me nt ar m. Ce ns ori n g reas o ns  will be descri be d 
b y treat me nt ar m,  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 baseli ne ass ess me nt  
•  N o e val ua ble p ost- b aseli ne assess me nt  
•  Start of ne w a ntica ncer  t hera p y 
•  E ve nt after 2 or m ore missi n g or n o n- e val ua ble p ost- baseli ne assess me nts  
•  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 parti ci pa nt s: 
•  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 or e C R F st u d y 
ter mi nati o n pa ge pri or t o t he a nal ysis c ut off; 
•  Partici pa nts wit h last k n o w n ali ve date > 1 4 wee ks  pri o r t o t he a nal ysis c ut off date ( d urati o n 
of 1 4 wee ks is base d o n t he assess me nt sc he d ul e of e ver y 3 m o nt hs f or s ur vi val f oll o w- u p 
i nter val + 1 wee k wi n d o w). 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
A partici pa nt  listi n g  will  be  als o  pr o vi de d  wit h  t he  f oll o wi n g  i nf or m ati o n:  treat me nt  ar m, 
partici pa nt  ide ntifier,  a g e, se x, race, ra n d o mizati o n date, date of last t u m or  assess me nt, date of 
e ve nt/ce ns ori n g, e ve nt/ce ns ori n g reas o n, ti me t o e ve nt. 
L o g- r a n k test  
T he pri mar y efficac y a n al ysis of P F S will be perf or me d base d o n t he F A S usi n g t he strata assi g ne d 
at ra n d o mizati o n.  
T he pri mar y efficac y a nal ysis will c o m pare t he P F S ti me bet wee n t he t w o treat me nt ar ms, a n d will 
be perf or me d usi n g a o ne -si de d stratifie d l o g-ra n k  test, acc or di n g t o testi n g strate g y defi ne d i n 
S ecti o n 6 .  
T he stratificati o n fact or a p plie d are i de ntical t o t h ose use d f or ra n d o mizati o n ( as ca pt ured via t he 
I R T at ra n d o mizati o n):  
•  S q ua m o us hist ol o g y 
•  N o ns q ua m o us hist ol o g y a n d ne ver s m o k e d  
•  N o ns q ua m o us hist ol o g y wit h a s m o ki n g hist or y. 
T he f oll o wi n g n ull h y p ot hesis will be teste d: 
𝐻𝐻0
𝑃𝑃𝑃𝑃𝑃𝑃: 𝜆𝜆𝑀𝑀
𝑃𝑃𝑃𝑃𝑃𝑃(𝑡𝑡) = 𝜃𝜃𝜆𝜆𝑃𝑃
𝑃𝑃𝑃𝑃𝑃𝑃(𝑡𝑡),𝜃𝜃≥1  vers us 𝐻𝐻1
𝑃𝑃𝑃𝑃𝑃𝑃: 𝜆𝜆𝑀𝑀
𝑃𝑃𝑃𝑃𝑃𝑃(𝑡𝑡) = 𝜃𝜃𝜆𝜆𝑃𝑃
𝑃𝑃𝑃𝑃𝑃𝑃(𝑡𝑡),𝜃𝜃< 1  
W here 𝜆𝜆⋅
𝑃𝑃𝑃𝑃𝑃𝑃(𝑡𝑡) re pr ese nts t he hazar d at ti me 𝑡𝑡 a n d 𝜃𝜃 t he u n k n o w n c o nsta nt of pr o p orti o nalit y of 
hazar ds i n t he tr eat me nt ar m s M  ( M 7 8 2 4/ bi ntraf us p alfa) a n d P  ( pe m br oliz u ma b). 
C o x’s re g ressi o n m o del  
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 Haza r d m o del stratifie d b y t he 
ra n d o mizati o n strata t o calc ulate t he h azar d rati o. Ra n d o mizati o n strata will be ta ke n as s p ecifie d 
a n d d oc u me nte d i n t he I R T . Eac h strat u m will defi ne a se parate baseli ne hazar d f u n cti o n ( usi n g 
t he ' S T R A T A' state me nt i n S A S P R O C P H R E G), i.e. f or t he i -t h strat u m t he hazar d f u n cti o n is 
e x presse d as: h(i;t) = h(i, 0;t) e x p( β X ), w here h(i, 0;t) defi nes t he b aseli ne h azar 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 ar m ( 0 = pe m br oliz u ma b, 1= M 7 8 2 4 ( bi ntraf us p alfa )) a n d 
beta  is  t he  u n k n o w n  re gressi o n  par a meter.  Ties will  be ha n dle d  b y  re placi n g  t he  pr o p orti o nal 
hazar ds m o d el b y t he discrete l o gistic m o del ( Ties = Discret e o pti o n i n S A S P R O C P H R E G). 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
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 /9 4  
 
 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
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 /9 4  
 
 
1 4. 4. 3  
Ti me t o F oll o w -u p f or P F S  
A Ka pla n -M eier a n al ysis  f or P F S f oll o w-u p d urati o n will 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 r e v ersi n g t he P F S ce ns ori n g a n d e ve nt i n dicat ors. 
Ka pla n -Mei er  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. I n partic ular, t he f oll o w-u p rat e at 3, 6, 9,  1 2 a n d 2 4 m o n t 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. 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
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 /9 4  
 
 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: 
C CI
C CI


Bintrafusp alfa (M7824) 1L NSCLC Adaptive Phase III RCT M7824 versus Pembrolizumab
MS200647-0037 - Version 5.0 
C O N F I D E N T I A L
I N F O R M A T I O N
63/94
Duration of Response (Secondary Endpoint)
Duration of response (DOR) is defined as the time from first documentation of objective response 
(CR or PR) to the date of first documentation of objective progression of disease (PD) or death 
due to any cause whichever occurs first. The analysis of DOR will be performed on unconfirmed 
objective response of CR or PR according to RECIST 1.1 as adjudicated by IRC. The censoring 
rules for DOR are as described above for PFS. The number of participants with ongoing response 
will be described as the number of censored participants with administrative censoring.
DOR = (date of PD or death/censoring – date of objective response + 1)/30.4375 (months). 
The analysis of DOR will be performed with a Kaplan-Meier method (product-limit estimates) and 
a summary of associated statistics will be presented including corresponding two-sided 95% CIs. 
The CIs for the median will be calculated according to Brookmeyer and Crowley (1982) and CIs 
for the survival function estimates at Month 3, 6, 9, 12 and 24 will be derived using the log-log 
transformation according to Kalbfleisch and Prentice (1980) (CONFTYPE=loglog default option 
in SAS PROC LIFETEST).  The estimate of standard error will be computed using Greenwood’s 
formula.  
The time and duration of response per participant may also be displayed in a swimmer graph in 
participants with unconfirmed CR/PR (delayed response is also considered).  
A participant listing will provide the following information: treatment arm, participant identifier, 
age, sex, race, date of randomization, date of first response, time to response, date of last tumor 
assessment, censored (Y/N), date of event/censoring, event/censoring reason, DOR. 
14.8.1
Sensitivity Analyses for DOR
The analysis of DOR will be repeated on confirmed CR/PR according to RECIST 1.1 as 
adjudicated by IRC. 
The analyses for DOR based on unconfirmed responses will be repeated for DOR based on 
confirmed responses (i.e. Kaplan-Meier analysis, listing of DOR, swimmer graph of time and 
duration of response in participants with confirmed CR/PR).
Global Version ID: 
Global Version ID: 
CCI
CCI


Bintrafusp alfa (M7824) 1L NSCLC Adaptive Phase III RCT M7824 versus Pembrolizumab
MS200647-0037 - Version 5.0 
C O N F I D E N T I A L
I N F O R M A T I O N
64/94
Overall Survival (Primary Endpoint) 
The overall survival (OS) time is defined as the date from randomization to death due to any cause: 
OS = (date of event/censoring – date of randomization + 1)/30.4375 (months).  
For participants alive at the time of data cutoff date or who are lost to follow up, OS will be 
censored at the last date known to be alive.  
The date of event / censoring is defined in Table 8.
Global Version ID: 
Global Version ID: 
CCI
CCI
CCI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
T a ble 8  
S ur vi v al E ve nt / Ce ns ori n g  
S ur vi v al st at u s  
D at e of e v e nt / c e n s ori n g  
C e n s ori n g  
P arti ci p a nt s  ali v e  or  l o st  t o  f oll o w -u p  
b ef or e or at c ut off  d at e  
L a st d at e k n o w n t o b e ali v e  
Y e s  
P arti ci p a nt s  w h o  di e d  b ef or e  or  at 
c ut off  d at e  
D at e of d e at h  
N o  
T he f oll o wi n g  c o m plete dates will be use d t o deter mi ne t he last date k n o w n t o be ali ve. O nl y t h e 
o nes a m o n g t he m t hat are bef ore or at data c ut off a n d w hic h are n ot i m p ute d s hall be use d i n t he 
deri vati o n. Dates p ast t he data c ut off will be i g n ore d b y t he deri vati o n: 
•  All partici pa nt  assess me nt dates ( bl o o d dra ws (la b orat or y, P K), vital si g ns, p erf or ma n ce stat us, 
E C G, t u m or assess me nts, P R O  assess me nts)  
•  Start a n d e n d dates of a ntica ncer t hera pies a d mi nistere d after I M P disc o nti n uati o n.  
•  A E start a n d e n d d ates  
•  Last k n o w n ali ve date  c ollecte d o n t he ‘ S ur vi val F oll o w- u p ’ e C R F ( d o n ot use f oll o w-u p date)  
•  I M Ps start a n d e n d dates (i ncl u di n g rei nitiati o n of treat me nt) 
•  Ra n d o mizati o n date 
•  C o m pleti o n/ Disc o nti n uati o n date  fr o m  t he  “ St u d y  Ter mi nati o n”  e C R F  pa ge  ( 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 or deat h) 
O nl y dates ass ociate d wit h act ual e xa mi nati o ns of t he partici pa nt re p orte d i n t he e C R F will be 
use d i n t he deri vati o n.   Dates ass ociate d wit h a tec h nical o perati o n u nrelate d t o parti ci pa nt stat us 
s uc h as t he date a bl o o d sa m ple was pr o cesse d will n ot be use d.  
T he a nal ysis of O S ti me will be perf or me d wit h a Ka pla n -Meier met h o d wit h t he sa me a p pr oac h 
descri be d  f or P F S  i n  S ecti o n 1 4. 4 . Ka pla n -Mei er  esti mates  ( pr o d uct -li mit  esti mates)  will  be 
prese nte d t o get her wit h a s u m mar y of ass ociate d st atistics i ncl u di n g c orres p o n di n g t w o -si de d 9 5 % 
CIs. T he y will be esti mate d at 1 2, 1 8, 2 4, 3 0, 3 6, 4 2, a n d 4 8 m o nt hs. 
A C o x ’s re gr essi o n m o del will be use d wit h t he sa me a p pr o ac h as f or P F S descri be d i n Secti o n 
1 4. 4 .   
T he f oll o wi n g n ull h y p ot hesis will be teste d: 
𝐻𝐻0
𝑃𝑃𝑃𝑃: 𝑃𝑃𝜆𝜆
𝑀𝑀𝑃𝑃(𝑃𝑃) = 𝑃𝑃𝑡𝑡𝜃𝜃
𝜆𝜆𝑃𝑃(𝑃𝑃),𝑃𝑃≥1  vers us 𝑃𝑃1
𝑡𝑡𝜃𝜃: 𝐻𝐻𝑃𝑃
𝑃𝑃𝑃𝑃(𝜆𝜆) = 𝑀𝑀𝑃𝑃𝑃𝑃
𝑃𝑃𝑡𝑡(𝜃𝜃),𝜆𝜆< 1  
W here 𝑃𝑃⋅
𝑃𝑃𝑃𝑃(𝑃𝑃) re prese nts t he h azar d at ti me 𝑡𝑡 a n d 𝜃𝜃 t he u n k n o w n c o nsta nt of pr o p orti o nalit y of 
hazar ds i n t he tr eat me nt ar m s M  ( M 7 8 2 4/ bi ntraf us p alfa) a n d P  ( pe m br oliz u ma b). 
𝜆𝜆0
𝑃𝑃𝑃𝑃 will be teste d acc or di n g t o t he testi n g strate g y des cri be d i n Secti o n  6 . 
La n -De M ets  al p ha  s pe n di n g  wit h  O’ Brie n -Fle mi n g -li ke  b o u n daries  will  be  a d o pte d  f or  t he 
c urre ntl y o bser ve d e v e nt size at c ut off d ate.  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI


Bintrafusp alfa (M7824) 1L NSCLC Adaptive Phase III RCT M7824 versus Pembrolizumab
MS200647-0037 - Version 5.0 
C O N F I D E N T I A L
I N F O R M A T I O N
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A participant listing will provide the following information: treatment arm, participant identifier, 
age, sex, race, date of randomization, date of event/censoring, event/censoring reason, and time to 
event.
14.11.2
Follow-up time since randomization
A Kaplan-Meier analysis will be performed on follow-up time using OS data by reverting the 
censoring flag (participants still alive or lost to follow-up are counted as events, deceased 
participants are counted as censored). Kaplan-Meier estimates (product-limit estimates) will be 
presented by treatment arm together with the median time of follow-up. In particular, the follow-
up rates at 3, 6, 9, 12 and 24 months will be estimated with 95% CIs. 
15
Safety Analyses
The subsections in this section include specifications for summarizing safety endpoints that are 
common across clinical studies such as adverse events, laboratory tests and vital signs. Baseline 
values for safety analysis are defined in Section 9 of this IAP “Definition of baseline and change 
from baseline”.
Adverse Events
Treatment emergent adverse events (TEAEs) are those events with onset dates occurring during 
the on-treatment period (as defined in Section 9 of this IAP) or if the worsening of an event is 
during the on-treatment period.
Changes in toxicity grade, seriousness or outcome of AEs are recorded as separate entries in the 
eCRF with associated end and start dates (start date equals end date of previous entry). Such entries 
reporting the same event in such immediately consecutive periods will be considered as one event 
in the analysis. These events will be kept as separate records in the database in order to maintain 
the full detailed history of the events. The start date of the initial record in the sequence is taken as 
start date of the entire event, similarly the end date of the last event in the sequence is taken as end 
Global Version ID:
Global Version ID:CCI
CCI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
date of t he e ntire e ve nt. T he o verall o utc o me of t he a d verse e v e nt is t he o utc o me of t he last e ve nt 
i n t he se q ue nce. D ur ati 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.  
All a nal yses des cri be d i n t his secti o n will be base d o n T E A Es if n ot ot her wise s pecifie d  a n d will 
be descri be d b y tr eat me nt ar m . 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. 
I n c o m plete A E-relate d d ates will be ha n dle d as st ate d i n Secti o n 9 . 
Rel ate d A d verse E ve nts  are t h ose A Es wit h relati o ns hi p t o I M P re p ort e d b y t he i n vesti gat or as 
relate d (i.e. a ns wer t o t h e q uesti o ns “ Relati o ns hi p wit h st u d y treat me nt” = “ Relate d” o n “ A d v ers e 
E ve nt  Details” e C R F   pa ge) a n d  t h ose  of  u n k n o w n  rel ati o ns hi p  (i.e.  n o  a ns wer  t o  t he  q u esti 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 Es)  ar e t h ose e ve nts re p orte d o n t he “ A d verse E ve nt D etails” e C R F 
pa ge wit h t he “ Seri o us A d verse E ve nt ” fiel d tic ke d “ Yes”.  
A d verse E ve nts Le a di n g t o Te m p or ar y Disc o nti n u ati o n are t h ose e ve nts lea di n g t o te m p orar y 
disc o nti n uati o n of st u d y treat me nt (a ns w er t o t he q uesti o n “ Acti o n(s) ta ke n wit h st u d y treat me nt ” 
i ncl u des “ Dr u g i nterr u pte d” o n “ A d verse E ve nt Details” e C R F pa ge).  
A d verse E ve nts L e a di n g t o Per m a ne nt Tre at me nt Disc o nti n u ati o n  are t h ose 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 (a ns wer t o t he q uesti o n “ Acti o n(s) ta ke n wit h st u d y 
treat me nt” i ncl u des “ Dr u g wit h dra w n” o n “ A d verse E ve nt Details” e C R F pa ge).  
A d verse  E ve nt  Le a di n g  t o  D e at h : A E s lea di n g  t o  deat h  (as  rec or de d  o n  t he “ A d vers e  E v e nt 
Details” e C R F p age, c ha n ge i n gra d e = “N o ” a n d o utc o me = “Fat al ”, or g ra de = “ Gra d e  5 or deat h 
relate d  t o  A E ” or  s eri o us  a d verse  e ve nt  =  “ Yes”  a n d seri o us ness  criteria  i ncl u de  “Res ult s  i n 
deat h ”). 
Blee di n g e ve nts are t h os e A Es bel o n gi n g t o t he Me d D R A S M Q Hae m orr ha ge ter ms (e xcl u di n g 
la b orat or y ter ms). 
 
A d verse E ve nts of S peci al I nterest ( A E SI): A E SI  will be i de ntifie d acc or di n g t o a pre -s pecifie d 
searc h list of Me d D R A Preferre d T er ms.    
Cate g ories of A E SIs i ncl u de (see d etails i n Secti o n 1 5. 2. 3 ): 
•  I nf usi o n-relat e d reacti o ns (I R Rs)  
•  I m m u ne-relat e d a d verse e ve nts (ir A Es)  
•  S ki n A E p ossi bl y relate d t o T G F β i n hi biti o n  
•  A ne mia . 
1 5. 1. 1  
All A d verse E ve nts  
A d verse e ve nts will be s u m marize d b y w orst se v erit y (acc or di n g t o N CI -C T C A E versi o n 5. 0 ) per 
partici pa nt , usi n g Me d D R A (latest versi o n) preferre d ter m as e ve nt cate g or y a n d Me d D R A  (lat est 
versi o n) pri mar y s yste m or ga n class ( S O C) b o d y t er m as B o d y S yste m cate g or y.  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
U nless ot her wise state d A Es will be dis pla ye d i n ter ms of fre q ue n c y ta bles: P T a n d pri mar y S O C 
i n al p ha betical or d er. 
If a n A E is re p orte d f or a gi ve n partici pa nt  m ore t ha n o nce d uri n g treat me nt, t he w orst se verit y 
a n d t he w orst relati o ns hi p t o IM P  will be ta b ulate d.  I n cas e a partici pa nt  h a d e ve nts wit h missi n g 
a n d n o n- missi n g gra des, t he ma xi m u m of t he n o n- mi ssi n g gra des will be dis pla ye d. 
A ta ble  prese nti n g  t he  o verall  s u m mar y  of  A Es  will  be  prese nte d  b y treat me nt  ar m  wit h  t he 
f oll o wi n g i nf or mati o n:  
•  T E A E s  
•  Relate d T E A Es  
•  Seri o us T E A Es  
•  Relate d seri o us T E A Es  
•  T E A E s N CI -C T C A E se v erit y gra de ( ≥3, ≥4)  
•  Relate d T E A E s N CI -C T C A E se verit y gra d e ( ≥3, ≥4)  
•  T E A Es lea di n g t o deat h 
•  Relate d T E A Es lea di n g t o deat h 
•  T E A Es a n d rel ate d T E A E s of s pecial i nterest:  
o  I nf usi o n-relat e d reacti o ns (I R Rs) 
o  I m m u ne-relat e d A Es (ir A Es)  
o  T G F - β i n hi biti o n me diate d s ki n T E A Es  
o  A ne mia  
•  Blee di n g T E A Es  
•  Relate d ble e di n g T E A Es  
Ta bles f or T E A Es fre q u e nc y c orr es p o n di n g t o eac h cate g or y i n t he o ver vie w ta ble a b o ve will be 
pr o vi de d b y M e d D R A pri mar y S O C ( or d ere d al p h a beticall y) a n d P T ( or dere d al p ha b eticall y)  a n d 
b y treat me nt ar ms.  Eac h partici pa nt  will be c o u nte d o nl y o nce wit hi n eac h P T or S O C.  Cate g ories 
f or T E A Es of s p ecial i nterest will be  descri b e d as detaile d i n  Secti o n 1 5. 2. 3  of t his I A P.  
T E A Es a n d r elate d T E A Es b y w orst gr a de will als o be s u m marize d, a n d P T s t hat differs b y at least 
5 % bet wee n tr eat me nt ar ms  will be prese nt e d gra p hicall y b y w orst gra d e a n d P T wit h b ar c hart 
fi g ures. 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
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 /9 4  
 
 
Cli nic a ltri als. g o v a n d E u dr a C T -re q uire me nts  
S u m mar y ta bles f or n o n - seri o us T E A Es e xcl u di n g S A Es a p pl yi n g fre q ue nc y t hres h ol d of 5 % will 
be pr o vi de d. 
T he f oll o wi n g listi n gs will be pr o vi de d: 
•  Listi n g of all A E s ( w het h er treat me nt-e mer g e nt or n ot): T E A Es a n d A E occ urri n g d uri n g 
rei nitiati o n p hase will be fla g ge d 
 
•  Listi n g of n o n -T E A E f or A Es occ urri n g after e nr oll me nt ( date of first si g nat ure of i nf or me d  
c o nse nt/ date of first si g n at ure of first i nf or m e d c o nse nt) b ut pri or t o t he first d ose of st u d y 
i nter ve nti o n 
Listi n g  of  A E s wit h  o nset  or  w orse ni n g  after  t he  o n -treat me nt  p eri o d  ( A Es  occ urri n g  d uri n g 
rei nitiati o n  p hase  will  be  fla g ge d). T h e  listi n g  of A Es will  c o ntai n  t he  f oll o wi n g  i nf or mati o n: 
treat me nt ar m, partici p a nt  i de ntifier, a ge, se x, race, first a n d last date of treat me nt a d mi nistrati o n, 
preferre d ter m, re p orte d ter m f or t he A E , start date, e n d date, d urati o n of A E (i n da ys), da y relati ve 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: 
C CI
C CI


Bintrafusp alfa (M7824) 1L NSCLC Adaptive Phase III RCT M7824 versus Pembrolizumab
MS200647-0037 - Version 5.0 
C O N F I D E N T I A L
I N F O R M A T I O N
70/94
to the first infusion, day relative to the most recent infusion prior to AE onset, relationship to IMP, 
toxicity grade, action(s) taken, outcome, seriousness (Y/N), AESI infusion-related (Y/N), AESI 
immune-related (Y/N), TGF-β inhibition mediated skin AESI (Y/N), Treatment-related anemia 
AESI (Y/N), Bleeding events (Y/N). The listing will be sorted by treatment arm, participant 
identifier, preferred term, start date and end date.
15.1.2
Adverse Events Leading to Treatment Discontinuation
Frequency tables summarizing the following actions taken with IMP in response to TEAEs will 
be prepared and presented by PT and primary SOC in alphabetical order: 
•
TEAEs leading to permanent treatment discontinuation 
•
Related TEAEs leading to permanent treatment discontinuation  
•
TEAEs leading to infusion rate reduction 
•
Related TEAEs leading to infusion rate reduction 
•
TEAEs leading to temporary IMP interruption 
•
Related TEAEs leading to temporary IMP interruption. 
The listing of AEs leading to permanent treatment discontinuation will also be provided with the 
relevant information.  
Deaths, Other Serious Adverse Events, and Other Significant Adverse 
Events
15.2.1
Deaths
All deaths, deaths within 30 days after last dose of IMP, death within 60 days after first dose as 
well as primary reason for death, will be tabulated based on information from the “Death” eCRF 
page.  
The following summaries will be provided by treatment arm: 
•
Number of deaths 
•
Number of deaths within 30 days after last dose of IMP
•
Number of deaths within 60 days after first dose of IMP
•
Primary reason of death
o
Progressive disease and/or disease related condition
o
Event unrelated to IMP
o
Event related to IMP
o
Unknown 
In addition, date and cause of death will be provided in an individual participant data listing 
together with selected dosing information (IMP received, date of first/last administration, number 
of infusions, day relative to first and last infusion) and will include columns for
Global Version ID: 
Global Version ID: CCI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
•  Partici pa nt i de ntifier, a n al ysis set, a ge, se x, race  
•  A Es wit h fatal o utc o me (list preferre d ter ms of A Es wit h o utc o me = fat al, Gra de 5 or Seri o us 
res ulti n g i n deat h) 
•  A ut o ps y perf or me d ( Yes/ N o/ U n k n o w n) 
•  Fla g f or d eat h wit hi n 3 0 da ys of last I M P i nter ve nti o n 
•  Fla g f or d eat h wit hi n 6 0 da ys of first I M P i nter ve nti o n. 
1 5. 2. 2  
Seri o us A d verse E ve nts  
T he  n u m ber  of partici pa nt s  wit h  seri o us  A Es  ( S A Es)  will  be des cri be d  b y  S O C  a n d  P T,  b y 
treat me nt ar ms:  
•  Seri o us T E A Es  
•  Relate d seri o us T E A Es  
Please ref er t o Secti o n  1 5. 1. 1 . A partici pa nt  listi n g will be pr o vi de d i ncl u di n g all SA E s. 
1 5. 2. 3  
A d verse E ve nts of S peci al Interest  
1 5. 2. 3. 1  
Inf usi o n -rel ate d R e acti o ns Incl u di n g Im me di ate 
H y perse nsiti vit y  
I nf usi o n-relat e d reacti o ns (I R R) are d efi ne d as a d verse e ve nts wit h P Ts o n a  pre-s pecifie d list of 
Me d D R A P Ts a n d di vi de d i nt o reacti o ns vers us si g ns a n d s y m pt o ms. 
Re acti o ns of I R R:  s h o ul d be c o nsi dere d w he n o nset is o n t he da y of i nf usi o n ( d uri n g or after t he 
i nf usi o n)  or  t he  da y  aft er  t he  i nf usi o n  (irres pecti ve  of  res ol uti o n  date)  f or  a n y  i nf usi o n-rel ate d 
reacti o n,  dr u g  h y pers e nsiti vit y,  a na p h ylactic  reacti o n,  h y perse nsiti vit y  a n d/ or  T y pe 1 
h y perse nsiti vit y. 
Si g ns  a n d  s y m pt o ms  of  I R Rs  a n d  h y perse nsiti vit y/ aller gic  re acti o n s: s h o ul d  be  c o nsi dere d 
w he n o nset is o n t he da y of 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 c o m pletel y wit h 
t he e n d date o n t he s a me da y of t he i nf usi o n or t he da y after. 
I R R will be s u m marize d b y t he f oll o wi n g varia bles per s u b gr o u p of I R R a n d o verall: 
•  N u m ber of partici pa nt s wit h at least o ne I R R b y t he w orst N CI -C T C A E t o xicit y gra de ( Gra de 
1/ G ra de 2/ G r a de 3/ Gra de 4/ Gra de 5/ missi n g gra de) 
•  N u m ber of partici pa nt s wit h I R R lea di n g t o per m a ne nt treat me nt disc o nti n uati o n 
•  Ti me relate d t o first o nset ( I nf usi o n 1/ I nf usi o n 2/ I nf usi o n 3/ I nf usi o n 4 or later).   
T he e v e 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 partici pa nt 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 i nf usi o n if its o nset is at t he sa me date ( b ut n ot bef ore 
d osi n g) or t he f oll o wi n g da y of dr u g i nf usi o n.   
M ore o ver, t he f oll o wi n g fre q ue n c y ta bles will be pr o vi de d b y w orst g ra d e, S O C, a n d P T: 
•  I R R b y worst gr a de, S O C, a n d P T 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
T he listi n g of I R Rs will als o be pr o vi de d wit h t he rele va nt i nf or ma ti o n (see descri pti o n of listi n g 
i n Secti o n  1 5. 1. 1 ). A listi n g dis pla yi n g I M P i nter v e nti o n t o get her wit h I R R will als o be dis pla ye d, 
i ncl u di n g a d mi nistrati o n date (da y) /ti me, I R R A E  P T , I R R A E gra de, I R R A E start da y/st o p da y, 
a n d I R R A E ti me relate d t o i nf usi o n. 
1 5. 2. 3. 2  
Im m u ne -rel ate 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 pr eferre d t er m matc hes a preferre d t er m o n t he list of pre -selecte d Me d D R A ter ms. 
2) T he A E o nset or w orse ni n g occ urs after t he first st u d y i nter ve nti o n a n d n o m ore t ha n 9 0 da ys 
after last  st u d y i nter ve nti o n, deat h or t o t he earliest date of s u bse q u e nt a ntica ncer 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.  
3) O n t he A E e C R F pa g e, t he q uesti o n “ Were C ortic oster oi ds, I m m u n os u p pressa nts, or h or m o nal 
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 i mA E e C R F pa ge, eit her:  
a.  T he q uesti o n “ D o es 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?” has t he 
a ns wer  “ N o” selecte d,  i n dicati n g  t hat  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 her me di cal c o n diti o n 
s uc h as a n i nf ecti o n or pr e-e xisti n g disease.  
O R  
b.   T he i mA E  e C R F  i n dicates  t hat  a  bi o ps y  was  perf or me d  a n d  t h e  q uesti o n  “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?” has t he a ns wer “ Yes” 
selecte d. 
I n  t h e  cas e  t hat  criteria  ( 1)  t hr o u g h  ( 3)  are  met,  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 ap plie d:  
•   If t he a ns wer t o “ D o es 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?” ( 4a) 
is missi n g, t he e ve nt will be c o nsi dere d as ir A E (irres pecti ve of bi o ps y res ults).  
•   If  t he  a ns w er  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 p erf or me d, a n d c o n diti o n ( 4a) is n ot satisfie d 
(i.e. “ Yes ” is selecte 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. 
P Ts  will  be  c o m pile d  i nt o  cate g ories  o n  t h e  basis  of  t he  list  of  pre -s electe d  Me d D R A  ter ms: 
I m m u ne-me diate d  ras h,  I m m u ne -me diate d  c olitis,  I m m u ne -me di ate d  p ne u m o nitis,  I m m u ne -
me diate d  he p atitis,  I m m u ne -me diate d  n e p hritis  a n d  re nal  d ysf u n cti o n,  I m m u ne -me diate d 
e n d ocri n o pat hies ( A dre n al i ns ufficie nc y, H y p o g o na dis m, Pit uitar y d ysf u ncti o n, T y pe 1 Dia bet es 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
Mellit us, T h yr oi d dis or ders), Ot her i m m u ne -me di ate d m y ositis, Ot her i m m u ne -me diate d a d vers e 
e ve nts.  
I m m u ne-relat e d a d verse e ve nts (ir A Es) will be descri be d i n t he f oll o wi n g ta bles: 
•  irA Es  
•  irA Es  b y t he w orst gra d e 
•  ir A Es lea di n g t o per ma n e nt treat me nt disc o nti n uati o n 
•  Seri o us irA Es  
•  M ore o ver, t h e fr e q ue nc y ta ble of ir A Es b y w orst gra de, cate g or y, s u b cate g or y (f or I m m u n e -
me diate d  e n d ocri n o pat hies),   s u b-s u bcate g or y  (f or  I m m u ne-me diate d  e n d ocri n o pat hies 
– 
t h yr oi d dis or ders) a n d P T will be pr o vi de d 
T he  listi n g  of  ir A E s will  als o  be  pr o vi de d  wit h  t he  rele va nt  i nf or mati o n  i ncl u di n g  a d diti o nal 
i nter ve nti o ns f or ir A Es (e. g. bi o psies, s ur gical pr oc e d ures, me dical pr oce d ures) . See descri pti o n 
of listi n g i n S ecti o n 1 5. 1. 1 . 
1 5. 2. 3. 3  
 T G F-β i n hi biti o n me di ate d s ki n a d verse e ve nts  
S ki n A E p ossi bl y relate d t o T G F -β i n hi biti o n will be selecte d bas e d o n M e dD R A P Ts acc or di n g 
t o a pre-s pecifie d Me d D R A searc h list:  
N arr o w defi niti o n: 
•  Kerat oaca nt h o ma  
•  S q ua m o us cell car ci n o ma of s ki n 
Br o a d defi niti o n  has a d diti o nal P Ts: 
•  H y per kerat h osis 
•  Acti nic kerat osis  
•  Basal cell carci n o ma  
•  Li p s q ua m o us cell car ci n o ma  
•  B o we n ’s disease 
T he o verall s u m mar y of s ki n T E A E s will i ncl u de t he f oll o wi n g cate g ories f or narr o w a n d br oa d 
defi niti o n: 
•  All s ki n T E A E s 
•  All s ki n T E A E s b y w orst gra de 
•  S ki n T E A E s lea di n g t o per ma ne nt treat me nt disc o nti n uati o n 
•  Seri o us s ki n T E A Es  
Ta bles f or s ki n T E A Es fr e q ue nc y will be pr o vi de d b y Me d D R A Preferre d Ter ms  (P T s) i n cl u di n g 
b ot h narr o w a n d br oa d d efi niti o n P Ts. 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
A listi n g of s ki n T E A E s will als o be pr o vi de d.  T his listi n g will als o pr o vi de, f or t he A E i de ntifie d 
fr o m t he P T list, t he n u m ber of lesi o ns, if a bi o ps y or a n e xcisi o n was d o n e a n d if it c o nfir me d t he 
dia g n osis a n d t he lesi o n l ocati o n c o mi n g fr o m  “T G F β M E DI A T E D S KI N R E A C TI O N ” e C R F 
pa ge.  
1 5. 2. 3. 4  
A ne mi a A d verse E ve nts  
T he f oll o wi n g H L T s a n d P Ts ( usi n g t he latest versi o n of Me d D R A a vaila bl e) will be use d t o select 
t he a ne mia A Es: 
•  A nae mias N E C ( H L T)  
•  A nae mias hae m ol ytic i m m u ne ( H L T)  
•  A nae mias hae m ol ytic N E C ( H L T)  
•  Hae m o gl o bi n decr eas e d ( P T)  
A listi n g  of  a ne mia a d verse  e ve nts  will  be als o pr o vi de d  wit h  t he  rele va nt  i nf or mati o n  (see 
descri pti o n of listi n g i n Secti o n  1 5. 1. 1). A t a ble dis pla yi n g t he o verall s u m mar y of A n e mia  A Es 
b y treat me nt ar m ma y b e  als o prese nte d . 
1 5. 2. 4  
Blee di n g e ve nts  
Blee di n g e ve nts are d efi ne d as a d vers e e v e nts wit h P Ts acc or di n g t o t he Me d D R A Sta n dar dise d 
Me d D R A  Q ueries  ( S M Q ) f or  Hae m orr ha g e  ter ms  (e xcl  la b orat or y  ter ms). Treat me nt -e mer ge nt 
b lee di n g e v e nts a n d treat me nt-e mer g e nt trial dr u g relate d blee di n g e ve nts will be s u m marize d i n 
a  fre q u e nc y  ta ble  pr ese nti n g  S O C  a n d  P T  s orte d  b y  al p ha betical  or d er.  T he  w orst  gra de  per 
partici pa nt, per S O C a n d per P T will be re p ort e d:  
- 
A n y gra de (i ncl u di n g missi n g gra de) 
- 
Gra de 1  
- 
Gra de 2  
- 
Gra de 3  
- 
Gra de 4  
- 
Gra de 5  
 
O n re q uest of I D M C, bas eli ne partici pa nts c h aract eristics li ke de m o gra p hic c haracteristics, hei g h t, 
wei g ht  a n d  B MI,  diseas e  hist or y,  prese n ce  of  a n y  blee di n g  e ve nts  i n  me dical  hist or y,  use  of 
a ntit hr o m b otic  a ge nts  (i n  me dical  hist or y  a n d  o n g oi n g  at  t he  start  of  blee di n g  e ve nt)  ma y  be 
s u m marize d i n partici pa nts wit h a n d wit h o ut blee di n g e ve nts acc or di n g t o t he defi niti o n a b o ve. 
A ntit hr o m b otic a ge nts cate g ories bel o n gi n g t o A T C c o de B 0 1 are c o nsi dere d. 
1 5. 2. 5  
T hree -Tier A p pr o ac h t o S u m m arizi n g a n d A n al yzi n g A Es  
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 n al yze a d verse e ve nts ( A Es) i n cli nical 
st u dies.  A Es  are  cate g orize d  i n  differe nt  tiers  a n d  a nal yze d  usi n g  differe nt  le vels  of  statistical 
a nal yses. All a nal yses will be perf or me d o n treat m e nt e mer ge nt A Es o nl y. 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
Ris k Me as ures  
T he f oll o wi n g statistics f or s u m marizi n g safet y d ata will be pr o vi de d: 
Cr u de R ate : is calc ul ate d as n u m ber of p artici pa nt s wit h s pecific A E o ut of t he t otal n u m ber of 
partici pa nts at ris k e x pr esse d as per ce nta g e.  
E x p os ure  A dj uste d  I nci de nce  R ate  ( E AI R) : is  defi ne d  as  t he  n u m ber  of partici pa nt s  wit h  a 
s pecific A E o ut of t he t otal e x p os ure -ti me a m o n g t he partici pa nt s i n t he treat me nt ar m at ris k of 
t he i nitial occ urre nce of t he e ve nt. If a partici pa nt  has m ulti ple e ve nts, t he e x p os ure peri o d of t he 
first  e ve nt  is  use d.  F or  a partici pa nt  wit h  n o  e ve nt,  t he  e x p os ure  peri o d  is  ce ns ore d  at  t he  last 
f oll o w-u p ti me f or t he A E s u m marizati o n peri o d. E AI R will be i n 1 0 0 partici pa nt years, u nless a  
differe nt  pr o vi des a m or e reas o na bl e n u m ber of di gits f or re p orti n g p ur p ose.  
Tier 1, 2 , a n d 3 i de ntific ati o ns 
All  A Es  will  be  classifie d  i nt o  Tier  2  or  Tier  3  base d  o n  t he  R ule - of-4.  If  t here  are  4  or  m ore 
partici pa nt s wit h  t he  re p orte d preferre d t er m  i n a n y  treat me nt ar m, t h at preferre d  ter m  will  be 
i ncl u de d i n Tier 2. Ot her wise it will be i ncl u de d i n Tier 3. 
F urt her t o t his, Tier 1 A Es will be i de ntifie d fr o m a list of pre-selecte d Me d D R A ter ms ( usi n g t he 
latest versi o n of Me d D R A a vaila ble).  I n cas e t hese e ve nts f ulfill t he R ule- of-4, Tier 1 a nal ysis 
met h o ds will be use d. Ot her wise, a nal yses will be d o ne acc or di n g t o Tier  3. T he  f oll o wi n g list of 
pre -selecte d c o m p osite ter ms base d o n s pecifie d Me d D R A q ueries will be use d : 
•  I m m u ne-relat e d a d verse e ve nts  
o  I m m u ne-relat e d p ne u m o nitis 
o  I m m u ne-relat e d c olitis 
o  I m m u ne-relat e d he patitis 
o  I m m u ne-relat e d e n d ocri n o pat hies 
 T h yr oi d dis or ders 
•  H y p ot h yr oi dis m  
•  H y pert h yr oi dis m  
•  T h yr oi ditis  
 A dre nal i ns uffi cie nc y  
 T y pe 1 Dia betes M ellit us  
 Pit uitar y d ysf u ncti o n  
 H y p o g o na dis m  
o  I m m u ne-relat e d ne p hritis a n d re nal d ysf u ncti o n 
o  I m m u ne-relat e d ras h 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
o  Ot her i m m u ne -rel ate d a d verse e v e nts 
•  I nf usi o n-relat e d reacti o ns 
o  Reacti o ns  
o  Si g ns a n d S y m pt o ms  
•  T G F - β i n hi biti o n me diate d s ki n reacti o ns  
•  A ne mia  
•  Blee di n g a d verse e ve nts  
•  I m paire d w o u n d h eali n g 
S u m m ar y st atistics  
T he f oll o wi n g s u m maries will be prese nte d: 
F or t he pr e- s pecifie d ter ms:: 
•  N u m ber  of partici p a nt s  a n d  perce nta ge  b y pre- s pecifi e d  ter ms  i n  eac h  treat me nt ar m 
acc o m pa ni e d  b y  Cr u de  Rate  differe nce  bet w ee n  treat me nt ar ms wit h  9 5 %  CI. CI  will  be 
ge nerat e d usi n g Mietti ne n & N ur mi ne n ( M N) m et h o d.  CI will n ot be pr o vi de d f or ter ms n ot 
f ulfilli n g t he r ule- of- 4. 
•  F orest pl ot s h o wi n g Cr u d e Rate a n d Cr u de Rate differe nce f or eac h pre -s pecifie d ter m i n Tier 
1 wit h 9 5 % M N CI 
•  N u m ber of p artici pa nt s,  n u m ber of partici pa nt- years a n d E AI R wit h 9 5 % CI usi n g P oiss o n 
met h o d b y pre -s pecifie d ter ms i n eac h treat me nt ar m. I n a d diti o n, E AI R differe n ce bet w ee n 
treat me nt ar ms al o n g wit h 9 5 % CI will be s h o w n.  T he CI f or E AI R differe n ce will be esti mate d 
base d o n M N or e q ui vale nt statistical met h o ds de pe n di n g o n t heir c o m p utati o nal efficie nc y. 
CIs will n ot be pr o vi de d f or ter ms bel o n gi n g t o Tier 3. 
•  F orest pl ot s h o wi n g E AI R a n d E AI R differe nce f or eac h pre -s p ecifie d t er m i n Tier 1 wit h 9 5 % 
CI  
F or a n y T E A Es:  
•  N u m ber of partici pa nt s a n d perce nta g e b y P T i n Tiers 2 a n d 3 a n d o verall i n eac h treat me nt 
ar m acc o m pa nie d b y Cr u de Rate differe n ce b et wee n treat me nt ar ms wit h 9 5 % CI. CI will be 
ge nerat e d usi n g M N met h o d. CI will n ot be pr o vi de d f or ter ms b el o n gi n g t o Tier 3. 
•  F orest pl ot s h o wi n g Cr u de Rate a n d Cr u de Rate differe n ce f or eac h Tier 2 T E A Es wit h 9 5 % 
M N CI  
•  N u m ber of p artici pa nt s,  n u m ber of partici pa nt- years a n d E AI R wit h 9 5 % CI usi n g P oiss o n 
met h o d b y P T  i n Tiers 2 a n d 3  i n eac h treat me nt ar m. I n a d diti o n, E AI R differe n ce b et wee n 
treat me nt ar ms al o n g wit h 9 5 % CI will be s h o w n.  T he CI f or E AI R differe n ce will be esti mate d 
base d o n M N or e q ui vale nt statistical met h o ds de pe n di n g o n t heir c o m p utati o nal efficie nc y.  
CIs will n ot be pr o vi de d f or ter ms bel o n gi n g t o Tier 3. 
•  F orest pl ot s h o wi n g E AI R a n d E AI R differe nce f or eac h Tier 2 T E A Es  wit h 9 5 % CI 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI


Bintrafusp alfa (M7824) 1L NSCLC Adaptive Phase III RCT M7824 versus Pembrolizumab
MS200647-0037 - Version 5.0 
C O N F I D E N T I A L
I N F O R M A T I O N
77/94
No multiplicity adjustment will be applied for Tier 1 and 2 TEAEs.
For presentation of tier 2 and 3 events in the main body of the CSR text, a cut of 5% in any of the 
treatment arms will be applied, while the corresponding end-of-text table will provide all of tier 2 
and 3 events.
Clinical Laboratory Evaluation
Treatment emergent laboratory assessments are any sample collected during on-treatment period.
Laboratory values (including corresponding normal ranges) converted in standard units will be 
used for summary statistics and shift tables.
Laboratory results will be classified according to the NCI-CTCAE Version 5.0. Additional 
laboratory results that are not part of NCI-CTCAE will be presented according to the categories:
low, normal and high (according to the laboratory normal ranges). Quantitative data will be
examined for trends using descriptive statistics (mean, StD, median, Q1, Q3, minimum, and 
maximum) of actual baseline values, on-treatment values and changes from baseline to each on-
treatment visit over time. The changes computed will be the differences from baseline. Participants 
without post baseline laboratory samples will be excluded from analyses with respect to values 
after the baseline. Qualitative data based on reference ranges will be described according to the 
categories (i.e. low, normal, and high).
Laboratory parameters with NCI-CTC grades available 
Laboratory parameters with NCI-CTC grades available will be analyzed with their respective NCI-
CTC name and direction of abnormality. For parameters which are graded with both low and high 
values, the toxicities will be summarized separately.  Low direction toxicity grades at baseline and 
post-baseline will be set to 0 when the variables are derived for summarizing high direction 
toxicity, and vice versa.  
For gradable parameters, the following summaries will be displayed by treatment arm:
•
Number and percentage of participants by worst on-treatment grade (>=1, >=3, >=4) 
•
Shift in toxicity grading from baseline to highest on-treatment toxicity grade 
The following figures will also be provided by treatment arm: 
•
Boxplots of the laboratory values by timepoint 
•
Boxplots of the change from baseline by timepoint 
The definitions of toxicity grading for each parameter are available in the NCI-CTCAE toxicity 
grading version 5.0 (in Appendix 18.1 of this IAP). 
For WBC differential counts (neutrophil, lymphocyte counts), the absolute value will be used 
when reported.  When only percentages are available (this is mainly important for neutrophils and 
lymphocytes, because the CTCAE grading is based on the absolute counts), the absolute value is 
derived as follows:
Global Version ID: 
Global Version ID: CCI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
Deri ve d diff er e ntial a bs ol ute c o u nt = ( W B C c o u nt) * ( Differe ntial % v al ue / 1 0 0) 
F or c alci u m , C T C A E gra di n g is base d o n C orrect e d Calci u m a n d I o nize d Calci u m ( C A L CI O), if 
a vaila ble. C orr ecte d Calci u m is calc ulate d fr o m Al b u mi n a n d Calci u m as f oll o ws:  
o  C orrecte d  cal ci u m  ( m m ol/ L)  =  meas ure d  t otal  calci u m  ( m m ol/ L)  +  0. 0 2  ( 4 0 – s er u m 
al b u mi n [ g/ L]) 
Cre ati ni ne Cle ar a nce ( Cr Cl) will be d eri ve d t hr o u g h t he C oc kcr oft-Ga ult f or m ula (C oc kcr oft 
a n d  Ga ult,  1 9 7 6) , fr o m  t he  ser u m  creati ni ne  meas ure me nts  i n  t he  “ F U L L  C H E MI S T R Y” a n d 
“ C O R E C H E MI S T R Y” e-crf pa g es, t he wei g ht i n t he “ VI T A L SI G N S” e-crf pa ge a n d t he a g e re -
calc ulate d at t he sa m pli n g date as f oll o ws: 
𝐻𝐻𝑃𝑃𝑃𝑃𝑃𝑃= 𝜆𝜆𝑀𝑀𝑃𝑃𝑃𝑃𝑃𝑃𝑡𝑡 ∗(1 4 0 −𝜃𝜃𝜆𝜆𝑃𝑃) ∗
𝑃𝑃𝑃𝑃
𝑃𝑃𝑡𝑡𝜃𝜃𝐻𝐻𝑃𝑃∗0. 8 1 3 6  
w here F A C T O R is ge n der- de pe n d e nt wit h val u e 1 ( male) or 0. 8 5 (fe m ale), A G E is t he s u bject a g e 
i n years, W T is t he s u bject wei g ht i n k g a n d S C R E A  is t he o bser ve d ser u m creati ni ne i n u m ol/l . 
T o xicit y  gra di n g  f or creati ni ne  cleara n ce  will  be  defi ne d  as  per  N CI -C T C A E  t o xicit y  gra di n g 
versi o n 5. 0, t he f oll o wi n g n or mal ra n ges will be c o nsi dere d: 1 1 0 t o 1 5 0 m L/ mi n i n males a n d 1 0 0 
t o 1 3 0 m L/ mi n i n fe males. 
L a b or at or y p ar a m eters wit h N CI- C T C gr a des n ot a v ail a ble 
F or all n o n- gra da ble p ar a meters, t he f oll o wi n g s u m maries will be dis pla ye d b y treat me nt ar m:  
•  S hift fr o m b aseli ne t o l o west  o n-treat me nt v al ue (classifie d as n or mal, hi g h, l o w) 
•  S hift fr o m baseli ne t o t he hi g hest o n-treat me nt val ue (classifie d as n or mal, hi g h, l o w) 
B o x pl ots  f or  la b orat or y  para meters  w here  t o xicit y  gra des  are  defi n e d  bas e d  o n  t he  rati o  of  t he 
para meter  val ues  a n d  t he  u p per  li mit  of  n or mal  ( U L N)  will  n ot  be  dis pla ye d  usi n g  t he  u nit  of 
meas ure me nt b ut i nstea d usi n g t he rati o of t he meas ure d val ue o v er U L N. T his c o m prises al kali ne 
p h os p hatase ( A L P), ala ni ne a mi n otra nsferas e ( A L T), as partate a mi n otra nsferase ( A S T), bilir u bi n, 
a n d creati ni ne. 
A L P, A L T, A S T, bilir u bi n a n d cre ati ni ne  
T he n u m ber a n d perce nt a ge of partici pa nt s wit hi n eac h of t he f oll o wi n g li ver f u ncti o n cate g ories 
d uri n g o n-treat me nt peri o d will be descri be d: 
•  A L T < 3 × U L N, A L T ≥ 3 × U L N, A L T ≥ 5 × U L N, A L T ≥ 1 0 × U L N, A L T ≥ 2 0 × U L N 
•  A S T < 3 × U L N, A S T ≥ 3 × U L N, A S T ≥ 5 x U L N, A S T ≥ 1 0 × U L N, A S T ≥ 2 0 × U L N 
•  ( A L T  a n d  A S T) < 3 × U L N, ( A L T  or  A S T)   ≥ 3 × U L N,  ( A L T  or  A S T)   ≥  5 × U L N,  ( A L T  or 
A S T)   ≥ 1 0 × U L N, ( A L T or A S T)  ≥ 2 0 × U L N 
•  T otal bilir u bi n < 2 × U L N, t otal bilir u bi n ≥ 2 × U L N  
•  C o nc urre nt A L T ≥ 3 × U L N a n d t otal b ilir u bi n ≥ 2 × U L N 
•  C o nc urre nt A S T ≥ 3 × U L N a n d t otal b ilir u bi n ≥ 2 × U L N 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI


Bintrafusp alfa (M7824) 1L NSCLC Adaptive Phase III RCT M7824 versus Pembrolizumab
MS200647-0037 - Version 5.0 
C O N F I D E N T I A L
I N F O R M A T I O N
79/94
•
Concurrent (ALT or AST)  ≥ 3×ULN and total bilirubin ≥ 2×ULN 
•
Concurrent (ALT or AST)  ≥ 3×ULN and total bilirubin ≥ 2×ULN and ALP > 2×ULN 
•
Concurrent (ALT or AST) ≥ 3×ULN and total bilirubin ≥ 2×ULN and ALP ≤ 2×ULN or 
missing
Concurrent measurements are those occurring on the same date. Categories will be cumulative, 
i.e., a participant with an elevation of AST ≥10×ULN will also appear in the categories ≥5×ULN 
and ≥3×ULN.  
A plot of highest values of ALT versus highest values of total bilirubin, both relative to the ULN 
will be provided. This eDISH plot (evaluation of drug-induced serious hepatotoxicity) will be 
divided into 4 quadrants by the lines through ALT ≥ 3×ULN and total bilirubin ≥2×ULN. The left 
lower quadrant is then considered normal or insignificant elevations in liver chemistries, the upper
left quadrant indicates patients with possible Gilbert’s cholestasis; the right upper quadrant are the 
possible Hy’s Law patients; the right lower quadrant is possible Temple’s Corollary (patients with 
ALT ≥ 3 x ULN but not satisfying Hy’s Law).
A plot of highest values of AST versus highest values of total bilirubin, both relative to the ULN 
will be also provided. 
In addition, a listing of total bilirubin, ALT, AST and ALP values during on-treatment period for 
participants with a post-baseline total bilirubin ≥ 2×ULN, ALT≥ 3×ULN or AST ≥ 3×ULN will 
be provided, including values expressed as multiples of ULN. Possible Hy’s Law patients will be 
flagged in this listing.
Separate listings of hematology and biochemistry will be created.  Each listing will include 
treatment arm, participant identifier, age, sex, race, first dose date, last dose date, laboratory 
parameter (units), visit, date, International System of Units (SI) value, lower limit of normal (LLN) 
, ULN, indicator of normal range (low, normal, high), toxicity grade according to NCI-CTCAE
and highest/lowest on treatment value flag.  These listings will be sorted by treatment arm, 
participant identifier, and laboratory measurement date. The baseline values and post-baseline 
values after the on-treatment period will be flagged.  
Pregnancy test
All test results for pregnancy test as collected on the “Pregnancy Test” eCRF page will be listed.  
Coagulation parameters 
Descriptive statistics of coagulation parameters results by visits will be performed, shift tables and 
listings will not be provided. 
Vital Signs
Vital signs data during on-treatment period will be summarized by treatment arm for the Safety 
analysis set.
Global Version ID:
Global Version ID:CCI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
All vital si g n para m eters will be s u m marize d usi n g descri pti ve st atistics ( mea n, St D , me dia n, Q 1, 
Q 3,  mi ni m u m,  ma xi m u m) of  act ual  b aseli ne  v al ues,  o n -treat me nt  v al ues  a n d  c ha n g es  fr o m 
baseli ne t o eac h visit o ver ti me. 
I n a d diti o n, t he ma xi m u m c ha n ges of vital si g n meas ure m e nts baseli ne t o ma xi m u m c ha n ges aft er 
start of 1st treat me nt will be gr o u pe d as f oll o ws:  
T a ble 9  
C ate g ories of M a xi m u m C h a n ge fr o m B aseli ne i n Vit al Si g ns 
B o d y t e m p er at ur e i n cr e a s e  fr o m b as eli n e  
< 3 7 ° C, 3 7 -< 3 8° C, 3 8 -< 3 9° C, 3 9 -< 4 0° C, ≥4 0° C  
< 1 °C , 1 -< 2 °C , 2 -< 3 °C, ≥ 3 °C 
B o d y w ei g ht i n cr e a s e  
< 1 0 %, ≥ 1 0 %  
B o d y w ei g ht d e cr e a s e  
< 1 0 %, ≥ 1 0 %  
H e art r at e i n cr e a s e fr o m b a s eli n e  
< 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  
H e art r at e d e cr e a s e fr o m b a s eli n e  
≤5 0  b p m ; > 5 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 cr e a s e fr o m b a s eli n e  
< 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 d e cr e a s e fr o m b a s eli n e  
≤9 5  m m H g; > 9 5  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 n cr e a s e fr o m b a s eli n e  
< 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 d e cr e a s e fr o m b a s eli n e  
≤4 5  m m H g; > 4 5  m m H g,  
≤2 0 m m H g, > 2 0 – 4 0 m m H g, > 4 0 m m H g  
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 c o nsi deri n g 
o nl y partici pa nt s wit h p ost baseli ne val ues: 
•  Ma xi mal shifts (c ha n ges i n cate g ories)  
T he f oll o wi n g p ote ntiall y  cli nicall y  si g nifica nt  a b n or malities  i n  vital  si g ns  will  be  als o 
s u m marize d: 
•  ≤ 9 5 m m H g a n d decr ease fr o m baseli ne ≥ 2 0 m m H g i n s yst olic bl o o d press ure 
•  ≥ 1 4 0 m m H g a n d i ncreas e fr o m baseli ne ≥ 2 0 m m H g i n s yst olic bl o o d press ure 
•  ≤ 4 5 m m H g a n d decr ease fr o m baseli ne ≥ 2 0 m m H g i n diast olic bl o o d press ure 
•  ≥ 9 0 m m H g a n d i ncreas e fr o m baseli ne ≥ 2 0 m m H g i n diast olic bl o o d press ure 
•  ≤ 5 0 b p m a n d decr ease fr o m baseli ne ≥ 2 0 b p m i n heart rate 
•  ≥ 1 0 0 b p m a n d i ncreas e fr o m baseli ne ≥ 2 0 b p m i n heart rate 
•  ≥ 1 0 % wei g ht i ncrease 
•  ≥ 1 0 % wei g ht decr eas e 
All vital si g ns will als o b e liste d, bas eli ne v al ues a n d p ost-bas eli ne val u es c ollecte d after t he o n-
treat me nt peri o d will be fla g ge d i n t he listi n g.  T he listi n g will i ncl u de treat me nt ar m, partici pa nt  
i de ntifier, a ge, se x, race, vital si g n para meter, visit, date, o n-treat me nt fla g, val ue, u nit, baseli ne 
val ue, a n d c h a n ge fr o m baseli ne.  Listi n gs will be s orte d b y treat me nt ar m, partici pa nt  ide ntifier, 
vital si g n para meter a n d vital si g n meas ure me nt d ate.  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI


Bintrafusp alfa (M7824) 1L NSCLC Adaptive Phase III RCT M7824 versus Pembrolizumab
MS200647-0037 - Version 5.0 
C O N F I D E N T I A L
I N F O R M A T I O N
81/94
Other Safety or Tolerability Evaluations
ECG
A listing of ECG values will be provided with the following information: treatment arm, 
participant identifier, age, sex, race, ECG parameter and unit, ECG date and value.  The listing 
will be sorted by treatment arm, participant identifier, ECG parameter, and ECG date. It will 
include ECG values collected at screening and at safety follow-up visits.  
ECOG Performance Status
The ECOG shift from baseline to the highest score during the on-treatment period will be 
summarized by treatment arm. ECOG performance status will also be presented in a listing at each 
time point. 
Safety analyses by PD-L1 statuses
Further analyses on TEAEs and AESI by PD-L1 assays statuses may be provided on IDMC 
request. 
The following safety tables may be provided by PD-L1 High/Not High statuses for PD-L1 assays 
of interest (e.g. SP263 assay): 
•
TEAEs by Worst Grade, SOC and PT 
•
Overview of Infusion-Related Reactions
•
Overview of Immune-Related AE
•
Overview of TGF-β inhibition mediated skin TEAE
•
Overview of Treatment-Related Anemia
Subset of participants with Haemoptysis, Gastrointestinal Haemorrhages or TEAE leading 
to Death
Specific listings may be provided for AEs of participants meeting at least one of the following 
criteria:  
•
haemoptysis : PT code = Haemoptysis
•
Gastrointestinal haemorrhage: SMQ=20000108
•
TEAE leading to death within 30 days from first IMP intervention
The following listings are considered: 
Global Version ID: 
Global Version ID: CCI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
Me dical hist or y  listi n g s h o wi n g t he f oll ow i n g i nf or mati o n: partici pa nt i de ntifier, treat me nt ar m, 
hae m o pt ysis ( Y/ N), gastr oi ntesti nal hae m orr ha g e( Y/ N), T E A E lea di n g t o d eat h ( Y/ N), d ate of first 
i nf usi o n of trial dr u g, d ate of last i nf usi o n of trial dr u g,  c o u ntr y, a ge, se x, race,  re p orte d me dical 
hist or y, s tart date of me dical hist or y, e n d date of me dical hist or y, relati o ns hi p t o st u d y c o n diti o n, 
o n g oi n g, g ra de, me dical hist or y of blee di n g e ve nts.  
C o nc o mita nt  me dicati o ns  listi n g  i ncl u di n g:  partici pa nt  i de ntifier,  treat me nt  ar m,  hae m o pt ysis 
( Y/ N), gastr oi ntesti nal hae m orr ha g e( Y/ N), T E A E lea di n g t o deat h ( Y/ N), d ate of first i nf usi o n of 
trial dr u g, d ate of last i nf usi o n of trial dr u g,  c o u ntr y, a ge, se x, race,  preferre d ter m of c o n c o mita nt 
me dicati o n,  me dicati o n  na me,  start  date  of  c o n c o mita nt  me dicati o n,  e n d  date  of  c o nc o mita nt 
me dicati o n,  d ose  ( u nits),  fre q ue n c y,  r o ute,  reas o n  f or  me dicati o n  (i n dicati o n),  reas o n  f or 
me dicati o n, use of a ntit hr o m b otic a ge nts ( Y/ N), c o nc o mita nt me dicati o n (ta ke n a n y ti me d uri n g 
o n- treat me nt). 
A d verse  E ve nts  listi n g  i ncl u di n g: partici pa nt  i d e ntifier,  treat me nt  ar m,  hae m o pt ysis  ( Y/ N), 
gastr oi ntesti nal hae m orr ha ge( Y/ N), T E A E lea di n g t o deat h ( Y/ N), Date of first i nf usi o n of trial 
dr u g, Date of last i nf usi o n of trial dr u g, p referre d ter m, i n vesti gat or ter m, start or c ha n ge date of 
A E , e n d date of A E, tr eat me nt-e mer g e nt  A E ( Y/ N), d urati o n of A E ( da ys), da y si nce first i nf usi o n 
of trial dr u g ( da ys), da y si nce m ost rece nt i nf usi o n pri or t o A E o nset ( da ys), r elati o ns hi p t o trial 
dr u g , gra de, ca usalit y fact or , acti o n ta ke n o n trial dr u g , outc o me , seri o us ness , co u ntr y , age , se x, 
race, dat e of i nitial ca ncer dia g n osis , T N M classificati o n at i nitial dia g n osis , T N M classificati o n 
at  st u d y  e ntr y,  p ri or  a ntica ncer  t hera p y,  t u m or  hist ol o g y,  tu m or  l ocati o n ,  blee di n g  e ve nts  i n 
me dical hist or y ( Y/ N), P T of blee di n g e v e nts i n me dical hist or y, a ntit hr o m b otic a ge nts (a n y pri or 
or c o nc o mita nt me dicati o n of A T C c o de B 0 1), l ast a vaila ble c ollecti o n date of he mat ol o g y test , 
h e m o gl o bi n val ue ( g/ L) , Platelets val ue ( 1 0 ^ 9/ L) , last a vaila ble c ollecti o n da te of c o a g ulati o n tests, 
P T val ue (sec) , a P T T val ue (sec) , I N R val u e (rati o). 
S u bset of p artici p a nts  wit h A L P i ncre ase T E A E or Ele v ate d A L P of Gr a de > = 1 d uri n g O n -
Tre at m e nt  
O n I D M C re q u est, a s peci fic listi n g ma y be pr o vi de d f or p artici pa nts meeti n g at lea st o ne of t he 
f oll o wi n g criteria:  
•  i ncreas e d A L P T E A E 
•  ele vate d A L P of gra de > = 1 o n treat me nt  
T his listi n g will i ncl u de , su bject wit h i ncrease d A L P T E A E  ( Y/ N) , S u bject wit h ele vate d A L P of 
gra de  > = 1  o n  treat me nt  ( Y/ N), A nal ysis  Visit , A nal ysis  Date , A nal ysis  Relati ve  Da y , O n -
Treat me nt Fla g , A L P v al ue , A L P U L N , R ati o A L P val ue/ U L N , A L P t o xicit y gra de , A L T val ue , 
A L T  U L N , Rati o  A L T  val ue/ U L N , A L T  t o xicit y  gra de , A S T  val ue , A S T  U L N , Rati o  A S T 
val ue/ U L N , A S T  t o xicit y  gra de , Bilir u bi n  val ue , Bilir u bi n  U L N , Rati o  Bilir u bi n  val ue/ U L N , 
Bilir u bi n t o xicit y gra de, G G T val ue , G G T U L N , rati o G G T val ue/ U L N , G G T t o xicit y gra de. 
 
 
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1 6  
A n al yses of Ot her E n d p oi nts  
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M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
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M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
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M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
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M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
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Bintrafusp alfa (M7824) 1L NSCLC Adaptive Phase III RCT M7824 versus Pembrolizumab
MS200647-0037 - Version 5.0 
C O N F I D E N T I A L
I N F O R M A T I O N
90/94
Patient-Reported Outcomes
Patient-reported outcomes will be collected using the European Organization for Research and 
Treatment of Cancer-Quality of Life Questionnaire Core-30 (EORTC-QLQ-C30), NSCLC 
symptom assessment questionnaire (NSCLC-SAQ) and European Quality of Life 5-dimensions 
5-level questionnaire (EQ-5D-5L). The PROs should be performed in the same sequence at each 
visit.
EORTC-QLQ-C30
The EORTC-QLQ-C30 is a cancer specific health-related quality of life questionnaire that has 
been widely used in clinical studies and investigations using PROs for individual participant 
management. It includes 5 function domains (physical, emotional, social, role, cognitive), 
8 symptoms domains (fatigue, pain, nausea/vomiting, constipation, diarrhea, insomnia, dyspnea, 
and appetite loss), as well as global health status. The EORTC also includes an item library from 
which items can be selected to supplement the core instrument. Items measuring rash, pruritus, 
and trouble by side effects will be added to the items on the C30. 
A score can be computed for each domain by taking the following steps: 
1) For each domain the average of the items that contribute to the domain should be estimated, 
this is the row score (i.e Row Score = Sum of the items responses that contribute to the 
domain/ number of non-missing items that contribute to the domain).
2) Subtract 1 from the row score obtained at step one 
3) Divide the result obtained at step 2 by the range of item score. The range of item score is 
the difference between the maximum possible value of row score and the minimum 
possible value (e.g. most items are scored 1 to 4, giving range = 3) 
4) If functional domain, subtract 1 from the result obtained at step 3) and multiply by 100 
5) If symptom domain/Global health status, multiply the result obtained at step 3 by 100 
The domain score will range from 0 to 100; a higher score represents a higher (“better”) level of 
functioning or a higher (“worse”) level of symptoms. 
NSCLC-SAQ
The NSCLC-SAQ is a 7-item patient-reported outcome questionnaire created to measure the 
cardinal symptoms of NSCLC (McCarrier, 2016).  Items measure 5 domains: 
•
Cough (item 1. “How would you rate your coughing at its worst…?”)
•
Pain (item 2. “How would you rate the worst pain in your chest over the last 7 days?” and 
item 3. “How would you rate the worst pain in areas other than your chest over the past 7 
days?”) 
Global Version ID: 
Global Version ID: CCI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
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•  D ys p nea (ite m 4. “ H o w ofte n di d y o u feel s h ort of breat h d uri n g us u al acti vities …? ”)  
•  Fati g ue (ite m 5. “ H o w ofte n di d y o u ha ve l o w e n er g y o ver t he last 7 da ys ?” a n d ite m 6. 
“ H o w ofte n di d y o u tire easil y o ver t he last 7 da ys?” ),  
•  A p petite l oss (ite m  7. “ H o w ofte n di d y o u ha ve a p o or a p petite o ver t he last 7 da ys?”).   
 
Eac h of t hes e ite ms is rate d i n ter ms of s y m pt o m se verit y or fre q ue n c y o n a 5 -p oi nt res p o nse scale 
( 1 = n o ne or n e ver; 5 = v er y se vere or al wa ys).  
T he sc ori n g al g orit h m of t he N S C L C- S A Q t otal sc ore is as f oll o ws:  
•  C o u g h D o mai n Sc ore: sc ore of t he c o u g h ite m, or missi n g if s ki p pe d 
•  Fati g ue D o mai n Sc ore: if b ot h ite ms pres e nt, c o m p ute mea n; or use sc ore fr o m 1 ite m if 
t he ot her is missi n g; or set t o missi n g if b ot h are s ki p pe d 
•  Pai n D o mai n Sc ore: if b ot h ite ms prese nt, use m ost se vere of b ot h; or us e sc ore fr o m 1 
ite m if t he ot her is missi n g; or set t o missi n g if b ot h are s ki p pe d 
•  D ys p nea D o mai n Sc or e: sc ore of t he s h ort ness of breat h ite m, or missi n g if s ki p pe d 
•  A p petite D o mai n Sc ore: sc ore o f t he p o or a p p etite ite m, or missi n g if s ki p pe d 
N S C L C -S A Q T otal Sc or e: s u m all fi ve d o mai n sc ores; if a n y are missi n g, a t otal sc ore is n ot 
c o m p ute d. T his creates a t otal sc ore ra n gi n g bet w ee n 0 a n d 2 0 wit h hi g her sc ores i n dicati n g 
m ore se ver e s y m pt o mat ol o g y. 
E Q - 5 D- 5 L 
T he  E Q - 5 D-5 L  is  a  6 -ite m  i nstr u me nt  de vel o pe d  b y  t he  E ur o Q ol  Gr o u p  as  a  meas ure  of 
healt h -rel ate d q ualit y of life t hat ca n b e use d i n a wi de ra n g e of healt h c o n diti o ns a n d treat me nts. 
T he E Q -5 D -5 L c o nsists of a d escri pti ve s yste m a n d a si n gle ite m E Q Vis u al A nal o g Scale ( V A S). 
T he  descri pti ve  s yste m  c o m prises  fi ve  di me nsi o ns:  m o bilit y,  self -care,  us ual  acti vities, 
pai n/ disc o mf ort a n d a n xiet y/ de pressi o n. Eac h E Q - 5 D- 5 L di me nsi o n has 5 res p o nse cate g ories: n o 
pr o ble ms,  sli g ht  pr o ble ms,  m o derate  pr o ble ms,  se vere  pr o bl e ms  a n d  e xtre me  pr o ble ms.  T he 
partici pa nt is as ke d t o i n dicate his/ her healt h state b y tic ki n g t he b o x ne xt t o t he m ost a p pr o priate 
state me nt i n eac h of t he 5 di me nsi o ns. T he res p o ns es (ra n gi n g fr o m 1 t o 5) t o t he 5 di me nsi o ns are 
s u m marize d i nt o a 5- di git pr ofile. 
T he E Q  V A S rec or ds t h e patie nt’s s elf -rate d h ealt h o n a vertical vis ual a nal o g ue scale ra n gi n g 
fr o m 0 t o 1 0 0.  
A nal yses o n Patie nt- Re p orte d O utc o mes will n ot be i ncl u de d i n t he C S R 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
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1 7  
Refere nces  
Aar o ns o n  N K,  A h me dzai  S,  Ber g ma n  B,  et  al.  T he  E ur o p ea n  Or ga nizati o n  f or  Researc h  a n d 
Treat me nt of Ca n cer Q L Q -C 3 0: a q u alit y - of-life i nstr u me nt f or use i n i nter nati o nal cli nical trials 
i n o nc ol o g y. J Natl Ca ncer I nst. 1 9 9 3 Mar 3; 8 5( 5): 3 6 5- 7 6 
A gresti, A. ( 2 0 0 7). A n I ntr o d ucti o n  t o Cate g orical Data A nal ysis ( 2 e d.). N e w Y or k: J o h n Wile y 
& S o ns. 
Br o o k me yer, R. a n d Cr o wle y, J. ( 1 9 8 2), A C o nfi de nce  I nter val f or  t he M e dia n S ur vi val Ti me, 
Bi o metrics, 3 8, 2 9 – 4 1. 
C he n  C,  A n ders o n  K,  Me hr otra  D V,  et  al. A  2 -i n-1  a da pti ve  p hase  2/ 3  desi g n  f or  e x pe dite d 
o nc ol o g y dr u g de vel o p m e nt. C o nte m p Cli n Trials. 2 0 1 8; 6 4: 2 3 8- 4 2. 
Cl o p per, C. J., & Pears o n, E. S. ( 1 9 3 4). T he Use of C o nfi de nce or Fi d u cial Li mits Ill ustrate d  i n 
t he Case of t he Bi n o mial. Bi o metri ka, 2 6, 4 0 4 – 4 1 3. 
D o d d  L E,  K or n  E L,  Frei dli n  B,  et  al. Bli n de d  i n de pe n de nt  ce ntral  re vie w  of  pr o gressi o n -free 
s ur vi val i n p hase III cli nical trials: i m p orta nt desi g n ele me nt or u n necessar y e x pe nse? J Cli n O nc ol. 
2 0 0 8 A u g 1; 2 6( 2 2): 3 7 9 1- 6. 
Eise n ha uer E A, T herass e P, B o gaerts J, et al. ( 2 0 0 9), Ne w res p o nse e v al 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; 4 5: 2 2 8- 4 7. 
E M A.  ( 1 3 Dec 2 0 1 2).  G ui deli ne  o n  t he  e val uati o n  of  a ntica ncer  me dici nal  pr o d ucts  i n  ma n.  
E ur o pea n Me dici n es A ge nc y. Retrie ve d fr o m  htt p:// w w w.e ma.e ur o pa.e u/ d o cs/e n _ G B/  d oc u me nt _ 
li brar y/ Scie ntific _ g ui deli ne/ 2 0 1 3/ 0 1/ W C 5 0 0 1 3 7 1 2 8. p df. 
F D A. ( 2 0 0 7). G ui da n ce f or I n d ustr y: Cli nical Trial E n d p oi nts f or t he A p pr o val of Ca ncer Dr u gs 
a n d Bi ol o gics. Was hi n gt o n D C: U S F o o d a n d Dr u g A d mi nistrati o n. 
Her d ma n M, G u de x C, Ll o y d A, et al. De v el o p me nt a n d preli mi nar y testi n g of t he n e w fi ve- le v el 
versi o n of E Q- 5 D ( E Q -5 D - 5 L). Q u al Life Res. 2 0 1 1 Dec; 2 0( 1 0): 1 7 2 7- 3 6. 
H o m mel G 1, Bretz F, Ma urer W. P o werf ul s h ort- c uts f or m ulti p le testi n g pr oce d ures wit h s pecial 
refere nce t o gate k ee pi n g strate gies. Stat Me d. 2 0 0 7 Se p 3 0; 2 6( 2 2): 4 0 6 3- 7 3. 
Kal bfleisc h, J. D. a n d Pr e ntice, R. L. ( 1 9 8 0), T he Statistical A nal ysis of Fail ure Ti me D ata, N e w 
Y or k: J o h n Wile y & S o ns. 
Ka pla n E L, Mei er P ( 1 9 5 8). N o n par a metric esti mati o n fr o m i nc o m plete o bser vati o ns. J A m Stat 
Ass oc. 5 3: 4 5 7- 8 1. 
Mc Carrier K P, At ki ns o n T M, De B us k  K P, et al. Q ualitati ve De vel o p me nt a n d C o nte nt Vali dit y of 
t he N o n-s mall Cell L u n g Ca ncer S y m pt o m Assess me nt Q uesti o n naire ( N S C L C-S A Q), A Patie nt -
re p orte d O ut c o me I nstr u me nt. Cli n T her. 2 0 1 6 A pr; 3 8( 4): 7 9 4- 8 1 0. 
Ta n g, P. A., P o n d, G. R., & C he n, E. X. ( 2 0 1 0, Ja n). I nfl u e nce of a n i n de pe n de nt re vie w  c o m mittee 
o n assess me nt of r es p o nse rat e a n d pr o gressi o n -free s ur vi val i n p hase III cli nical trials. A n n O nc ol, 
2 1( 1), 1 9- 2 6. 
Ye Y, Li A, Li u L, Y a o B. A gr o u p s e q ue ntial H ol m pr oce d ure wit h m ulti ple pri mar y e n d p o i nts. 
Stat Me d. 2 0 1 3 Mar 3 0; 3 2( 7): 1 1 1 2- 2 4 
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Bi ntr af us p alf a ( M 7 8 2 4) 1 L N S C L C A d a pti ve P h ase I II R C T M 7 8 2 4 vers us Pe m br oliz u m a b  
M S 2 0 0 6 4 7- 0 0 3 7 - Versi o n 5. 0 
 
 
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 /9 4  
 
 
E ur o pea n Ce ntre f or Disease Pre ve nti o n a n d C o ntr ol. Data o n C O VI D- 1 9 ge o gra p hic distri b uti o n 
b y  c o u ntr y. 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- data - g e o gra p hic-
distri b uti o n -c o vi d- 1 9-cas es- w orl d wi de, accesse d a n d d o w nl oa de d o n 2 6 J u ne 2 0 2 0. 
S ha h baz H, G u pta M. Creati ni ne Cleara nce. 2 0 2 0 Se p 2. I n: Stat Pearls [I nt er net]. Treas ure Isl a n d 
( F L): Stat Pearls P u blis hi n g. 
 
 
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Gl o bal Versi o n I D: C CI


Bintrafusp alfa (M7824) 1L NSCLC Adaptive Phase III RCT M7824 versus Pembrolizumab
MS200647-0037 - Version 5.0 
C O N F I D E N T I A L
I N F O R M A T I O N
94/94
18
Appendices
IAP_MS200647-0037 List of outputs
The list of outputs will be provided in a separate Appendix of this IAP. 
Toxicity grading for laboratory parameters according to NCI-CTCAE 
v. 5 
Toxicity gradings will be described in a separate Appendix of this IAP. 
Important Protocol Deviations
Important protocol deviations list is provided as a separate appendix of this IAP.
Adaptation Plan
A report of  simulation results (adaptation plan) showing that the family-wise error rate is 
controlled under broad variation of assumptions is provided as a separate appendix of this IAP. 
Literature (SAP template)
References for study specific literature are provided in Section 17.  
GBS internal guidance documents: 
•
Standard analyses for Time to event endpoints In Oncology Trials from GBS Perspective 
•
Definition and Analysis of Best Overall Response in Oncology Trials from GBS 
Perspective 
•
Proposal for Primary Definition of Progression Free Survival (PFS) endpoint In Oncology 
Trials from GBS Perspective
•
Guidance on subgroup analyses, interpretations and its consequences for future trial 
planning from GBS Perspective 
•
Standards for implementation of 3-tier Approach to Summarizing and Analyzing AEs in 
Clinical Trials and Safety summaries
Global Version ID:
Global Version ID:CCI