An Adaptive Phase III, Multicenter, Randomized, Open-Label, Controlled Study of M7824 (Bintrafusp Alfa) Versus Pembrolizumab as a First-line Treatment in Patients With PD-L1 Expressing Advanced Non-small Cell Lung Cancer
Phase: PHASE3
Conditions: Non-small Cell Lung Cancer
Sponsor: EMD Serono Research & Development Institute, Inc.

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.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
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
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 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