Comparative Effectiveness of Different Targeted Therapies for BRAF-mutated Unresectable/Metastatic Melanoma in the United States
Conditions: Melanoma
Sponsor: Pfizer

C LI NI C A L A N D M E DI C A L C O N T R O L L E D D O C U M E N T ( C M C D)
R E Q UI R E D F O R M/ T E M P L A T E 
I de ntifier
Versi o n
Title
Effecti ve D ate
C T 2 4 -WI -G L 0 2 -
R F 0 7
2. 0
S U M M A R Y O F C H A N G E S I N 
A M E N D E D N O N -I NT E R V E N TI O N A L 
S T U D Y P R O T O C O L
0 1 -J u n-2 0 2 2
P FI Z E R G E N E R A L B U SI N E S S
Staff m ust al wa ys refer t o a n d f oll o w  t he c urre nt official electr o nic d oc u me nt re p osit or y versi o n.
T his d oc u me nt was create d base d o n
Q M S 0 4 -G S O P -S D -G L 0 6 9. 0 C M C D F or ms Te m plate W O R D 0 1 -N o v -2 0 2 1
Pa ge 1 of 3 3
Pr ot oc ol # : C 4 2 2 1 0 2 8
O C E A N MI S T - C o m p ar ati ve effecti ve ness of differe nt 
t ar gete d t her a pies f or B R A F-m ut ate d 
u nresect a ble/ met ast atic mel a n o m a i n t he U nite d St ates
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 2 of 3 3
S U M M A R Y O F C H A N G E S I N A M E N D E D 
N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
T his a me n de d pr ot oc ol descri bes a re vise d a p pr oac h f or assess me nt of c o m parati ve effecti ve ness 
of e nc orafe ni b pl us bi ni meti ni b relati ve t o ot her tar gete d t hera pies f or B R A F-m utate d 
u nresecta ble/ metastat ic mela n o ma. A nalys es c o n d ucte d base d o n t he ori gi nal l y s u b mitte d
pr ot oc ol f or st u d y C 4 2 2 1 0 2 8 were li mite d t o descri pti ve a n d u na dj uste d a nal yses of real-w orl d 
data fr o m Flatir o n Healt h, as t he sa m ple size of t he i de ntifie d e nc orafe ni b pl us bi ni meti ni b st u d y 
c o h ort was j u d ge d t o be t o o s mall f or c o n d uct of a dj uste d c o m parati ve effecti ve ness a nal ys es.
Base d o n t he fi n di n gs of a rece ntl y c o m plete d st u dy ( Pr ot oc ol # C 4 2 2 1 0 3 5 : Over all s urviv al 
( O S) i n p atie nts wit h met ast atic B R A F V 6 0 0-m ut a nt mel a n o m a tre ate d wit h e nc or afe ni b pl us 
bi ni meti ni b i n t he C O L U M B U S tri al vers us i n re al -w orl d pr actice d at a ), w hic h s h o we d 
c o nsiste nt O S o utc o mes bet wee n t he C O L U M B U S trial Flatir o n Healt h after acc o u nti n g f or 
differe nces i n patie nt pr ofiles, i n t his a me n de d pr ot oc ol, t o enric h t he sa m ple size f or t he 
e nc orafe ni b pl us bi ni meti ni b c o m bi nati o n c o h ort, data will be p o ole d acr oss Flatir o n a n d 
C O L U M B U S , a n d c o m pare d vers us real-w orl d data f or ot her tar gete d t hera pies as descri be d 
f urt her bel o w. 
K e y  ele me nts of t he re vise d a p pr oac h are s u m marize d bel o w :
1.
P o oli n g of d at a f or e nc o r afe ni b + bi n i meti ni b p atie nts acr oss t he p h ase 3 
C O L U M B U S tri al a n d t he Fl atir o n He alt h re al -w orl d d at a b ase : T h e p o oli n g of data 
f or e nc orafe nib + bi ni meti ni b patie nts acr o ss t hese t w o s o urces is j ustifie d b y t he res ults 
of st u d y C 4 2 2 1 0 3 5, w hic h s h o we d, t hat after har m o nizi n g ke y patie nt selecti o n criteria,
a dj usti n g f or differe nces i n baseli ne c haracteristics, a n d i m p uti n g missi n g data o n 
baseli ne c haracteristics, O S f or metastatic B R A F V 6 0 0 -m uta nt mela n o ma patie nts was 
si milar acr oss t he C O L U M B U S trial a n d real -w orl d practice data fr o m t he Flatir o n 
Healt h data base ( H R = 1. 0 3 , 9 5 % CI: 0. 5 3 , 1. 5 4; p = 0. 9 0 ). Gi ve n t h is e m pirical 
c o nsiste nc y i n O S o utc o mes, p o oli n g patie nts acr oss t hese setti n gs ca n be j ustifie d a n d 
all o ws f or a lar ger sa m ple size f or assess me nt of c o m parati ve effecti ve ness of 
e nc orafe ni b + bi ni meti ni b vers us ot her tar gete d t hera pies. 
2.
A p plic ati o n of ke y p atie nt selecti o n criteri a c o nsiste nt wit h t he C O L U M B U S tr i al
f or all tre at me nt gr o u ps: T o e ns ure i ncl u de d patie nt p o p ulati o ns are c o m para ble acr oss 
setti n gs, ke y patie nt selecti o n criteria a p plie d fr o m t he C O LU M B U S trial will als o be 
a p plie d t o all treat me nt gr o u ps dra w n fr o m t he Flatir o n real -w orl d data base. T h ese 
i ncl u de t he f oll o wi n g: a ge ≥1 8 y ears at i nitiati o n of tar gete d t hera p y, metastatic B R A F 
V 6 0 0 E/ K m utate d mela n o ma wit h o ut ce ntral ner v o us s y ste m metastases, u ntreate d or 
wit h pri or first-li ne i m m u n ot hera py, a n d E C O G perf or ma nce stat us of 0 or 1.
3.
I m p ut ati o n of missi n g d at a o n b aseli ne c h ar acteristics : T o all o w f or m ore 
c o m pre he nsi ve a dj ust me nt f or c o nf o u n di n g d ue t o differe nces i n baseli ne c haracteristics 
bet wee n treat me nt gr o u ps , m ulti ple i m p utati o n will be c o n d ucte d t o acc o u nt f or missi n g 
data i n baseli ne c haracteristics. 
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 3 of 3 3
T he a p pr oac h o utli ne d here lar gel y f oll o ws t he a p pr oac h descri be d i n Pr ot oc ol # C 4 2 2 1 0 3 5 , wit h 
mi n or u p dates t o t he selecti o n criteria, a dj ust me nt fact ors a n d statistical met h o ds f oll o wi n g 
disc ussi o ns wit h a cli nical e x pert i n mela n o ma a n d f urt her re vie w of t he cli nical trial a n d real -
w orl d data .
Cl assific ati o n o f C h a n ge a s S u bst a nti al a n d N o n -S u bst a nti al a n d R ati o n ale
T his is a S u bsta ntial Pr ot oc ol A me n d me nt f or t he reas o ns descri be d a b o ve .
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 4 of 3 3
N O N -I N T E R V E N TI O N A L ( NI) S T U D Y P R O T O C O L
St u d y i nf or m ati o n
Title
O C E A N MI S T - C o m parati ve effecti ve ness of differe nt 
tar gete d t hera pies f or B R A F-m utate d 
u nresecta ble/ metastatic mela n o ma i n t he U nite d States
Pr ot oc ol n u m ber
C 4 2 2 1 0 2 8
Pr ot oc ol versi o n i de ntifier
2 . 0
D ate
1 9 J U L 2 0 2 3
Acti ve s u bst a nce
E nc orafe ni b pl us Bi ni meti ni b
Me dici n al pr o d uct
B raft o vi ® pl us M e kt o vi® 
Rese arc h q uesti o n a n d o bjecti ves
T he st u d y  o bjecti ve is t o descri be a n d c o m pare O S i n 
patie nts wit h metastatic B R A F V 6 0 0 -m uta nt mela n o ma 
treate d wit h e nc orafe ni b pl us bi ni meti ni b 
( E N C O + BI NI) v ers us ot her tar gete d t hera pies . 
A ut h or (s)
, P har m D, M S
 Sc D
 A nal ysis Gr o u p, I nc.
 P h D
, A nalys is Gr o u p, Inc.
, Sc D
, A nalys is Gr o u p, Inc.
 P h D
, A nal ysis Gr o u p, I nc.
T his d oc u me nt c o ntai ns c o nfi de ntial i nf or mati o n bel o n gi n g t o Pfizer. E xce pt as ot her w ise a gree d t o i n writi n g, 
b y  acce pti n g or re vie wi n g t his d oc u me nt, y o u a gree t o h ol d t his i nf or mati o n i n c o nfi de nce a n d n ot c o p y or 
d iscl ose it t o ot hers (e xce pt w here re q uire d b y a p plica ble la w) or use it f or u na ut h orize d p ur p oses. I n t he e ve nt 
of a n y act ual or s us pecte d breac h of t his o bli gati o n, Pfizer m ust be pr o m ptl y n otifie d.
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 5 of 3 3
1. T A B L E O F C O N T E N T S
1. T A B L E O F C O N T E N T S .......................................................................................................5
2. LI S T O F A B B R E VI A T I O N S................................................................................................7
3. R E S P O N SI B L E P A R TI E S ....................................................................................................9
4. A M E N D M E N T S A N D U P D A T E S .....................................................................................1 0
5. MI L E S T O N E S .....................................................................................................................1 2
6. R A TI O N A L E A N D B A C K G R O U N D ................................................................................1 3
7. R E S E A R C H Q U E S TI O N A N D O BJ E C TI V E S .................................................................1 4
8. R E S E A R C H M E T H O D S ....................................................................................................1 4
8. 1. St u d y  desi g n............................................................................................................1 4
8. 2. Setti n g ......................................................................................................................1 4
8. 2. 1. I ncl usi o n criteria .........................................................................................1 4
8. 2. 1. 1. C O L U M B U S trial ....................................................................................1 5
8. 2. 1. 2. Flatir o n Healt h data .................................................................................1 5
8. 2. 2. E xcl usi o n criteria ........................................................................................1 6
8. 3. Varia bles ..................................................................................................................1 7
Ta ble 1. Ke y  e x p os ures, o utc o mes, a n d patie nt baseli ne c haracteristics .......................1 7
8. 4. Data s o urces ............................................................................................................1 9
8. 5. St u d y  size ................................................................................................................2 0
8. 6. Data ma na ge me nt ....................................................................................................2 0
8. 7. Data a nal y sis ...........................................................................................................2 1
8. 7. 1. A na l ysis of baseli ne c haracteristics ............................................................2 1
8. 7. 2. U na dj uste d c o m paris o n of O S bet wee n treat me nt gr o u ps ..........................2 1
8. 7. 3. I m p utati o n of missi n g data o n baseli ne c haracteristics ..............................2 1
8. 7. 4. A dj uste d c o m paris o n of O S bet wee n treat me nt gr o u ps .............................2 2
8. 7. 5. E x pl orat or y  a nalys es of P F S .......................................................................2 2
8. 8. Q ualit y  c o ntr ol.........................................................................................................2 3
8. 9. Stre n gt hs a n d li mitati o ns of t he researc h met h o ds ..................................................2 3
8. 1 0. Ot her as pects......................................................................................................... 2 4
9. P R O T E C TI O N O F H U M A N S U BJ E C T S ..........................................................................2 5
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 6 of 3 3
9. 1. Patie nt i nf or mati o n ..................................................................................................2 5
9. 2. Patie nt c o nse nt .........................................................................................................2 5
9. 3. I nstit uti o nal re vie w b oar d (I R B)/I n de pe n de nt et hics c o m mittee (I E C) ..................2 5
9. 4. Et hical c o n d uct of t he st u d y ....................................................................................2 5
1 0. M A N A G E M E N T A N D R E P O R TI N G O F A D V E R S E E V E N T S/ A D V E R S E 
R E A C TI O N S ......................................................................................................................2 6
1 1. P L A N S F O R DI S S E M I NA TI N G A N D C O M M U NI C A TI N G S T U D Y R E S U L T S ........2 7
1 2. R E F E R E N C E S ..................................................................................................................2 8
1 3. LI S T O F T A B L E S .............................................................................................................2 9
1 4. LI S T O F FI G U R E S ...........................................................................................................2 9
A N N E X 1. LI S T O F S T A N D -A L O N E D O C U M E N T S .........................................................2 9
A N N E X 2. A D DI TI O N A L  I N F O R M A TI O N.........................................................................2 9
A P P E N DI X: T A B L E S H E L L S ...............................................................................................3 0
A p pe n d i x Ta ble 1: Baseli ne patie nt c haracteristics, b y treat me nt gr o u p.......................3 0
A p pe n di x Ta ble 2: Ka pla n -Meier a nal ys es c o m pari n g O S bet wee n t reat me nt gr o u ps .3 2
A p pe n di x Ta ble 3: U na dj uste d a n d a dj uste d hazar d rati os c o m pari n g O S bet wee n 
treat me nt gr o u ps ........................................................................................................3 2
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 7 of 3 3
2. LI S T O F A B B R E VI A TI O N S
A b bre vi ati o n
Defi niti o n
1 L
F irst-li ne
A E
A d verse e ve nt
AJ C C
A merica n J oi nt C o m mittee o n Ca ncer
B MI
B o d y mass i n de x 
B R A F
v- Raf m uri ne sarc o ma viral o nc o ge ne h o m ol o g B pr otei n
CI
C o nfi de nce i nter val 
C T D
C li nical trial data
D A B + T R A M
Da brafe ni b + Tra meti ni b
E C O G
E ur o pea n C o o perati ve O nc ol o g y  Gr o u p
E H R
E lectr o nic healt h rec or d 
E N C O + BI NI
E nc orafe ni b + B i ni meti ni b
F D A
F o o d a n d Dr u g A d mi nistrati o n 
G P P
G o o d P har mac oe pi de mi ol o g y  Practices
G R A C E
G o o d Researc h f or C o m parati ve Effecti ve ness
HI P A A
Healt h I ns ura nce P orta bilit y  a n d Acc o u nta bilit y Act
H R
Hazar d rati o
I C D- 9
I nter nati o nal Classificati o n of Diseases 9t h Re visi o n
I C D-1 0
I nter nati o nal Classificati o n of Diseases 1 0t h Re visi o n
I E C
I n de pe n de nt Et hics C o m mittee 
I O
I m m u n ot hera py
I RB
I nstit uti o nal Re vie w B oar d
I S P E
I nter nati o nal S ociety f or P har mac oe pi de mi ol o g y  
I S P O R
I nter nati o nal S ociety f or P har mac oec o n o mics a n d O utc o mes Researc h
K M
Ka pla n -Meier
L D H
L actate de h ydr o ge nase
L O T
L i ne of t hera py
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 8 of 3 3
M E K  
M it o ge n-acti vate d pr otei n ki nase ( M A P K) ki nase
MI C E
M ulti ple i m p utati o n b y c hai ne d e q uati o ns
N DI
Nati o nal Deat h I n de x
NI
N o n -i nter ve nti o nal
O S
O verall s ur vi val
P F S
P r o gressi o n free s ur vi val
R E CI S T
Res p o nse E val uati o n C riteria i n S oli d T u m o urs
R W D
R eal- w orl d data 
S M R
S ociet y  of Mela n o ma Researc h
T T
T ar gete d t hera p y
U S
U nite d States 
V E M + C O BI
Ve m urafe ni b + C o bi meti ni b
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 9 of 3 3
3. R E S P O N SI B L E P A R TI E S
Pri nci p al I n vesti g at or (s) of t he Pr ot oc ol
N a m e, de gree(s)
J o b Title
Affili ati o n
A d dress
Kristi na C he n, P har m D  
Direct or, Braft o vi/ 
Me kt o vi ( Mela n o ma)
Pfizer, I nc. 
1 P ortla n d Street, 
Ca m bri d ge, M A, 0 2 1 3 9
Ga uta m Sajee v, Sc D
Vice Presi de nt
A nal ysis Gr o u p, I nc.
1 1 1 H u nti n gt o n A ve n ue, 
1 4 t h Fl o or, B ost o n, M A 
0 2 1 9 9
Ja mes Si g n or o vitc h, 
P h D
Ma na gi n g Pri nci pal
A nal ysis Gr o u p, I nc.
1 1 1 H u nti n gt o n A ve n ue, 
1 4 t h Fl o or, B ost o n, M A 
0 2 1 9 9
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 1 0 of 3 3
4. A M E N D M E N T S A N D U P D A T E S
Si g nifica nt u p dates ha ve bee n ma de t o t he data s o urce a n d a nal yt ical a p pr oac h c o m pare d t o t he 
ori gi nal O C E A N MI S T pr ot oc ol s u b missi o n . Bel o w, we pr o vi de a hi g h-le vel o ver vie w of t he ke y 
differe nces wit h a d diti o nal details descri be d i n Secti o ns 5 -8 a n d Secti o n 1 2 bel o w.
D at a S o urce U p d ates

I n t his st u dy, d ata f or e nc orafe ni b pl us bi ni meti ni b patie nts will be p o ole d fr o m t he p hase 
3 C O L U M B U S trial a n d t he Flatir o n Healt h real -w orl d data base t o ma xi mize sa m ple 
size. In c o ntrast, t he ori gi nal st u d y desi g n , o nly use d e nc orafe ni b pl us bi ni meti ni b data 
fr o m Flatir o n Healt h. T his p o oli n g is j ustifie d base d o n t he e m pirical c o nsiste nc y i n O S 
o utc o mes acr oss C O L U M B U S a n d Flatir o n Healt h after har m o nizi n g ke y patie nt 
selecti o n criteria, a dj usti n g f or differe nces i n base li ne c haracteristics, a n d i m p uti n g 
missi n g data o n baseli ne c haracteristics (H R = 1. 0 3, 9 5 % CI : 0. 5 3, 1. 5 4; p = 0. 9 0), 
descri be d i n st u d y C 4 2 2 1 0 3 5 . 
A n al ytic al A p pr o ac h U p d ates

T o e ns ure i de ntificati o n of patie nt p o p ulati o ns i n Flatir o n t hat are c o m para ble to patie nts 
i n t he C O LU M B U S trial, ke y  patie nt selecti o n criteria relate d t o a ge, E C O G perf or ma nce 
sc ore, hist or y of brai n metastasis a n d pri or use of i m m u n ot hera p y a n d tar gete d t hera pies
fr o m t he C O L U M B U S trial will be a p plie d t o all treat me nt gr o u ps i n Flatir o n Healt h . 

T o e ns ure t hat re prese ntati o n of eac h tar gete d t hera p y fr o m t he real-w orl d data was as 
c o m pre he nsi ve as p ossi ble a n d t hat patie nts were f oll o we d fr o m treat me nt i nitiati o n 
c o nsiste nt wit h t he C O L U M B U S trial, patie nts i ncl u de d i n eac h treat me nt c o h ort will be
re q uire d t o ha ve i n de x dates (i.e., treat me nt i nitiati o n dates) t hat were o n or after t he date s
of F D A a p pr o val of t h at tar gete d t hera py i n metastatic mela n o ma (s pecificall y, 0 9 
Ja n uar y 2 0 1 4 f or D A B + T R A M, 1 0 N o ve m ber 2 0 1 5 f or V E M + C O BI a n d 2 7 J u ne 2 0 1 8 
f or E N C O + BI NI). T his is i n c o ntrast t o t he ori gi nal a p pr oac h, w hic h defi ne d t he f oll o w-
u p peri o d f or all c o h orts as be gi n ni n g fr o m 2 0 N o ve m ber 2 0 1 5. T his c o ul d ha ve le d t o 
t he e xcl usi o n of s o me patie nts i nitiati n g D A B + T R A M bef ore a p pr o val, a n d c o ul d 
p ote ntiall y  i na d verte ntl y i ncl u de off -la bel usa ge of E N C O + BI NI.

F or t he real -w orl d c o h orts, patie nt baseli ne c haracteristics will be o btai ne d fr o m visits ≤3 
m o nt hs pri or t o t he i n de x date, wit h data fr o m visits cl osest i n ti me t o t he i n de x date 
bei n g use d as a vaila ble. I n c o ntrast, i n t he ori gi nal pr ot oc ol, t o ma xi mize a vaila bilit y of 
baseli ne c haracteristics, t he ‘ baseli ne’ peri o d was all o we d t o i ncl u de visits u p t o 6 m o nt hs 
pri or t o treat me nt i nitiati o n. T h e decisi o n t o use a stricter defi niti o n of baseli ne here was 
base d o n cli nical i n p ut t hat certai n baseli ne c haracteristics of i nterest (e. g., E C O G P S) are 
best assesse d cl osest t o t he i n de x date , des pite p ote ntial f or i ncrease d missi n g ness. T o 
a d dress missi n g ness, i m p utati o n of baseli ne c haracteristics was c o n d ucte d as descri be d 
bel o w. 
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 1 1 of 3 3

K e y cli nical c haracteristics li ke E C O G a n d L D H were missi n g at baseli ne f or 4 0 -6 0 % of 
patie nts i n t he ori gi nal st u d y  c o h ort, w hic h w o ul d ha ve ha m pere d a bility t o a dj ust f or 
p ote ntial c o nf o u n di n g d ue t o t hese fact ors . T o a d dress missi n g ness, we will i m p ute data 
usi n g m ulti ple i m p utati o n b y c hai ne d e q uati o ns pri or t o c o n d ucti n g a dj uste d a nal ys es. 
I m p utati o n m o dels will be base d o n baseli ne c haracteristics t hat w o ul d be c o nsi dere d i n 
a dj uste d m o del s f or O S. 

I n verse pr o ba bilit y of treat me nt wei g hti n g wit h o ut a n y i m p utati o n was pr o p ose d i n t he 
ori gi nal st u d y desi g n t o acc o u nt f or baseli ne differe nces. I nstea d, we will use
m ulti varia ble C o x pr o p orti o nal hazar ds m o dels fit t o eac h of t he i m p ute d datase t a n d 
c o m bi ne d res ults acr oss all i m p utati o ns. T his a p pr oac h is preferre d as it all o ws us t o 
assess h o w i ncl u de d c o variates are ass ociate d wit h O S i n o ur fi nal m o dels, i n a d diti o n t o 
esti mati n g differe nces bet wee n t he treat me nts of i nterest.

C o m paris o ns of O S a n d P F S were stratifie d b y first -li ne a n d sec o n d-li ne of t hera p y i n t he 
ori gi nal st u d y desi g n. A nal y ses c o n d ucte d i n t his re vise d pr ot oc ol will n ot be stratifie d by 
li ne of t hera py t o all o w f or a lar ger sa m ple size t o c o m pare O S a n d P F S acr oss tar gete d 
t hera py treat me nt c o h orts. A li ne of t hera py v aria ble will be i ncl u de d i n C o x pr o p orti o nal 
hazar d m o dels , w hic h ca n facilitate f ut ure a nalys es of c o m parati ve effecti ve ness b y li ne 
of t hera p y if re q uire d. 
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 1 2 of 3 3
5. MI L E S T O N E S
Milest o ne
Pl a n ne d d ate
A me n d me nt t o st u d y pr ot oc ol
1 9 Ma y
2 0 2 3
C o m pleti o n of statistical a nal yses
7 J u ne 2 0 2 3
A bstract s u b missi o n t o S ociet y f or Mela n o ma Researc h
(S M R ) 2 0 2 3 C o n gress
2 1 J u ne 2 0 2 3
Fi nal st u d y re p ort
2 1 J ul y 2 0 2 3
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 1 3 of 3 3
6. R A TI O N A L E A N D B A C K G R O U N D
Mela n o ma , ca use d w he n mali g na nt ca ncer cells f or m i n mela n oc y tes, is t he fift h m ost c o m m o n 
ca ncer i n t he U nite d States ( U S) a n d t he dea dliest f or m of s ki n ca ncer .1 I nci de nce of mela n o ma 
has bee n i ncreasi n g o ver rece nt deca des , wit h t he o verall i nci de nce rate of 2 2 9. 1 cases per 
milli o n pers o n base d o n rece nt esti mates. Base d o n A merica n Ca ncer S ociet y  estimates, t here 
were a n esti mate d 9 9, 7 8 0 ne w cases of mela n o ma a n d ~7, 6 5 0 deat hs fr o m mela n o ma i n t he U S 
i n 2 0 2 2.1- 3
A p pr o xi matel y 9 % of mela n o ma patie nts are dia g n ose d wit h re gi o nal s prea d t o l y m p h n o des a n d 
4 % are dia g n ose d wit h metastatic disease. 1 C o m pare d t o patie nts wit h l ocalize d mela n o ma, 
patie nts wit h metastatic mela n o ma ha ve p o orer pr o g n osis a n d w orse o utc o mes, w hic h ca n be 
f urt her w orse ne d b y t he prese nce of v-Raf m uri ne sarc o ma viral o nc o ge ne h o m ol o g B pr otei n 
(B R A F ) m utati o ns .4 T he B R A F pr otei n pla y s a n i m p orta nt r ole i n n or mal cell gr o wt h, 
pr oliferati o n, differe ntiati o n, a n d s ur vi val. 5 T he prese nce of B R A F V 6 0 0 m utati o ns, f o u n d i n 
~ 4 0 – 6 0 % of mela n o ma cases, ca n lea d t o s ustai ne d mit o ge n -acti vate d pr otei n ki nase ( M A P K) 
ki nase ( M E K) pat h wa y  si g nali n g, res ulti n g i n t u m or gr o wt h a n d pr o gressi o n.6
Rec o m me n de d treat me nt o pti o ns f or metastatic mela n o ma i ncl u de i m m u n ot hera p y (I O), w hic h 
atte m pts t o sti m ulate h ost res p o nses t o effect uate t u m or destr ucti o n, a n d tar gete d t hera pies ( T T), 
w hic h i n hi bit m olec ular pat h wa y s t o pre ve nt t u m or gr o wt h a n d mai nte na nce.7 T he disc o ver y  of 
tar gete d t hera p y as a treat me nt f or mela n o ma has e mer ge d as a milest o ne de vel o p me nt i n 
o nc ol o gical researc h. 8 I n 2 0 1 8, t he U S F o o d a n d Dr u g A d mi nistrati o n ( F D A) a p pr o ve d t he use 
of e nc orafe ni b ( B R A F T O VI ®) i n c o m bi nati o n wit h bi ni meti ni b ( M E K T O VI ®) f or t he treat me nt 
of patie nts wit h u nresecta ble or metastatic mela n o ma wit h a B R A F V 6 0 0 E or V 6 0 0 K m utati o n 
(as detecte d by a n F D A -a p pr o ve d test) base d o n t he pi v otal p hase 3 C O L U M B U S trial. 9, 1 0 T his 
acc o m pa nie d e xisti n g B R A F -/ ME K- i n hi bit or t hera pies i ncl u di n g da brafe ni b pl us tra meti ni b 
( F D A a p pr o val 0 9 Ja n uar y  2 0 1 4) a n d ve m urafe ni b pl us c o bi meti ni b ( F D A a p pr o val 1 0 
N o ve m ber 2 0 1 5).
T here is i ncreasi n g i nterest i n e val uati n g c o m parati ve effecti ve ness of B R A F -/ ME K- i n hi bit or 
t hera pies. I n a rece nt st u d y, we s h o we d t hat o verall s ur vi val ( O S) f or metastatic B R A F V 6 0 0-
m uta nt mela n o ma patie nts was si milar acr oss t he C O L U M B U S trial a n d real -w orl d practice data 
fr o m t he Flatir o n Healt h data base (Hazar d Rati o [ H R ] = 0. 9 4, 9 5 % C o nfi de nce I nter val [CI ]: 
0. 4 3, 1. 4 5) after har m o nizi n g ke y patie nt selecti o n criteria, a dj usti n g f or differe nces i n baseli ne 
c haracteristics, a n d i m p uti n g missi n g data o n baseli ne c haracteristics . Gi ve n t his e m pirical 
c o nsiste nc y i n O S o utc o mes, p o oli n g patie nts acr oss t hese setti n gs ca n be j ustifie d a n d all o ws f or 
a lar ger sa m ple size f or assess me nt of c o m parati ve effecti ve ness of e nc orafe ni b + bi ni meti ni b 
vers us ot her tar gete d t hera pies. T o t hat e n d, t his st u d y  will e x pa n d o n t his pri or w or k a n d
c o m pare O S bet wee n patie nts recei vi n g e nc orafe ni b + bi ni meti ni b i n t he p o ole d P hase 3 
C O L U M B U S trial a n d t he Flatir o n Healt h Electr o nic Healt h Rec or ds ( E H R) data base vers us 
patie nts recei vi n g ot her tar gete d t hera pies . Baseli ne pr ofiles of patie nts will als o be c o m pare d t o 
c haracteri ze differe nces i n patie nts recei vi n g differe nt t hera pies a n d a dj ust me nts will be ma de f or 
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 1 4 of 3 3
differe nces acr oss treat me nt gr o u ps i n baseli ne fact ors ass ociate d wit h O S. Missi n g ness f or ke y 
baseli ne c haracteristics will be a d dresse d usi n g a vali date d m ulti ple i m p utati o n a p pr oac h.1 2
7. R E S E A R C H Q U E S TI O N A N D O B J E C TI V E S
Pri mar y  O bjecti ve
T o c o m pare O S bet wee n patie nts wit h metastatic B R A F V 6 0 0 -m uta nt mela n o ma i nitiati n g 
e nc orafe ni b pl us bi ni meti ni b ( E N C O + BI NI ) vers us da brafe ni b pl us tra meti ni b (D A B + T R A M ) or 
ve m urafe ni b pl us c o bi meti ni b ( V E M + C O BI )
E x pl orat or y  O bjecti ve
T o c o m pare pr o gressi o n free s ur vi val ( P F S ) bet wee n patie nts wit h meta static B R A F V 6 0 0 -
m uta nt mela n o ma i nitiati n g E N C O + BI NI vers us D A B + T R A M or V E M + C O BI
T h is o bjecti ve is desi g nate d as e x pl orat or y  as, u nli ke f or O S, differe nces i n assess me nt of P F S 
bet wee n cli nical trial data ( C T D) a n d real-w orl d data (R W D ) setti n gs ma y e xist t hat precl u de 
vali d c o m paris o ns of t his o utc o me acr oss t hese setti n gs. S uita bilit y  of c o m parati ve a nalys es of 
P F S will be deter mi ne d f oll o wi n g a d diti o nal e x pl orati o n t o c haracterize n u m ber a n d fre q ue nc y  
of assess me nts of P F S , a n d f urt her a nalys es of c o m para bilit y of P F S o utc o mes acr oss trial a n d 
real-w orl d setti n gs .
8. R E S E A R C H M E T H O D S 
8. 1. St u d y desi g n 
T his is a retr os pecti ve c o h ort st u d y  c o m pari n g O S o utc o mes bet wee n patie nts wit h B R A F V 6 0 0-
m uta nt metastatic mela n o ma i nitiati n g E N C O + BI NI vers us D A B + T R A M or V E M + C O BI . 
C o m paris o ns will be a dj uste d f or differe nces i n baseli ne c haracteristics acr oss treat me nt gr o u ps, 
a n d acc o u nt f or missi n g data o n a dj ust me nt fact ors. P F S will als o be i n vesti gate d as a n 
e x pl orat or y e n d p oi nt, s u bject t o c o m para bility of P F S o ut c o me assess me nt bet wee n cli nical trial 
a n d real -w orl d setti n gs. 
8. 2. Setti n g
P atie nts wit h B R A F V 6 0 0 -m uta nt metastatic mela n o ma i nitiati n g treat me nt wit h E N C O + BI N I, 
D A B + T R A M or V E M + C O BI .
8. 2. 1. I ncl usi o n criteri a
I ncl usi o n criteria t hat will be use d t o i de ntif y patie nts i nitiati n g t he tar gete d t hera pies of i nterest 
are pr o vi de d se paratel y f or t he cli nical trial a n d real -w orl d data s o urces bel o w.
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 1 5 of 3 3
8. 2. 1. 1. C O L U M B U S tri al
K e y  i ncl usi o n criteria i n t he C O L U M B U S trial were: 

Hist ol o gicall y c o nfir me d dia g n osis of l o call y a d va nce d, u nresecta ble, or metastatic 
c uta ne o us mela n o ma or u n k n o w n pri mar y  mela n o ma 

A merica n J oi nt C o m mittee o n Ca ncer ( AJ C C) disease sta ge of III B, III C, I V M 1a, 
I V M 1 b, or I V M 1c at trial e nr ol me nt 

Prese nce of B R A F V 6 0 0 E or V 6 0 0 K m utati o n i n t u m or tiss ue pri or t o e nr oll me nt 

At least 1 8 y ears of a ge at ra n d o mizati o n

Easter n C o o perati ve O nc ol o g y  Gr o u p ( E C O G) stat us of 0 or 1 at ra n d o mizati o n 

Treat me nt nai ve or ha d pr o gresse d o n or after pre vi o us first -li ne ( 1 L) i m m u n ot hera py at 
ra n d o mizati o n wit h n o pri or B R A F - or M E K -i n hi bit or t hera p y i n t he a dj u va nt setti n g
Patie nts fr o m t he C O L U M B U S trial i ncl u de d i n t his a nal y sis will be t h ose patie nts:

Ra n d o mize d t o E N C O + BI NI ar m of t he trial t o recei ve 4 5 0 m g o nce dail y e nc orafe ni b 
a n d 4 5 m g t wice dail y bi ni meti n i b c o m bi nati o n t hera p y
8. 2. 1. 2. Fl atir o n He alt h d at a
Pfizer has c o ntracte d wit h Flatir o n f or a c ust o m data e xtract c o ntai ni n g i nf or mati o n o n patie nts 
wit h a d va nce d mela n o ma . Eli gi bilit y criteria a p plie d t o t he Flatir o n c ust o m data recei ve d by 
Pfizer i ncl u de:

Dia g n ose d wit h mela n o ma
base d o n I nter nati o nal Classificati o n of Disease 9t h a n d 1 0 t h
Re visi o ns (IC D -9: 1 7 2. x; I CD- 1 0: C 4 3 x, D 0 3 x) a n d ≥2 visits o n differe nt da y s i n t he 
Flatir o n data base o n or after Ja n uar y  1, 2 0 1 1.

Cli nicall y  co nfir me d dia g n osis of mela n o ma w it h pat h ol o gic sta ges III or I V at i nitial 
dia g n osis or earlier sta ge disease wit h a first l oc ore gi o nal or dista nt rec urre nce o n or after 
Ja n uar y 1, 2 0 1 1.

A ge ≥1 8 y ears at t he ti me of a d va nce d mela n o ma dia g n osis .

E vi de nce of ≥1 B R A F p ositi ve test res ult at a n y ti me base d o n la b orat or y or ge netic 
a nal ys is res ults.

Treat me nt wit h ≥1 B R A F -i n hi bit or (i.e., e nc orafe ni b, da brafe ni b, ve m urafe ni b) a n d 
treat me nt wit h ≥1 M E K -i n hi bit or (i.e., bi ni meti ni b, tra meti ni b, c o bi meti ni b) i n 1 L  or 2 L  
li ne of t hera p y ( LO T) , as defi ne d per Flatir o n's L O T b usi ness r ules .
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 1 6 of 3 3

Earliest L O T c o ntai ni n g a B R A F - a n d M E K -i n hi bit or ≥3 m o nt hs pri or t o data c ut off
( defi ne d as 3 0 Se pte m ber 2 0 2 1)
K e y  i ncl usi o n criteria fr o m t he C O LU M B U S trial will be a p plie d t o t he Flatir o n R W D 
p o p ulati o n t o ali g n t he p o p ulati o ns t o t he e xte nt p ossi ble bet wee n t he C T D a n d R W D s o urces.
T he s a m ple of patie nts fr o m t he Flatir o n H ealt h E H R data f or t his st u d y will be i de ntifie d usi n g 
t he f oll o wi n g a d diti o nal criteria a p plie d t o t he c ust o m data c ut recei ve d fr o m Flatir o n :

At least 1 8 y ears of a ge at t he i n de x date

C o nfir me d B R A F V 6 0 0 E or V 6 0 0 K acti vati n g m utati o n re p orte d i n t he data base d o n 
la b orat or y or ge netic a nal ysis res ults

Treat me nt -nai ve or ha d pre vi o us 1 L  IO at i n de x date i n t he t hera pe utic setti n g, base d o n 
re vie w of me dicati o n or ders or a d mi nistrati o n pri or t o t he i n de x date.

E C O G stat us of 0 or 1 at t he i n de x date
T he f oll o wi n g criteria will be a d diti o nall y  use d t o i de ntif y patie nts recei vi n g eac h of t he 
treat me nts of i nterest:

E N C O + BI NI tre at me nt gr o u p: A t least 1 or der or a d mi nistrati o n of E N C O + BI NI
treat me nt after t he dia g n osis of metastatic mela n o ma a n d after 2 7 J u ne 2 0 1 8 ( F D A 
a p pr o val date f or E N C O + BI NI f or use i n patie nts wit h metastatic mela n o ma) .

D A B + T R A M tre at me nt gr o u p: A t least 1 or der or a d mi nistrati o n of D A B + T R A M
treat me nt after t he dia g n osis of metastatic mela n o ma a n d after 0 9 Ja n uar y  2 0 1 4 ( F D A 
a p pr o val date f or D A B + T R A M f or use i n patie nts wit h metastatic mela n o ma).

V E M + C O BI tre at me nt gr o u p: A t least 1 or der or a d mi nistrati o n of V E M + C O BI
treat me nt after t he dia g n osis of metastatic mela n o ma a n d after 1 0 N o ve m ber 2 0 1 5 ( F D A 
a p pr o val date f or V E M + C O BI f or use i n patie nts wit h metastatic mela n o ma).
T he i n de x date i n eac h treat me nt gr o u p will be t he date of treat me nt i nitiati o n.
8. 2. 2. E xcl usi o n cr iteri a
Patie nts meeti n g a n y o f t he f oll o wi n g criteria will n ot be i ncl u de d i n t he st u d y:

Patie nts wit h pri or B R A F - or M E K -i n hi bit or t hera p y

Patie nts wit h E C O G perf or ma nce stat us ≥ 2 (at t he ti me of ra n d o mizati o n f or patie nts 
fr o m C O L U M B U S, duri n g t he baseli ne peri o d f or patie nts i n Flatir o n E H R)

P atie nts wit h a hist ory of le pt o me ni n ge al met ast ases i ncl u di n g br ai n, s pi n al c or d, or 
nerv o us syste m met ast ases ( b ase d o n b r ai n M RI or C T sc a n wit h c o ntr ast -e n h a nce d 
br ai n M RI as t he preferre d assess me nt i n C O L U M B U S a n d b ase d o n t he f oll o wi n g 
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 1 7 of 3 3
di a g n ostic c o des i n Fl atir o n E H R: I C D- 9-C M: 1 9 8. 3, 1 9 8. 4 or I C D -1 0 -C M: C 7 9. 3 1, 
C 7 9. 3 2, C 7 9. 4 0, C 7 9. 4 9) pri or t o i n dex

F or R W D patie nts, c o nc urre nt e nr oll me nt i n a cli nical trial.
8. 3. V ari a bles
T a ble 1 pr o vi des a s u m mar y of e x p os ure, o utc o me, a n d patie nt baseli ne c haracteristics t hat will 
be e val uate d wit hi n t he st u d y .
T a ble 1. Ke y e x p os ures, o utc o mes, a n d patie nt baseli ne c haracteristics 
V ari a ble
R ole
D at a s o urce(s)
O per ati o n al defi niti o n /c ate g ories
Treat me nt gr o u p
( E N C O + BI NI, 
D A B + T R A M , 
V E M + C O BI )
E x p os ure
C O L U M B U S
trial data; 
Flatir o n E H R
I n dicates w het her patie nts i nitiate d E N C O + BI NI , 
D A B + T R A M or V E M + C O BI treat me nt
O S
Pri mar y O utc o me
C O L U M B U S
trial data, 
Flatir o n 
I n t he C O L U M B U S trial data, defi ne d as t he ti me fr o m t he 
date of ra n d o mizati o n t o t he date of deat h d ue t o a n y 
ca use; if deat h is n ot o bser ve d, patie nts will be ce ns ore d at 
t he date of last c o ntact or t he data a nal ysis c ut-off date 
(e. g., 1 5 Se pte m ber 2 0 2 0) , w hic he ver occ urs first
I n Flatiro n E H R, will be defi ne d as t he ti me fr o m t he i n de x 
date t o t he date of deat h; patie nts wit h o ut a date of deat h 
will be ce ns ore d at t heir last k n o w n acti vit y date (e. g., t he 
last cli nical n ote date) or t he e n d of t he f oll o w-u p peri o d ,
w h ic he ver occ urs first
P F S
E x pl orat or y O utc o me
C O L U M B U S
trial data, 
Flatir o n her
I n t he C O L U M B U S trial data, defi ne d as t he ti me fr o m t he 
date of ra n d o mizati o n t o t he date of t he first d oc u me nte d 
disease pr o gressi o n or deat h d ue t o a n y ca use, w hic he ver 
occ urre d first; if a patie nt di d n ot ha ve a n e ve nt at t he 
a nal ysis c ut -off date, P F S will be ce ns ore d at t he date of 
t he last a de q uate t u m o ur assess me nt
I n Flatir o n E H R, will be defi ne d as t he ti me fr o m t he i n de x 
date t o eit her t he date of first disease pr o gressi o n e ve nt or 
deat h i n t he a bse nce of pr o gressi o n; patie nts wit h o ut 
disease pr o gressi o n or deat h will be ce ns ore d at t he last 
date t he patie nt c o ul d ha ve bee n assesse d f or p r o gressi o n 
(e. g., t he last cli nical n ote date) or t he data a nal ysis c ut -off 
date (e. g., 3 0 Se pte m ber 2 0 2 1), w hic he ver occ urs first
A ge at baseli ne 
( years)
Baseli ne C haracteristic / 
P ote ntial C o nf o u n der
C O L U M B U S
trial data 
Flatir o n E H R
Patie nt a ge; defi ne d at t he ti me of st u d y ra n d o mizati o n f or 
C O L U M B U S trial data a n d at t he ti me of treat me nt 
i nitiati on f or Flatir o n E H R
Se x
Baseli ne C haracteristic / 
P ote ntial C o nf o u n der
C O L U M B U S
trial data; 
Flatir o n E H R
Male, Fe male, I nterse x, or U n k n o w n/ Missi n g
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 1 8 of 3 3
Race
Baseli ne C haracteristic / 
P ote ntial C o nf o u n der
C O L U M B U S
trial data; 
Flatir o n E H R
Asia n, Blac k, W hite, Ot her/ M ulti -Race , or 
U n k n o w n/ Missi n g
B o d y mass i n de x 
( B MI) at i n de x
Baseli ne C haracteristic / 
P ote ntial C o nf o u n der
C O L U M B U S
trial data; 
Flatir o n E H R
Defi ne d as wei g ht (i n k g) di vi de d b y s q uare d hei g ht (i n 
m 2) 
E C O G at i n de x
Baseli ne C haracteristic / 
P ote ntial C o nf o u n der
C O L U M B U S
trial data; 
Flatir o n E H R
0, 1, U n k n o w n/ Missi n g; defi ne d d uri n g t he baseli ne peri o d 
of b ot h t he C O L U M B U S trial data a n d Flatir o n E H R
B R A F m utati o n 
stat us
Baseli ne C haracteristic / 
P ote ntial C o nf o u n der
C O L U M B U S
trial data; 
Flatir o n E H R
V 6 0 0 E , V 6 0 0 K , U n k n o w n/ Missi n g
AJ C C d isease sta ge 
at i nitial mela n o ma 
dia g n osis
Baseli ne C haracteristic / 
P ote ntial C o nf o u n der
C O L U M B U S
trial data; 
Flatir o n E H R
0, I, II, III, I V, or U n k n o w n/ Missi n g ; defi ne d at i nitial 
mela n o ma dia g n osis f or C O L U M B U S trial data a n d 
Flatir o n E H R
AJ C C d isease sta ge 
at treat me nt 
i nitiati o n
Baseli ne C haracteristic
C O L U M B U S
trial data
III B, III C, I V M 1a, I V M 1 b, or I V M 1c; defi ne d at treat me nt 
i nitiati o n i n t he C O L U M B U S trial data. N ot a vaila ble i n 
t he Flatir o n E H R
Lactate 
de h y dr o ge nase 
( L D H) at i n de x
Baseli ne C haracteristic / 
P ote ntial C o nf o u n der
C O L U M B U S
trial data; 
Flatir o n E H R
E val uate d i n u nits per liter ( U/ L) a n d defi ne d at trial 
baseli ne i n C O L U M B U S trial a n d d uri n g t he baseli ne 
peri o d i n Flatir o n E H R
Ti me fr o m i nitial 
mela n o ma dia g n osis 
t o metastatic disease
Baseli ne C haracteristic / 
P ote ntial C o nf o u n der
C O L U M B U S
trial data; 
Flatir o n E H R
D urati o n (i n m o nt hs) fr o m mela n o ma dia g n osis t o t he 
de vel o p me nt of metastatic disease
Ti me fr o m 
metastatic
mela n o ma dia g n osis 
t o treat me nt 
i nitiati o n
Baseli ne C haracteristic / 
P ote ntia l Co nf o u n der
C O L U M B U S
trial data; 
Flatir o n E H R
D urati o n (i n m o nt hs) fr o m metastatic mela n o ma dia g n osis 
t o t he i nitiati o n of treat me nt
Year of treat me nt
i nitiati o n
Baseli ne C h aracteristic
C O L U M B U S
trial data; 
Flatir o n E H R
Cale n dar year w he n treat me nt was i nitiate d
Re gi o n
Baseli ne C haracteristic
C O L U M B U S
trial data; 
Flatir o n E H R
E ur o pe, N ort h A merica, A ustralia, Ot her, or Missi n g
Treat me nt 
e x perie nce i n t he 
t hera pe utic setti n g
Baseli ne C haracteristic / 
P ote ntia l Co nf o u n der
C O L U M B U S
trial data; 
Flatir o n E H R
I n dicates w het her patie nts recei ve d tar gete d t hera p y as 
first-li ne treat me nt (e. g., Treat me nt naï ve) or as sec o n d-
li ne treat me nt after a pri or li ne of i m m u n ot hera p y 
treat me nt (e. g., Pri or 1 L I O t hera p y)
Pri or syste mic 
thera p ies i n t he 
a dj u va nt setti n g
Baseli ne C haracteristic 
/P o te ntial C o nf o u n der
C O L U M B U S
trial data; 
Flatir o n E H R
I n dicates w het her patie nts pre vi o usl y recei ve d s yste mic 
t hera p y (e. g., pri or s ur ger y, ra di ot hera p y, i m m u n ot hera p y, 
or c he m ot hera p y) bef ore i nitiati n g treat me nt
Pri or sur ger y i n t he 
a dj u va nt setti n g
Baseli ne C ha racteristic / 
P ote ntial C o nf o u n der
C O L U M B U S
trial data; 
Flatir o n E H R
I n dicates w het her patie nts pre vi o usl y use d s ur ger y t o 
re d uce/re m o ve t u m ors as a f or m of treat me nt
Pri or ra di ot hera p y
i n t he a dj u va nt 
setti n g
Baseli ne C haracteristic / 
P ote ntial C o nf o u n de r
C O L U M B U S
trial data; 
Flatir o n E H R
I n dicates w het her patie nts u n der we nt ra di ot hera p y a m o n g 
t h ose recei vi n g pri or s yste mic t hera p y
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 1 9 of 3 3
Pri or I O or 
c he mot hera p y i n t he 
a dj u va nt setti n g
Baseli ne C haracteristic / 
P ote ntial C o nf o u n der
C O L U M B U S
trial data; 
Flatir o n E H R
I n dicates w het her patie nts u n der we nt c he m ot hera p y or 
i m m u n ot hera p y a m o n g t h ose recei vi n g pri or s yste mic 
t hera p y
N u m ber of L O Ts 
after T T treat me nt 
i nitiati o n
Baseli ne C haracteristic / 
P ote ntial C o nf o u n der
C O L U M B U S
trial data; 
Flat ir o n E H R
I n dicates t he n u m ber of L O Ts occ urri n g after treat me nt 
i nitiati o n ( 0, 1, ≥2, or Missi n g)
N u m ber of or ga ns 
i n v ol ve d
Baseli ne C haracteristic
C O L U M B U S
trial data; 
Flatir o n E H R
I n dicates n u m ber of or ga ns i n v ol ve d or sites of metastases 
at baseli ne ( 1 , 2, or ≥3), wit h all patie nts ha vi n g at least 1 
site gi ve n dia g n osis of metastatic disease.
T his data was c ollecte d a n d re p orte d i n C O L U M B U S. I n 
Flatir o n E H R, it will be deri ve d base d o n c o u nti n g t he 
n u m ber of disti nct sites rec or de d as ha vi n g metastases 
base d o n I C D c o des.
Prese nce of l u n g 
metastases
Baseli ne C haracteristic
C O L U M B U S
trial data; 
Flatir o n E H R
I n dicates w het her patie nts ha d l u n g metastases. 
T his data was c ollecte d a n d re p orte d i n C O L U M B U S. I n 
Flatir o n E H R, it will be deri ve d base d o n ha vi n g I C D 
c o des reflecti n g prese nce of l u n g or res pirat or y or ga n 
metastases ( I C D-9: 1 9 7, 1 9 7. 1; I C D -1 0: C 7 8. 0 1, C 7 8. 0 2, 
C 7 8. 1, C 7 8. 2, C 7 8. 3 0, C 7 8. 3 9 ).
Prese nce of li ver 
metastases
Baseli ne C haracteristic
C O L U M B U S
trial data; 
Flatir o n E H R
I n dicates w het her patie nts ha d li ver metastases.
T his data was c ollecte d a n d re p orte d i n C O L U M B U S. I n 
Flatir o n E H R, it will be deri ve d base d o n ha vi n g I C D 
c o des reflecti n g prese nce of li ver metastases ( I C D-9: 
1 9 7. 7; I C D -1 0: C 7 8. 7 )
Prese nce of ot her 
metastases
Baseli ne C haracteristic
C O L U M B U S
trial data; 
Flatir o n E H R
I n dicates w het her patie nts ha d prese nce of ot her metastases
(e. g., a dre nal gla n ds, b o ne, di gesti ve tract/s yste m, ki d ne y, 
l y m p h n o des, re pr o d ucti ve or ga ns, or u ns pecifie d sites).
T his data was c olle cte d a n d re p orte d i n C O L U M B U S. I n 
Flatir o n E H R, it will be deri ve d base d o n ha vi n g I C D 
c o des reflecti n g prese nce of ot her metastases (I C D -9: 1 9 6, 
1 9 6. 1, 1 9 6. 2, 1 9 6. 3, 1 9 6. 5, 1 9 6. 6, 1 9 6. 8, 1 9 6. 9, 1 9 7. 4, 
1 9 7. 5, 1 9 7. 6, 1 9 7. 8, 1 9 8, 1 9 8. 5, 1 9 8. 7, 1 9 8. 8 9; I C D -1 0 : 
C 7 7. 0, C 7 7. 1, C 7 7. 2, C 7 7. 3, C 7 7. 4, C 7 7. 5, C 7 7. 8, C 7 7. 9, 
C 7 8. 4, C 7 8. 5, C 7 8. 6, C 7 8. 8 0, C 7 8. 8 9, C 7 9. 0 0, C 7 9. 0 1, 
C 7 9. 0 2, C 7 9. 1 1, C 7 9. 5 1, C 7 9. 5 2, C 7 9. 6 0, C 7 9. 6 1, C 7 9. 6 2, 
C 7 9. 7 0, C 7 9. 7 1, C 7 9. 7 2, C 7 9. 8 1, C 7 9. 8 9, C 7 9. 9)
8. 4. D at a s o urces 
C O L U M B U S trial 
C O L U M B U S w as a t w o -part, m ultice nter, ra n d o mize d, o pe n -la bel, P hase 3 cli nical trial.1 0 Part 1 
of t he trial i n vesti gate d t he effecti ve ness a n d safet y  of t hree treat me nt re gi me ns i n patie nts wit h 
l ocall y a d va nce d u nresecta ble or metastatic B R A F V 6 0 0-m uta nt metastatic mela n o ma w h o were 
treat me nt naï ve or w h ose ca ncer ha d pr o gresse d after 1 L I O. I n Part 1 of t he trial, patie nts were 
ra n d o mize d t o o ne of t hree treat me nt ar ms: 1) 4 5 0 m g o nce daily e nc orafe ni b a n d 4 5 m g t wice 
dail y  bi ni meti ni b ( n = 1 9 2), 2) 9 6 0 m g t wice daily v e m urafe ni b ( n = 1 9 1) a n d 3) 3 0 0 m g o nce dail y 
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 2 0 of 3 3
e nc orafe ni b ( n = 1 9 4). Ra n d o mizati o n was stratifi e d b y AJ C C disease sta ge (III B, III C, I V M 1a, 
I V M 1 b, or I V M 1c), E C O G perf or ma nce stat us ( 0, 1), a n d B R A F V 6 0 0 m utati o n pr ofile ( V 6 0 0 E, 
V 6 0 0 K). Pr o gressi o n -free s ur vi val was t he pri mar y e n d p oi nt i n t he trial, w hile O S was o ne of t he 
sec o n dar y e n d p oi nts. Patients were e nr olle d i n Part 1 of t he trial bet wee n 3 0 Dece m ber 2 0 1 3 
t hr o u g h 1 0 A pril 2 0 1 5.
T he E N C O + BI NI ar m of Part 1 of t he tria l will be use d i n t his st u d y  ( data base l oc k date: 1 5 
Se pte m ber 2 0 2 0). Part 2 of t he trial c o m pare d e nc orafe ni b 3 0 0 m g o nce dail y  pl us bi ni meti ni b 
4 5 m g t wice dail y  vers us e nc orafe ni b 3 0 0 m g o nce dail y al o ne a n d will n ot be c o nsi dere d.
Flatir o n Healt h E H R
T he Flati r o n Healt h E H R data base is a l o n git u di nal, de-i de ntifie d real-w orl d data base deri ve d 
fr o m E H Rs c ollecte d i n U S ca ncer cli nics. T he data base c o vers m ore t ha n 2. 6 milli o n acti ve 
ca ncer patie nts t reate d at o ver 8 0 0 sites of care acr oss 4 U S ce ns us re gi o ns. Patie nt-le vel data 
i ncl u des b ot h str uct ure d ( dia g n osis, de m o gra p hics, la b orat or y  val ues, bi o mar ker i nf or mati o n, 
dr u g or ders, visits, etc.) a n d u nstr uct ure d ( p h ys icia n n otes, ra di ol o g y, a n d pat h ol o g y re p orts, etc.) 
s o urces. Data o n deat h is dra w n fr o m st r uct ure d or u nstr uct ure d data fiel ds i n t he E H R, a n d 
p u blicl y  a vaila ble s o urces of m ortalit y i ncl u di n g t he U S S ocial Sec urit y Deat h In de x, a n d 
c o m mercial o bit uar y data.1 3
Pfizer has c o ntracte d wit h Flatir o n f or a c ust o m data e xtract c o ntai ni n g i nf or mati o n o n patie nts 
wit h a d va nce d mela n o ma w h o recei ve d treat me nt wit h
B R A F - or M E K -i n hi bit or t hera pies. 
Patie nts meeti n g t he eli gi bilit y criteria defi ne d f or t his st u d y will be o btai ne d fr o m t his c ust o m 
data e xtract as descri be d i n Secti o n 8. 2 a n d use d i n all a nal ys es. 
8. 5. St u d y size
T he n u m ber of patie nts eli gi ble f or t he st u d y will be deter mi ne d i n acc or da nce wit h t he sa m ple 
selecti o n c o n d ucte d per t he criteria descri be d i n Secti o n 8. 2 .
8. 6. D at a m a n a ge me nt 
Clea n, patie nt -le vel datasets f or C O L U M B U S a n d Flatir o n Healt h data will be ge nerate d f or use 
t hr o u g h o ut t he st u dy. T his pr ocess will e ntail basic e x pl orat or y c hec ks t o e ns ure data i nte grit y,
clea ni n g a n d ref or matti n g t he ra w data as nee de d , a n d creati n g varia bles f or all ke y  st u d y 
meas ures. All data will be st ore d a n d ma i ntai ne d o n a sec ure e ncr y pte d n o n-cl o u d-base d ser ver 
a n d accesse d o ver a sec ure i nter nal pri vate wi de area net w or k. T he data will be ma de accessi ble 
o nl y  t o i n di vi d uals w or ki n g o n t he c urre nt st u d y. N o atte m pt will be ma de t o i de ntif y i n di vi d ual 
patie nts, h os pitals, or p h ysicia ns. A nal ys es will be c o n d ucte d usi n g S A S versi o n 9. 4 a n d/ or R 
versi o n 4. 1. 0 or later .
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 2 1 of 3 3
8. 7. D at a a n al ysis 
8. 7. 1. A n al ysis of b aseli ne c h ar acteristics
Patie nt baseli ne c haracteristics at or pri or t o t he i n de x visit will be s u m marize d f or all treat me nt 
gr o u ps . Patie nt c haracteristics t o be s u m marize d will be base d o n a vaila bilit y i n b ot h data 
s o urces a n d cli nical i n p ut. A list of c haracteristics e x pecte d t o be s u m marize d is pr o vi de d i n
T a ble 1 . 
Baseli ne c haracteri stics will be s u m marize d at t he i n de x date if meas ure d at t hat ti me. I n t he 
Flatir o n data, f or baseli ne c haracteristics t hat are n ot meas ure d at t he i n de x date, t he cl osest 
a vaila ble meas ure t o t he i n de x date wit hi n a baseli ne peri o d will be use d. I nf or me d b y  cli nical 
i n p ut a n d c o nsi derati o ns of data a vaila bilit y, t he b aseli ne peri o d will be defi ne d as a 3- m o nt h ti me 
wi n d o w pri or t o a n d i ncl u di n g t he i n de x date.  
Patie nt baseli ne c haracteristics will be s u m marize d descri pti vel y usi n g mea n ( wit h sta n dar d 
de viati o n) a n d me dia n ( wit h i nter q uartile ra n ge) f or c o nti n u o us varia bles a n d c o u nt ( wit h 
pr o p orti o ns) f or cate g orical varia bles. Missi n g ness f or eac h baseli ne c haracteristic (at t he i n de x 
date or wit hi n t he baseli ne peri o d) will als o be s u m marize d.
8. 7. 2. U n a dj uste d c o m p aris o n of O S bet wee n tre at me nt gr o u ps
O S will be defi ne d as descri be d i n Secti o n 8. 3. O S will be s u m marize d f or eac h treat me nt gr o u p 
(i.e., E N C O + BI NI [p o ole d acr oss C O L U M B U S a n d Flatir o n E H R] , D A B + T R A M a n d 
V E M + C O BI) . A n u na dj uste d c o m paris o n of O S acr oss treat me nt gr o u ps will be c o n d ucte d usi n g 
Ka pla n -Meier ( K M) a nal y ses. O S o ver ti me i n t hese treat me nt gr o u ps will be pl otte d a n d 
c o m pare d usi n g a l o g-ra n k test, wit h me dia n s ur vi val ti me a n d s ur vi val pr o p orti o ns re p orted at 
selecte d ti me p oi nts (e. g., 6 m o nt hs, 1 year, 2 years). Hazar d rati os f or O S c o m pari n g 
E N C O + BI NI relati ve t o D A B + T R A M a n d V E M + C O BI will be esti mate d base d o n a u ni varia ble 
C o x pr o p orti o n hazar ds m o del. T he pr o p orti o nal hazar ds ass u m pti o n will be asses se d usi n g tests 
of Sc h oe nfel d resi d uals. 1 4
8. 7. 3. I m p ut ati o n of missi n g d at a o n b aseli ne c h ar acteristics
Pre vi o us a nal ys es of t he Flatir o n data ha ve f o u n d t hat t here are m o derate t o lar ge a m o u nts of 
missi n g data o n baseli ne c haracteristics s uc h as E C O G perf or ma nce sc ore a n d L D H. 1 2 As 
a nal ys es restricte d t o patie nts wit h n o n -missi n g data are hi g hl y li kely t o be biase d, i m p utati o n of 
missi n g data o n ke y  baseli ne c haracteristics is nee de d t o e ns ure t hat a dj uste d a nalys es of O S 
bet wee n t he trial a n d R W D setti n gs are base d o n all eli gi ble patie nts. 
I n t his st u dy, m ulti ple i m p utati o n b y c hai ne d e q uati o ns ( MIC E) 1 5 will be use d t o i m p ute missi n g 
data o n baseli ne c haracteristics . Briefl y, t he MI C E met h o d i m p utes data f or a missi n g patie nt 
c haracteristic base d o n iterati ve re gressi o ns of o bser ve d data f or t hat c haracteristic o n o bser ve d 
a n d i m p ute d val ues of ot her baseli ne c haracteristics. T his pr ocess will be re peate d f or eac h 
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 2 2 of 3 3
c haracteristic u ntil sta ble esti mates are o btai ne d, a n d t he e ntire pr oce d ure will be re peate d s o t hat 
m ulti ple datasets wit h i m p ute d val ues f or baseli ne c haracteristics are create d. 
Baseli ne c haracteristics t o be i m p ute d will i ncl u de E C O G perf or ma nce sc ore, L D H , a n d ot her 
cli nical or de m o gra p hic c haracteristics (e. g., race, B MI, etc.) . A d diti o nal varia bles (e. g., a ge, se x, 
AJ C C dia g n osis, ti me fr o m M M dia g n osis t o treat me nt i nitiati o n, ti me fr o m i nitial dia g n osis of 
mela n o ma t o metastatic disease, n u m ber of or ga ns at baseli ne, metastatic sites, treat me nts i n t he 
t hera pe utic setti n g, treat me nts i n t he a dj u va nt setti n g ) will be c o nsi dere d f or i ncl usi o n i n t he 
MI C E pr oce d ure base d o n t heir rele va nce f or a dj ust me nt a n d de gree of missi n g ness i n t he st u d y 
sa m ple. As rec o m me n de d i n t he literat ure, t he MI C E a p pr oac h will be use d t o create m ulti ple 
datasets (e. g., 1 0 0 datasets) wit h i m p ute d val ues, w hic h will be use d a n d c o m bi ne d i n s u bse q ue nt 
a nal ys es. 1 5
Missi n g data o n baseli ne c haracteristics will be i m p ute d f or all treat me nt gr o u ps . A nal y ses of 
baseli ne c haracteristics descri be d i n Secti o n 8. 7. 1 will be re peate d f or eac h i m p ute d dataset, a n d 
t he n s u m marize d acr oss all i m p ute d datasets. 
8. 7. 4. A dj uste d c o m p aris o n of O S bet wee n tre at me nt gr o u ps
Fi nall y , a n a dj uste d c o m paris o n of O S acr oss treat me nt gr o u ps (i.e., E N C O + BI NI [p o ole d acr oss 
C O L U M B U S a n d Flatir o n E H R ], D A B + T R A M a n d V E M + C O BI) will be c o n d ucte d. Hazar d 
rati os will be esti mate d base d o n a m ulti varia ble C o x pr o p orti o nal hazar d m o del, a dj usti n g f or 
ke y  baseli ne c haracteristics k n o w n or e x pecte d t o be relate d t o O S i n metastatic mela n o ma (e. g., 
a ge, se x, race, B M I, E C O G, L D H, ti me fr o m i nitial mela n o ma dia g n osis t o metastatic disease, 
ti me fr o m metastatic dia g n osis t o treat me nt i nitiati o n, treat me nt e x perie nce i n t he t hera pe utic 
setti n g, pri or I O/c he m ot hera p y i n t he a dj u va nt setti n g, pri or s ur ger y i n t he a dj u va nt setti n g).
S pecific a dj ust me nt fact ors liste d here ma y be re vise d base d o n e x pert cli nical i n p ut. 
T he a dj uste d a nal yses will be c o n d ucte d i n eac h of t he datasets wit h i m p ute d baseli ne 
c haracteristic val ues i n t ur n. Lo g -hazar d rati os f or O S c o m pari n g treat me nt wit h E N C O + BI N I 
relati ve t o D A B + T R A M a n d V E M + C O BI eac h i m p ute d dataset will be o btai ne d, a n d s u m mar y  
H R s o btai ne d b y  p o oli n g res ults acr oss all i m p ute d datasets will be ge nerate d usi n g R u bi n’s 
r ules.1 6
8. 7. 5. E x pl or at or y a n al yses of P F S 
A nal y ses assessi n g P F S will als o be e x pl ore d. P F S will be defi ne d as descri be d i n Secti o n 8. 3. 
P F S will be s u m marize d f or all treat me nt gr o u ps. 
S uita bilit y  of c o m parati ve a nalys es of P F S bet wee n treat me nt gr o u ps will be deter mi ne d 
f oll o wi n g a d diti o nal data e x pl orati o n t o c haracterize n u m ber a n d fre q ue nc y of assess me nts of 
P F S a vaila ble i n t hese setti n gs, a n d disc ussi o n of c o m para bilit y of t he assess me nt of disease 
pr o gressi o n i n R W D vs C T D. If a nal ys es of P F S are dee me d s uita ble base d o n t hese e val uati o ns, 
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 2 3 of 3 3
u na dj uste d a n d a dj uste d c o m paris o ns of P F S will be c o n d ucte d usi n g t he met h o ds descri be d i n 
Secti o ns 8. 7. 2 a n d 8. 7. 4 .
8. 8. Q u alit y c o ntr ol
Best practice g ui deli nes will be f oll o we d t o e ns ure pr oject q ualit y, i ncl u di n g str uct ure d 
or ga nizati o n of pr oject materials (e. g., data e xtracts, statistical s oft ware pr o gra ms, o ut p ut ta bles) 
a n d sta n dar d i nter nal a u dit pr ocess. T he a u dit pr ocess b ot h c o nfir ms t he vali d it y of t he a nal ytical 
a p pr oac h a n d e ns ures t hat all pr o gra ms a n d res ults are acc urate.
8. 9. Stre n gt hs a n d l i mit ati o ns of t he rese arc h met h o ds
T he stre n gt hs of t his st u d y i ncl u de:

K e y  i ncl usi o n criteria wit h res pect t o dia g n osis, disease sta ge, a ge, B R A F V 6 0 0 m utati o n 
a n d E C O G stat us i n t he C O LU M B U S trial will be a p plie d t o t he Flatir o n R W D t o t he 
e xte nt p ossi ble t o o btai n a c o m para ble gr o u p of patie nts acr oss b ot h setti n gs

A dj ust me nt will be ma de f or m ulti ple baseli ne c haracteristics t o miti gate bias d ue t o 
p ot e ntial differe nces i n t hese c haracteristics acr oss t he treat me nt gr o u ps

C o ncer ns a b o ut differe nces i n o utc o me assess me nt acr oss trial a n d R W D setti n g s are 
miti gate d f or O S gi ve n t he a vaila bilit y of a real-w orl d m ortalit y  e n d p oi nt i n t he Flatir o n 
R W D t hat has hi g h se nsiti vit y , s pecificity, p ositi ve pre dicti ve val ue s, ne gati ve pre dicti ve 
val ues a n d a gree me nt w he n c o m pare d a gai nst t he Nati o nal Deat h I n de x ( N DI), t he g ol d -
sta n dar d s o urce f or m ortalit y data i n t he U S.1 7
T he li mitati o ns of t his st u d y  i ncl u de t he f oll o wi n g:

A p plicati o n of t he C O L U M B U S trial i ncl usi o n criteri o n re q uiri n g at least 1 meas ura ble 
lesi o n base d o n Res p o nse E val uati o n Criteria i n S oli d T u m ors ( R E CIS T) versi o n 1. 1 
criteria will n ot be i m ple me nte d d ue t o a bse nce i n Flatir o n E H R of s ys te matic 
ra di o gra p hic i ma gi n g t o assess t u m or res p o nse as re q uire d by R E CI S T.

W hile a dj ust me n t will be ma de f or a vaila ble baseli ne c haracteristics acr oss treat me nt 
gr o u ps , differe nces d ue t o fact ors t hat were n ot a dj uste d f or m a y  still c o ntri b ute t o 
o bser ve d differe nces i n O S bet wee n setti n gs. F or i nsta nce, data o n n u m ber a n d sites of 
metastases , w hile sys te maticall y c ollecte d i n t he C O L U M B U S trial, ca n o nl y be deri ve d 
base d o n I C D c o des i n Flatir o n E H R. Base d o n cli nical i n p ut, data o n n u m ber a n d sites 
of metastases will ver y  li kel y be u n deresti mate d i n t he Flatir o n E H R , a n d n ot 
c o m para ble t o t he c orres p o n di n g data fr o m C O L U M B U S , precl u di n g a dj ust me nt f or 
t hese varia bles.  
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 2 4 of 3 3

T he a nal ys is c o n d ucte d here is a nal o g o us t o a n ‘i nte nt-t o-treat’ pers pecti ve , a n d 
t heref ore will n ot acc o u nt f or p ote ntial differe nces i n a d here nce a n d p ost-baseli ne 
treat me nts bet wee n trial a n d real-w orl d setti n gs. 

T he C O L U M B U S trial was a m ulti-nati o nal trial t hat recr uite d patie nts fr o m 1 6 0 + sites 
i n 2 8 c o u ntries, a n d t heref ore c o vers a br oa der ra n ge of ge o gra p hies t ha n t he U S -base d 
Flatir o n R W D; differe nces i n bac k gr o u n d care acr oss ge o gra p hies a n d care setti n gs ma y  
c o ntri b ute t o differe nces i n o utc o mes bet wee n t he C T D a n d R W D.
8. 1 0. Ot her as pects
N ot a p plica ble.
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 2 5 of 3 3
9. P R O T E C TI O N O F H U M A N S U B J E C T S
9. 1. P atie nt i nf or m ati o n 
T his st u d y  i n v ol ves data t hat e xist i n a n o n ymize d str uct ure d f or mat a n d c o ntai n n o patie nt 
pers o nal i nf or mati o n. 
9. 2. P atie nt c o nse nt
As t his st u d y  i n v ol ves a n o n ymize d str uct ure d data, w hic h acc or di n g t o a p plica ble le gal 
req uire me nts d o n ot c o ntai n data s u bject t o pri vac y la ws, o btai ni n g i nf or me d c o nse nt fr o m 
patie nts b y  Pfizer is n ot re q uire d.
9. 3. I nstit uti o n al re vie w b o ar d (I R B)/I n de pe n de nt et hics c o m mittee (I E C)
T his retr os pecti ve data base a nal ys is d oes n ot i n v ol ve t he c ollecti o n, use, or tra ns mittal of 
i n di vi d uall y i de ntifia ble data. As s uc h, t he st u dy falls wit hi n t he defi niti o n of e xe m pt researc h 
u n der 4 5 C F R 4 6. 1 0 4( d)( 4)(ii) a n d I R B a p pr o val is n ot re q uire d. Beca use t he dataset d oes n ot 
i ncl u de i n di vi d uall y i de ntifiable healt h i nf or mati o n u n der 4 5 C F R 1 6 4. 5 1 4, 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 d o n ot a p ply.
9. 4. Et hic al c o n d uct of t he st u d y
T he st u d y  will be c o n d ucte d i n acc or da nce wit h le gal a n d re g ulat or y re q uire me nts, as well as 
w it h scie ntific p ur p ose, val ue a n d ri g or a n d f oll o w ge nerally acce pte d researc h practices
descri be d i n i n G ui deli nes f or G o o d P har mac oe pi de mi ol o g y  Practices ( G P P) iss ue d b y t he 
I nter nati o nal S ociety f or P har mac oe pi de mi ol o g y  (I S P E), G o o d Practices f or O utc o mes Researc h 
iss ue d b y t he I nter nati o nal S ociet y f or P har mac oec o n o mics a n d O utc o mes Researc h (I S P O R), 
a n d t he G o o d Researc h f or C o m parati ve Effecti ve ness ( G R A C E) Pri nci ples .1 8 -2 0
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 2 6 of 3 3
1 0. M A N A G E M E N T A N D R E P O R TI N G O F A D V E R S E E V E N T S/ A D V E R S E 
R E A C TI O N S 
T his st u d y  i n v ol ves electr o nic healt h rec or ds data t hat e xist as str uct ure d data b y t he ti me of 
st u d y start or a c o m bi nati o n of e xisti n g str uct ure d data a n d u nstr uct ure d data, w hic h will be 
c o n verte d t o str uct ure d f or m d uri n g t he i m ple me ntati o n of t he pr ot oc ol s olel y  by a c o m p uter 
usi n g a ut o mate d/al g orit h mic met h o ds, s uc h as nat ural la n g ua ge pr ocessi n g.
I n t hese data s o urces, i n di vi d ual patie nt data are n ot retrie ve d or vali date d, a n d it is n ot p ossi ble 
t o lin k (i.e., i de ntif y  a p ote ntial ass ociati o n bet wee n) a partic ular pr o d uct a n d me dical e ve nt f or 
a n y i n di vi d ual. T h us, t he mi ni m u m criteria f or re p orti n g a n a d verse e ve nt ( A E) (i.e., i de ntifia ble 
patie nt, i de ntifia ble re p orter, a s us pect pr o d uct, a n d e ve nt) ca n n ot be met.
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 2 7 of 3 3
1 1. P L A N S F O R DI S S E MI N A TI N G A N D C O M M U NI C A TI N G S T U D Y R E S U L T S
I n t he e ve nt of a ny pr o hi biti o n or restricti o n i m p ose d (e. g., cli nical h ol d) b y a n a p plica ble 
c o m pete nt a ut h orit y i n a n y area of t he w orl d, or if t he i n vesti gat or, A nal ys is Gr o u p, is a ware of 
a n y ne w i nf or mati o n w hic h mi g ht i nfl ue nce t he e val uati o n of t he be nefits a n d ris ks of a Pfizer 
pr o d uct, Pfizer s h o ul d be i nf or me d i m me diatel y.
Base d o n t he a nal ys is res ults a n d disc ussi o ns wit h Pfizer, a n a bstract a n d/ or ma n uscri pt ma y be 
pre pa re d. If feasi ble, a n a bstract will be s u b mitte d t o t he S ociet y  f or Mela n o ma Researc h (S M R ) 
2 0 2 3 c o nfere nce. A st u d y  re p ort s u m marizi n g t he bac k gr o u n d, o bjecti ves, met h o ds, res ults, a n d 
c o ncl usi o n of t he st u d y will be pre pare d.
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 2 8 of 3 3
1 2. R E F E R E N C E S
1.
S E E R Ca ncer Stat Facts: Mela n o ma of t he S ki n. . Nati o nal Ca ncer I nstit ute. 
htt ps://seer.ca ncer. g o v/statfacts/ ht ml/ mela n. ht ml
2.
A C S. A meric a n C a ncer S ociety. C a ncer F acts &  Fi g ures 2 0 2 1. 2 0 2 1. 
3.
S ociet y  A C. Ca ncer Facts & Fi g ures 2 0 2 2. A merica n Ca ncer S ociet y. 
4.
Pa uls o n K G, G u pta D, Ki m T S, et al. A ge -S pecific I nci de nce of Mela n o ma i n t he U nite d 
States. J A M A Der m at ol o gy. 2 0 2 0; 1 5 6( 1): 5 7. d oi: 1 0. 1 0 0 1/ja ma der mat ol. 2 0 1 9. 3 3 5 3
5.
H ol derfiel d M, De u ker M M, Mc C or mic k F, Mc Ma h o n M. Tar geti n g R A F ki nases f or
ca ncer t hera p y:  B R A F-m utate d mela n o ma a n d be y o n d. N at ure Revie ws C a ncer . 2 0 1 4; 1 4( 7): 4 5 5-
4 6 7. d oi: 1 0. 1 0 3 8/ nrc 3 7 6 0
6.
N y  L, Her n ber g M, N ya kas M, et al. B R A F m utati o nal stat us as a pr o g n ostic mar ker f or 
s ur vi val i n mali g na nt mela n o ma: a s yste matic re vie w a n d meta-a nal ys is. Act a O nc ol o gic a . 
2 0 2 0; 5 9( 7): 8 3 3 -8 4 4. d oi: 1 0. 1 0 8 0/ 0 2 8 4 1 8 6 x. 2 0 2 0. 1 7 4 7 6 3 6
7.
Va n ne ma n M, Dra n off G. C o m bi ni n g i m m u n ot hera p y  a n d tar gete d t hera pies i n ca ncer 
treat me nt. N at ure revie ws c a ncer . 2 0 1 2; 1 2( 4): 2 3 7-2 5 1. 
8.
B hatia P, Frie dla n der P, Za karia E A, Ka n dil E. I m pact of B R A F m utati o n stat us i n t he 
pr o g n osis of c uta ne o us mela n o ma: a n area of o n g oi n g researc h. A n n als of tr a nsl ati o n al 
me dici ne . 2 0 1 5; 3( 2)
9.
F D A a p pr o ves e nc orafe ni b a n d bi ni meti ni b i n c o m bi nati o n f or u nresecta ble or metastatic 
mela n o ma wit h B R A F m utati o ns. 2 0 1 8. htt ps:// w w w.f da. g o v/ dr u gs/res o urces -i nf or mati o n-
a p pr o ve d -dr u gs/f da -a p pr o ves -e nc orafe ni b-a n d -bi ni meti ni b -c o m bi nati o n -u nresecta ble -or -
metastatic -mela n o ma -braf
1 0.  
D u m mer R, Asciert o P A, G o gas HJ, et al. E nc orafe ni b pl us bi ni meti ni b vers us 
ve m urafe ni b or e nc orafe ni b i n patie nts wit h B R A F -m uta nt mela n o ma ( C O L U M B U S): a 
m ultice ntre, o pe n -la bel, ra n d o mise d p hase 3 trial. T he L a ncet O nc ol o gy . 2 0 1 8; 1 9( 5): 6 0 3-6 1 5. 
1 1. 
P oc o c k SJ. T he c o m bi nati o n of ra n d o mize d a n d hist orical c o ntr ols i n cli nical trials. 
J o ur n al of c hr o nic dise ases . 1 9 7 6; 2 9( 3): 1 7 5-1 8 8. 
1 2.
Si g n or o vitc h J, M os h y k A, Z ha o J, et al. O verall s ur vi val i n t he real -w orl d a n d cli nical 
trials: a case st u dy vali dati n g e xter nal c o ntr ols i n a d va nce d mela n o ma. F ut ure O nc ol . A pr 
2 0 2 2; 1 8( 1 1): 1 3 2 1 -1 3 3 1. d oi: 1 0. 2 2 1 7/f o n -2 0 2 1 -1 0 5 4
1 3.
C urtis M D, Griffit h S D, T uc ker M, et al. De vel o p me nt a n d Vali dati o n of a Hi g h -Q ualit y  
C o m p osite Real -W orl d M ortalit y  E n d p oi nt. He alt h Serv Res . Dec 2 0 1 8; 5 3( 6): 4 4 6 0 -4 4 7 6. 
d oi: 1 0. 1 1 1 1/ 1 4 7 5 -6 7 7 3. 1 2 8 7 2
1 4.
Gra m bsc h P M, T her nea u T M. Pr o p orti o nal hazar ds tests a n d dia g n ostics base d o n 
wei g hte d resi d uals. Bi o metrik a . 1 9 9 4; 8 1( 3): 5 1 5-5 2 6. 
1 5.
W hite I R, R o y st o n P, W o o d A M. M ulti ple i m p utati o n usi n g c hai ne d e q uati o ns: Iss ues 
a n d g ui da nce f or practice. St at Me d . Fe b 2 0 2 0 1 1; 3 0( 4): 3 7 7-9 9. d oi: 1 0. 1 0 0 2/si m. 4 0 6 7
1 6.
R u bi n D B. M ulti ple i m p ut ati o n f or n o nres p o nse i n s urveys . v ol 8 1. J o h n Wile y & S o ns; 
2 0 0 4.
1 7. 
Z ha n g Q, G ossai A, M o nr oe S, N uss ba u m N C, Parri nell o C M . Vali dati o n a nal ysis of a 
c o m p osite real- w orl d m ortalit y  e n d p oi nt f or patie nts wit h ca ncer i n t he U nite d States. He alt h 
Serv Res . Dec 2 0 2 1; 5 6( 6): 1 2 8 1-1 2 8 7. d oi: 1 0. 1 1 1 1/ 1 4 7 5 -6 7 7 3. 1 3 6 6 9
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 2 9 of 3 3
1 8.
Ber ger M L, S o x H, Will ke RJ, et al. G o o d practices f or real ‐ w orl d data st u dies of 
treat me nt a n d/ or c o m parati ve effecti ve ness: rec o m me n dati o ns fr o m t he j oi nt IS P O R ‐IS P E 
S pecial Tas k F orce o n real ‐ w orl d e vi de nce i n healt h care decisi o n ma ki n g. V al ue i n He alt h . 
2 0 1 7; 2 0( 8): 1 0 0 3 -1 0 0 8. 
1 9.
I nter nati o nal S ociety f or P har mac oec o n o mics a n d O utc o mes Researc h I. I S P O R G o o d 
Practices Re p orts. Accesse d 2 8 Marc h 2 0 2 3, htt ps:// w w w.is p or. or g/ he or -res o urces/ g o o d-
practices
2 0.
P u blic P olic y  C o m mittee IS o P. G ui deli nes f or g o o d p har mac oe pi de mi ol o g y practice 
( G P P). P h ar m ac oe pi de mi ol o gy a n d dr u g s afety . 2 0 1 6; 2 5( 1): 2-1 0. 
1 3. LI S T O F T A B L E S 
T a ble
Descri pti o n
T a ble 1. Ke y  e x p os ures, o utc o mes, a n d patie nt 
baseli ne c haracteristics i n t he treat me nt gr o u ps
Ta ble s u m marizi n g e x p os ure, o utc o me, a n d 
patie nt baseli ne c haracteristics t hat will be 
e val uate d wit hi n t he st u d y.
T a ble 2. Ka pla n -Meier a nal y ses c o m pari n g O S 
bet wee n treat me nt gr o u ps
Ta ble s u m marizi n g K M a nal ys es fr o m t he 
E N C O + BI NI , D A B + T R A M a n d V E M + C O BI
treat me nt gr o u ps
T a ble 3. U na dj uste d a n d a dj uste d hazar d rati os 
c o m pari n g O S bet wee n treat me nt gr o u ps
Ta ble s u m marizi n g hazar d rati os c o m pari n g 
E N C O + BI NI t o t he D A B + T R A M a n d 
V E M + C O BI treat me nt gr o u ps
1 4. LI S T O F FI G U R E S
N o ne .
A N N E X 1. LI S T O F S T A N D -A L O N E D O C U M E N T S
N o ne.
A N N E X 2. A D DI TI O N A L I N F O R M A TI O N
N ot a p plica ble.
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 3 0 of 3 3
A P P E N DI X: T A B L E S H E L L S
A p pe n di x T a ble 1: Baseli ne patie nt c haracteristics , b y treat me nt gr o u p
E N C O + BI NI  
V E M + C O BI
D A B + T R A M
N = 
N = 
N =
De m o gr a p hic C h ar acteristics
A ge at baseli ne ( years) 
Mea n ( S D)
Me dia n (I Q R)
Se x, n ( %)
Fe male
Male
Missi n g, n ( %)
Race, n ( %)
W hite/ Ca ucasia n
Blac k/ Africa n A merica n
Asia n
Nati ve A merica n or Pacific Isla n der
Ot her
Missi n g
B MI ( k g/ m 2)
Mea n ( S D)
Me dia n (I Q R)
Missi n g, n ( %)
Year of treat me nt i nitiati o n, n ( %)
2 0 1 4
2 0 1 5
2 0 1 6
2 0 1 7
2 0 1 8
2 0 1 9
2 0 2 0
2 0 2 1
Re gi o n , n ( %)
N ort h A merica
E ur o pe
A ustralia
Ot her
Missi n g
Dise ase -Rel ate d C h ar acteristics
N u m ber of or ga ns i n v ol ve d ( metastatic sites) at baseli ne, n ( %)
1
2
≥3
Missi n g
L u n g metastasis , n ( %)
N o
Yes
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 3 1 of 3 3
Missi n g
Li ver metastasis , n ( %)
N o
Yes
Missi n g
Ot her metastasis , n ( %)
N o
Yes
Missi n g
Ti me fr o m i nitial mela n o ma dia g n osis t o metastatic disease ( mo nt hs)
Mea n ( S D)
Me dia n (I Q R)
Missi n g, n ( %)
Ti me fr o m metastatic mela n o ma dia g n osis t o treat me nt i nitiati o n ( m o nt hs)
Mea n ( S D)
Me dia n (I Q R)
Missi n g, n ( %)
B R A F m utati o n stat us, n ( %)
V 6 0 0 E
V 6 0 0 K
E C O G perf or ma nce stat us, n ( %)
0
1
≥2
Missi n g
AJ C C sta ge at i nitial mela n o ma dia g n osis , n ( %)
0
I
II
III
I V
U n k n o w n
Missi n g
AJ C C sta ge at treat me nt i nitiati o n, n ( %)
Sta ge III C
Sta ge I V
Missi n g
L D H cate g ories, n ( %)
≤ U L N
> U L N
Missi n g
Tre at me nt -Rel ate d C h ar acteristics
Treat me nt e x perie nce i n t he t hera pe utic setti n g , n ( %)
Treat me nt nai ve
Pri or 1 L I O t hera p y
Pri or s yste mic t hera pies i n t he a dj u va nt setti n g, n ( %)
Yes
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 3 2 of 3 3
N o
Pri or I O or c he m ot hera p y i n t he a dj u va nt setti n g, n ( %)
Yes
N o
Pri or s ur ger y i n t he a dj u va nt setti n g, n ( %)
Yes
N o
N u m ber of L O Ts after tar gete d t hera p y , n ( %)
0
1
≥2
Missi n g
A p pe n di x T a ble 2: Ka pla n -Meier a nal ys es c o m pari n g O S bet wee n treat me nt gr o u ps
E N C O + BI NI  
V E M + C O BI
D A B + T R A M
N = 
N = 
N =
S u m m ar y of de at hs, ce ns ori n g 
a n d me di a n s ur vi v al
Deat h, n ( %)
Ce ns ore d, n ( %)
Me dia n f oll o w -u p ( 9 5 % CI)
Me dia n O S ( 9 5 % CI)
K a pl a n - Meier b ase d estim ates of % of p atie nts re m ai ni n g 
ali ve at differe nt ti me p oi nts 
6 M o nt hs
1 2 M o nt hs
1 8 M o nt hs
2 4 M o nt hs
3 0 M o nt hs
3 6 M o nt hs
A p pe n di x T a ble 3: U na dj uste d a n d a dj uste d hazar d rati os c o m pari n g O S bet wee n treat me nt 
gr o u ps
Res ults fr o m a dj uste d m o dels i n A p pe n di x Ta ble 3 will be base d o n m ulti ple i m p utati o n via 
m ulti variate i m p utati o n b y  c hai ne d e q uati o ns. E x pecte d a dj ust me nt fact ors are liste d bel o w; 
s pecific f u ncti o nal f or ms/cate g orizati o n of a dj ust me nt fact ors will be base d o n t he data.
U n a dj uste d m o del
A dj uste d m o del
H R ( 9 5 %  CI)
H R ( 9 5 %  CI)
Tre at me nt gr o u p
D A B + T R A M vs. E N C O + BI NI 
(ref)
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)

Braft o vi T M [E nc orafe ni b] + Me kt o vi ® [ Bi ni meti ni b] 
C 4 2 2 1 0 2 8 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
V 2. 0, 1 9 J ul y 2 0 2 3
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -G L 0 2 -R F 0 7 2. 0 S u m m ary of C h a n ges i n A me n de d N o n -I nterve nti o n al St u dy Pr ot oc ol 0 1 -J u n-2 0 2 2
Pa ge 3 3 of 3 3
V E M + C O BI vs. E N C O + BI NI 
(ref)
A dj ust me nt f act ors
A ge ( years)
Male vs fe male
Asia n race vs. W hite
Ot her race vs. W hite
U n k n o w n race vs. W hite
B MI ( k g/ m 2)
E C O G ( 1 vs. 0)
L D H ( > U L N vs. ≤U L N)
Treat me nt naï ve vs. pri or 1 L 
I O treat me nt
Pri or I O/c he m ot hera p y ( Yes 
vs. N o)
Pri or s ur ger y ( Yes vs. N o)
Ti me fr o m i nitial mela n o ma 
dia g n osis t o metastatic disease
Ti me fr o m metastatic disease 
t o treat me nt i nitiati o n
0 9 0 1 7 7 e 1 9 e d 9 e 6 6 8\ Fi n al\ Fi n al O n: 1 2- O ct- 2 0 2 3 1 7: 0 9 ( G M T)