Overall Survival (OS) in Patients With Metastatic BRAFV600-mutant Melanoma Treated With Encorafenib Plus Binimetinib in the COLUMBUS Trial Versus in Real-world Practice Data
Conditions: Metastatic 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 2
4. 0
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  T E M P L A T E F O R S E C O N D A R Y 
D A T A C O L L E C TI O N S T U D Y 
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 pl ate W O R D 0 1 -N o v -2 0 2 1
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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 verall s ur vi val ( 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 i n t he C O LU M B U S trial 
vers us i n real -w orl d practice data
Pr ot oc ol n u m ber
C 4 2 2 1 0 3 5
Pr ot oc ol versi o n i de ntifier
1 . 0
D ate
2 4 Fe br uar y  2 0 2 3
Acti ve s u bst a nce
E nc orafe ni b pl us B i ni meti ni b
Me dici n al pr o d uct
B rafto 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) i n t he P hase 3 C O L U M B U S cli nical 
trial vers us i n real-w orl d data ( R W D) fr o m Flatir o n 
Healt h. 
T his st u d y  will hel p c o nte xt ualize real-w orl d cli nical 
effecti ve ness of E N C O + BI NI a n d assess t he 
s uita bilit y of p o oli n g cli nical trial a n d R W D o n 
E N C O + BI NI fr o m t hese t w o s o urces f or use i n f ut ure 
real-w orl d st u dies.
A ut h or (s)
, P har m D
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 
discl 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 d 4 1 6 a 8 2\ Fi n al\ Fi n al O n: 0 8- O ct- 2 0 2 4 1 5: 4 5 ( G M T)
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 3 5 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 1. 0 , 0 8 Fe br uar 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 2 4. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -J u n -2 0 2 2   
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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 .......................................................................................................2
2. LI S T O F A B B R E VI A T I O N S................................................................................................4
3. R E S P O N SI B L E P A R TI E S ....................................................................................................6
4. A M E N D M E N T S A N D U P D A T E S .......................................................................................7
5. MI L E S T O N E S .......................................................................................................................8
6. R A TI O N A L E A N D B A C K G R O U N D ..................................................................................9
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 0
8. R E S E A R C H M E T H O D S................................ ....................................................................1 0
8. 1. St u d y  desi g n............................................................................................................1 0
8. 2. Setti n g ......................................................................................................................1 0
8. 2. 1. I ncl usi o n criteria .........................................................................................1 0
8. 2. 2. E xcl usi o n criteria ........................................................................................1 2
8. 2. 3. S u b gr o u p a nal ys es ......................................Err or! B o o k m ar k n ot defi ne d.
8. 3. Varia bles ..................................................................................................................1 2
8. 4. Data s o urces ............................................................................................................1 4
8. 5. St u d y  size ................................................................................................................1 4
8. 6. Data ma na ge me nt................................ ....................................................................1 4
8. 7. Data a nal y sis ...........................................................................................................1 5
8. 7. 1. A nal y sis of baseli ne c haracteristics ............................................................1 5
8. 7. 2. U na dj uste d c o m paris o n of O S bet wee n E N C O + BI NI c o h orts i n C ol u m b us 
trial vers us i n Flatir o n R W D............................................................................1 5
8. 7. 3. I m p utati o n of missi n g data o n baseli ne c haracteristics i n Flatir o n R W D.. 1 6
8. 7. 4. A dj uste d a nal ys is of O S bet wee n E N C O + BI NI c o h orts i n C ol u m b us trial 
vers us i n Flatir o n R W D................................ ...................................................1 6
8. 7. 5. E x pl orat or y  a nalys es of P F S .......................................................................1 7
8. 8. Q ualit y  c o ntr ol.........................................................................................................1 7
8. 9. Stre n gt hs a n d li mitati o ns of t he researc h met h o ds ..................................................1 7
8. 1 0. Ot her as pects .........................................................................................................1 8
9. P R O T E C TI O N O F H U M A N S U BJ E C T S ..........................................................................1 9
9. 1. Patie nt i nf or mati o n................................ ..................................................................1 9
9. 2. Patie nt c o nse nt .........................................................................................................1 9
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) ..................1 9
0 9 0 1 7 7 e 1 9 d 4 1 6 a 8 2\ Fi n al\ Fi n al O n: 0 8- O ct- 2 0 2 4 1 5: 4 5 ( 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 3 5 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 1. 0 , 0 8 Fe br uar 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 2 4. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -J u n -2 0 2 2   
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9. 4. Et hical c o n d uct of t he st u d y ....................................................................................1 9
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 0
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 1
1 2. R E F E R E N C E S ..................................................................................................................2 2
1 3. LI S T O F T A B L E S .............................................................................................................2 3
1 4. LI S T O F FI G U R E S ...........................................................................................................2 3
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 3
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 3
A P P E N DI X: T A B L E S H E L L S ...............................................................................................2 4
0 9 0 1 7 7 e 1 9 d 4 1 6 a 8 2\ Fi n al\ Fi n al O n: 0 8- O ct- 2 0 2 4 1 5: 4 5 ( 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 3 5 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 1. 0 , 0 8 Fe br uar 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 2 4. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -J u n -2 0 2 2   
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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
first-li ne
AJ C C
A merica n J oi nt C o m mittee o n Ca ncer
B MI
b o d y  mass in 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
co nfi de nce inter val 
C T D
cli nical trial d ata
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
electr o nic h ealt h rec or d 
E N C O + BI NI
E nc orafe ni b + B i ni meti ni b
E S M O
E ur o pea n S ociet y of Me dical O nc ol o g y
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
h azar d rati o
I C D- 9-C M
I nter nati o nal Classificati o n of Diseases 9t h Re visi o n 
Cli nical M o dificati o n
I C D- 1 0-C M
I nter nati o nal Classificati o n of Diseases 1 0t h Re visi o n 
Cli nical M o dificati o n
I E C
I n de pe n de nt Et hics C o m mittee 
I O
Im m u n ot hera p y
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 ociet y 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
lactate d e h y d r o ge nase
M A P K
m it o ge n-acti vate d p r otei n k i nase 
0 9 0 1 7 7 e 1 9 d 4 1 6 a 8 2\ Fi n al\ Fi n al O n: 0 8- O ct- 2 0 2 4 1 5: 4 5 ( 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 3 5 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 1. 0 , 0 8 Fe br uar 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 2 4. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -J u n -2 0 2 2   
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MI C E
m ulti variate im p utati o n b y  chai ne d eq 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 sur vi val
P F S
p r o gressi o n free sur vi val
R E CI S T
R es p o nse E val uati o n C riteria i n S oli d T u m o urs
R W D
real- worl d d ata 
S A S
Statistical A nal y sis S oft ware
S S DI
S ocial Sec urit y  Deat h I n de x
T T
tar gete d thera p y
U S
U nite d States 
0 9 0 1 7 7 e 1 9 d 4 1 6 a 8 2\ Fi n al\ Fi n al O n: 0 8- O ct- 2 0 2 4 1 5: 4 5 ( 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 3 5 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 1. 0 , 0 8 Fe br uar 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 2 4. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -J u n -2 0 2 2   
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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
0 9 0 1 7 7 e 1 9 d 4 1 6 a 8 2\ Fi n al\ Fi n al O n: 0 8- O ct- 2 0 2 4 1 5: 4 5 ( 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 3 5 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 1. 0 , 0 8 Fe br uar 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 2 4. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -J u n -2 0 2 2   
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4. A M E N D M E N T S A N D U P D A T E S
N o ne . 
0 9 0 1 7 7 e 1 9 d 4 1 6 a 8 2\ Fi n al\ Fi n al O n: 0 8- O ct- 2 0 2 4 1 5: 4 5 ( 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 3 5 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 1. 0 , 0 8 Fe br uar 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 2 4. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -J u n -2 0 2 2   
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5. MI L E S T O N E S
Milest o ne
Pl a n ne d d ate
C o m pleti o n of feasi bilit y assess me nt
2 3 Ja n uar y 2 0 2 3
De vel o p me nt of st u d y pr ot oc ol/statistical a nal ysis pla n
2 4 Fe br uar y 2 0 2 3
C o m pleti o n of statistical a nal yses
2 1 A pril 2 0 2 3
A bstract s u b missi o n t o E ur o pea n S ociet y of Me dical O nc ol o g y (E S M O ) 2 0 2 3
1 0 Ma y
2 0 2 3
Fi nal st u d y re p ort
0 2 J u ne 2 0 2 3
0 9 0 1 7 7 e 1 9 d 4 1 6 a 8 2\ Fi n al\ Fi n al O n: 0 8- O ct- 2 0 2 4 1 5: 4 5 ( 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 3 5 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 1. 0 , 0 8 Fe br uar 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 2 4. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -J u n -2 0 2 2   
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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 esti mates, 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 u tati 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) 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 py (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 ys t o pre ve nt t u m or gr o wt h a n d mai nte nance .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 b y 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 hese is i ncreasi n g i nterest i n usi n g real -w orl d data ( R W D) t o e val uate effecti ve ness of e nc orafe ni b
pl us bi ni meti ni b ( E N C O + BI NI) . O ne i m p orta nt use of t he e mer gi n g R W D f or E N C O + BI NI is t o 
assess h o w cli nical effecti ve ness i n real-w orl d practice c o m pares t o efficac y o bser ve d i n cli nical 
trials. Cli nical trial data ( C T D) a n d real - w orl d data o n E N C O + BI NI ma y als o be p o ole d t o pr o vi de a 
lar ger sa m ple size f or f ut ure e vi de nce ge nerati o n st u dies, pr o vi de d o utc o mes are s ufficie ntl y 
c o nsiste nt bet wee n C T D a n d R W D setti n gs. 
H o we ver, use of R W D prese nt s i m p orta nt c halle n ges.1 1 I n ge neral, d iffere nces i n baseli ne 
c haracteristics bet wee n patie nts e nr olle d i n cli nical trials a n d patie nts recei vi n g treat me nt i n R W D 
setti n gs ca n res ult i n bias. W hile t his c o ncer n ca n be miti gate d wit h a de q uate statistical a dj ust me nt, 
m issi n g data i n R W D s o urces o n k e y  c o nf o u n ders of o utc o mes m a y  als o h a m per a bilit y t o a dj ust f or 
s uc h baseli ne differe nces. S uita bilit y  of R W D f or s pecific uses t heref ore nee ds t o be assesse d o n a 
case-b y -case basis c o nsi deri n g details of t he R W D data s o urce a n d o utc o mes of i nterest .
I n t his st u dy, we will c o m pare o verall s ur vi val ( O S) bet wee n patie nts recei vi n g E N C O + BI NI i n t he 
P hase 3 C O L U M B U S trial vers us i n the Flatir o n Healt h Electr o nic Healt h Rec or ds ( E H R ) data base .
Baseli ne pr ofiles of patie nts will als o be c o m pare d acr oss t hese setti n gs t o c haracterize differe nces i n 
patie nts recei vi n g E N C O + BI NI a n d a dj ust me nts will be ma de f or differe nces 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 m ulti ple 
i m p utati o n a p pr oac h t hat has bee n vali date d f or Flatir o n Healt h E H R data i n metastatic mela n o ma .1 2
T his st u d y  will hel p c o nte xt ualize real-w orl d cli nical effecti ve ness of E N C O + BI NI, a n d assess t he 
0 9 0 1 7 7 e 1 9 d 4 1 6 a 8 2\ Fi n al\ Fi n al O n: 0 8- O ct- 2 0 2 4 1 5: 4 5 ( 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 3 5 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 1. 0 , 0 8 Fe br uar 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 2 4. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -J u n -2 0 2 2   
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s uita bilit y of p o oli n g C T D a n d R W D o n E N C O + BI NI fr o m t hese 2 s o urces f or use i n f ut ure R W E 
st u dies.
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 N C O + BI NI  i n t he C O L U M B U S P hase 3 trial vers us Flatir o n Healt h real-w orl d practice data .
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 metastatic mela n o ma i nitiati n g 
E N C O + BI NI i n t he C O L U M B U S P hase 3 trial vers us Flatir o n Healt h real-w orl d practice data .
T his o bjecti ve is desi g nate d as e x pl orat or y  i n t his st u d y as, u nli ke f or O S, differe nces i n assess me nt 
of P F S bet wee n trial a n d 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 nal yses of P F S 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 
R W D vs i n C T D, 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. 
8. R E S E A R C H M E T H O D S 
8. 1. St u d y d esi 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 i n t he C O L U M B U S cli nical trial vers us real -
w orl d practice data e x tracte d fr o m t he Flatir o n Healt h E H R data base. C o m paris o ns will be a dj uste d 
f or differe nces i n baseli ne c haracteristics acr oss E N C O + BI NI patie nts i n t hese setti n gs, a n d acc o u nt 
f or missi n g data o n a dj ust me nt fact ors i n t he Flatir o n Healt h E H R data base. 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 bilit y of o utc o me assess me nt bet wee n 
t hese 2 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 will 
be i ncl u de d fr o m t he C O L U M B U S cli nical trial a n d fr o m R W D e xtracte d fr o m t he Flatir o n Healt h 
E H R data base.
8. 2. 1. I ncl usi o n criteri a
I ncl usi o n criteria are pr o vi de d se paratel y f or t he 2 data s o urces bel o w. Ke 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 ocall 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 
0 9 0 1 7 7 e 1 9 d 4 1 6 a 8 2\ Fi n al\ Fi n al O n: 0 8- O ct- 2 0 2 4 1 5: 4 5 ( 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 3 5 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 1. 0 , 0 8 Fe br uar 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 2 4. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -J u n -2 0 2 2   
Pa ge 1 1 of 2 6

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 o f 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
Patie nts fr o m t he C O LU M B U S trial i ncl u de d i n t his a nal ysis 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 ni b c o m bi nati o n t hera p y, a n d

Wit h
a vaila ble data o n m ortalit y
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 . K e y  i ncl usi o n criteria fr o m t he C O L U 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 2 data s o urces.
Eli gi bilit y  criteria a p plie d t o t he Flatir o n c ust o m data e xtracte d recei ve d b y Pfizer i ncl u de d:

Dia g n osis of mela n o ma ( I nter nati o nal Classificati o n of Diseases 9t h or 1 0 t h Re visi o n Cli nical 
M o dificati o n
- I CD- 9- C M: 1 7 2. X; I C D - 1 0-C M: C 4 3. x ) a n d sec o n dar y mali g na nc y or 
metastasis ( I CD- 9- C M: 1 9 6. x, 1 9 7. x, 1 9 8. x; I C D - 1 0-C M: C 7 7. x, C 7 8. x, C 7 9. x ). 

C o nfir me d B R A F V 6 0 0 E/ 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.

At 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 wit hi n t he a vaila ble data c ut peri o d ( 0 1 Ja n uar y  2 0 1 1 t o 0 1 Ja n uar y 2 0 2 2)

Or der or a d mi nistrati o n of E N C O + BI NI t reat me nt at least 3 m o nt hs pri or t o t he data c ut off 
date (e. g., 0 1 Oct o ber 2 0 2 2)
T he sa m ple of patie nts fr o m t he Flatir o n healt 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 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 ); t he date of t he first s uc h or der or a d mi nistrati o n of E N C O + BI NI 
will be ta ke n as t he i n de x d ate.

At least 1 8 y ears of a ge at t he i n de x date

Treat me nt -nai ve or ha d pre vi o us 1 L I O at i n de x date, 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
0 9 0 1 7 7 e 1 9 d 4 1 6 a 8 2\ Fi n al\ Fi n al O n: 0 8- O ct- 2 0 2 4 1 5: 4 5 ( 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 3 5 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 1. 0 , 0 8 Fe br uar 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 2 4. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -J u n -2 0 2 2   
Pa ge 1 2 of 2 6

Wit h a vaila ble data o n m ortalit y  
8. 2. 2. E xcl usi o n criteri a
Patie nts meeti n g a n y of 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 o ut i nf or mati o n o n m ortalit 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, d uri n g t he baseli ne peri o d f or patie nts i n Flatir o n E H R )

Patie nts wit h a hist or y  of or c o nc urre nt u veal or m uc osal mela n o ma, basal cell or s q ua m o us 
cell carci n o ma (as per trial i ncl usi o n criteria ); this e xcl usi o n will als o be a p plie d t o R W D 
patie nts

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 
eval uate d wit hi n t he st u d y .
T a ble 1. K e y e x p os ures, o utc o mes, a n d patie nt baseli ne c haracteristics i n t he C O L U M B U S trial data a n d 
Flatir o n Healt h E H R data
V ari a ble
R ole
D at a s o urce(s)
O per ati o n al defi niti o n
E N C O + BI NI
C o h ort
( C ol u m b us or 
Flatir o n)
E x p os ure
C ol u m b us trial 
data ; Flatir o n 
E H R
B i nar y varia ble i n dicati n g w het her E N C O + BI NI patie nts 
are deri ve d fr o m t he C ol u m b us trial data vs. Flatir o n E H R
p o p ulati o n
O S
Pri mar y O utc o me
C ol u m b us trial 
data , Flatir o n 
E H R
I n C ol u m b us 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 Flatir o n E H R , 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 hic he ver occ urs first
P F S
E x pl orat or y O utc o me
C ol u m b us trial 
data , Flatir o n 
E H R
I n C ol u m b us 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 , 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 
0 9 0 1 7 7 e 1 9 d 4 1 6 a 8 2\ Fi n al\ Fi n al O n: 0 8- O ct- 2 0 2 4 1 5: 4 5 ( 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 3 5 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 1. 0 , 0 8 Fe br uar 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 2 4. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -J u n -2 0 2 2   
Pa ge 1 3 of 2 6
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 e n d of t he st u d y peri o d (e. g., 
0 1 Ja n uar y 2 0 2 2), w hic he ver occ urs first
A ge at i n de x
Baseli ne C haracteristic / 
P ote ntial C o nf o u n der
C ol u m b us 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 ol u m b us trial data a n d treat me nt i nitiati o n 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 ol u m b us trial 
data ; Flatir o n 
E H R
Male, Fe male, I nterse x, a n d U n k n o w n/ Missi n g
Race
Baseli ne C haracteristic / 
P ote ntial C o nf o u n der
C ol u m b us trial 
data ; Flatir o n 
E H R
Asia n, Blac k , W hite, Ot her/ M ultirace, a n d 
U n k n o w n/ Missi n g
Et h nicit y
Baseli ne C haracteristic / 
P ote ntial C o nf o u n der
C ol u m b us trial 
data ; Flatir o n 
E H R
His pa nic/ Lati n o, N o n - His pa nic/ Lati n o, a n d 
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 ol u m b us trial 
data ; Flatir o n 
E H R
D efi 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 ol u m b us 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 C ol u m b us trial data a n d Flatir o n E H R
Disease sta ge at 
dia g n osis
Baseli ne C haracteristic / 
P ote ntial C o nf o u n der
C ol u m b us trial 
data ; Flatir o n 
E H R
III B, III C, I V M 1a, I V M 1 b, or I V M 1c; defi ne d at 
metastatic mela n o ma dia g n osis f or b ot h C ol u m b us trial 
data a n d Flatir o n E H R
L actate 
de h y dr o ge nase 
( LD H ) at i n de x
Baseli ne C haracteristic / 
P ote ntial C o nf o u n der
C ol u m b us trial 
data ; Flatir o n 
E H R
E val uate d i n u nits p er liter ( U/ L) a n d defi ne d at trial 
baseli ne i n C ol u m b us 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 
d ia g n osis t o 
m etastatic 
d isease
Baseli ne C haracteristic / 
P ote ntial C o nf o u n der
C ol u m b us 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 
dia g n osis t o 
treat me nt 
i nitiati o n
Baseli ne C haracteristic / 
P ote ntial C o nf o u n der
C ol u m b us 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 E N C O + BI NI treat me nt
Year of 
E N C O + BI NI 
Treat me nt
Baseli ne C haracteristic
C ol u m b us trial 
data ; Flatir o n 
E H R
Cale n dar year w he n E N C O + BI NI treat me nt was i nitiate d
Pri or S yste mic 
T hera p y
Baseli ne C haracteristic / 
P ote ntial C o nf o u n der
C ol u m b us trial 
data ; Flatir o n 
E H R
Bi nar y varia ble i n dicati n g 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 
E N C O + BI NI
Pri or S ur ger y
Baseli ne C haracteristic / 
P ote ntial C o nf o u n der
C ol u m b us trial 
data ; Flatir o n 
E H R
A bi nar y varia ble i n dicati n g 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
Baseli ne C haracteristic / 
P ote ntial C o nf o u n der
C ol u m b us trial 
data ; Flatir o n 
E H R
A bi nar y varia ble i n dicati n g 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 d 4 1 6 a 8 2\ Fi n al\ Fi n al O n: 0 8- O ct- 2 0 2 4 1 5: 4 5 ( 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 3 5 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 1. 0 , 0 8 Fe br uar 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 2 4. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -J u n -2 0 2 2   
Pa ge 1 4 of 2 6
Pri or 
I m m u n ot hera p y
Baseli ne C haracteristic / 
P ote ntial C o nf o u n der
C ol u m b us trial 
data ; Flatir o n 
E H R
A bi nar y varia ble i n d icati n g w het her patie nts u n der we nt 
i m m u n ot hera p y a mo n g t h ose recei vi n g pri or s yste mic 
t hera p y
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 was 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 m e 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  IO . 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 dail y  e nc orafe ni b a n d 4 5 m g t wice daily bi ni meti ni b 
( n = 1 9 2), 2) 9 6 0 m g t wice dail y ve m urafe ni b ( n = 1 9 1) a n d 3) 3 0 0 m g o nce dail y e nc orafe ni b ( n = 1 9 4). 
Ra n d o mizati o n was stratifie 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 m a 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. Patie nts 
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 trial 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 daily 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 ysicia 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. D ata o n 
deat h is dra w n fr o m str 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 m a w h o recei ve d treat me nt wit h E N C O + BI NI. A c o h ort of E N C O + BI NI 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 
C lea 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 grity;  
0 9 0 1 7 7 e 1 9 d 4 1 6 a 8 2\ Fi n al\ Fi n al O n: 0 8- O ct- 2 0 2 4 1 5: 4 5 ( 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 3 5 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 1. 0 , 0 8 Fe br uar 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 2 4. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -J u n -2 0 2 2   
Pa ge 1 5 of 2 6
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 ble s f or all ke y st u d y meas ures. 
All data will be st ore d a n d mai ntai ne d o n a sec ure e ncr ypte 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 ud 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 y sicia ns. A nal yses 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
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 E N C O + BI NI 
gr o u ps fr o m b ot h data s o urces . 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 haracteristics 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 a t 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. T he b aseli ne peri o d will be defi ne d as a ti me 
wi n d o w ra n gi n g bef ore a n d p ote ntiall y  sh ortl y a fter (e. g., ~ 3 m o nt hs pri or t o ~ 1 m o nt h after) t he i n de x 
d ate. Differe nt d urati o ns of t he ti me wi n d o w will be c o nsi dere d t o ma xi mize data a vaila bilit y on 
baseli ne c haracteristics; s pecific d urati o ns will be selecte d base d o n data a vaila bilit y an d g ui de d b y  
cli nical i n p ut. 
Patie nt baseli ne c haracteristics will be s u m marize d descri pti vely 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. M issi 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 E N C O + BI NI c o h orts i n C ol u m b us tri al vers us i n 
Fl atir o n R W D
O S will be s u m marize d f or E N C O + BI NI c o h orts i n t he C ol u m b us trial a n d Flatir o n R W D . In t he 
C ol u m b us trial , O S will be 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 was 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 w hic he ver occ urs first. In Flatir o n R W D , O S 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 hic he ver 
occ urs first.
A n u na dj uste d c o m paris o n of O S wit h E N C O + BI NI i n t he C ol u m b us trial vers us i n Flatir o n R W D 
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 2 c o h orts 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 sur vi val pr o p orti o ns 
re p orte d at selecte d ti me p oi nts (e. g., 6 m o nt hs, 1 year, 2 years). A hazar d rati o f or O S c o m pari n g 
E N C O + BI NI i n C ol u m b us trial vers us i n Flatir o n R W D will be esti mate d base d o n a u ni varia ble 
0 9 0 1 7 7 e 1 9 d 4 1 6 a 8 2\ Fi n al\ Fi n al O n: 0 8- O ct- 2 0 2 4 1 5: 4 5 ( 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 3 5 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 1. 0 , 0 8 Fe br uar 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 2 4. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -J u n -2 0 2 2   
Pa ge 1 6 of 2 6
C o x pr o p orti o n hazar ds m o del. T he pr o p orti o n al hazar ds ass u m pti o n will be assesse 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 i n Fl atir o n R W D
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 y ses 
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 variate i m p utati o n b y  c hai ne d e q uati o ns ( MI C 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 hara cteristic 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 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 disease 
sta ge. A d diti o nal varia bles will be c o nsi dere d f or i ncl usi o n i n t he MIC 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, whic h will be use d a n d c o m bi ne d i n s u bse q ue nt a nalys es. 1 5
A nal y ses of baseli ne c haracteristics i n R W D descri be d i n S ecti 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 a n al ysis of O S bet wee n E N C O + BI NI c o h orts i n C ol u m b us tri al vers us i n 
Fl atir o n R W D
Fi nall y , a n a dj uste d c o m paris o n of O S bet wee n E N C O + BI NI c o h orts i n t he C ol u m b us trial a n d 
Flatir o n R W D 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 o d y mass i n de x, E C O G perf or ma nce sc ore, 
disease sta ge, L D H, ti me fr o m dia g n osis t o metastatic disease, ti me fr o m metastatic dia g n osis t o 
E N C O + BI NI i nitiati o n a n d use of pri or t hera pies). 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 y ses will be c o n d ucte d usi n g t he C ol u m b us trial dataset a n d eac h of t he R W D 
datasets wit h i m p ute d baseli ne c haracteristic val ues i n t ur n. L o g -hazar d rati os f or t he differe nce i n 
O S wit h E N C O + BI NI bet wee n t he C ol u m b us trial a n d eac h i m p ute d dataset will be o btai ne d, a n d a 
s u m mar y H R 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
0 9 0 1 7 7 e 1 9 d 4 1 6 a 8 2\ Fi n al\ Fi n al O n: 0 8- O ct- 2 0 2 4 1 5: 4 5 ( 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 3 5 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 1. 0 , 0 8 Fe br uar 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 2 4. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -J u n -2 0 2 2   
Pa ge 1 7 of 2 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 s u m marize d f or E N C O + BI NI c o h orts i n 
t he C ol u m b us trial a n d i n Flatir o n R W D. In C T D, P F S will be 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 nted 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 ys is 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 or assess me nt. I n R W D, P F S will be d efi 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 pr o gressi o n (e. g., t he las t cli nical n ote date) or t he e n d of t he f oll o w- u p
peri o d, w hic he ver occ urs first.
S uita bilit y  of c o m parati ve a nalys es of P F S bet wee n E N C O + BI NI c o h orts i n t he C ol u m b us vers us i n 
Flatir o n R W D 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 yses of P F S are dee me d s uita ble base d o n 
t hese e val uati o ns, u na dj uste d a nd 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 S ecti o ns 8. 7. 2 a n d 8. 7. 4 .
8. 8. Q u alit y co 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 dit 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 t he f oll o wi n g:

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 the C O L U 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 E N C O + BI NI patie nts acr oss b ot h setti n gs

A dj ust me nt ca n be ma de f or m ulti ple baseli ne c haracteristics t o miti gate bias d ue t o 
p ote ntial differe nces i n t hese c haracteristics acr oss t he E N C O + BI NI c o h orts i n t he 
C ol u m b us trial vers us t he Flatir o n R W D 

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 gs 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 P V, N P D 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 In 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 h e li mitati o ns of t his st u d y  i ncl u de t he f oll o wi n g:
0 9 0 1 7 7 e 1 9 d 4 1 6 a 8 2\ Fi n al\ Fi n al O n: 0 8- O ct- 2 0 2 4 1 5: 4 5 ( 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 3 5 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 1. 0 , 0 8 Fe br uar 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 2 4. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -J u n -2 0 2 2   
Pa ge 1 8 of 2 6

A p plicati o n of t he C ol u m b us 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 CI S 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 y ste 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 b y R E CI S T .

W hile a dj ust me nt will be ma de f or o bser ve d differe nces i n ke y  baseli ne c haracteristics,
differe nces d ue t o fact ors t hat were n ot meas ure d or n ot a vaila ble i n b ot h C ol u m b us a n d 
Flatir o n R W D (e. g., sites of metastases a n d n u m ber of metastases) ma 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.

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 ol u m b us 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 trial a n d R W D

W hile c o m para bilit y  of O S o utc o mes f or E N C O + BI NI c o h orts i n t he C ol u m b us trial a n d i n 
Flatir o n R W D ma y  be de m o nstrate d here, s uita bilit y of p o oli n g data acr oss ot her s o urces 
a n d f or a nal ys es of ot her o utc o mes will still nee d t o be e val uate d o n a case- b y -case basis
8. 1 0. Ot her as pects
N ot a p plica ble.
0 9 0 1 7 7 e 1 9 d 4 1 6 a 8 2\ Fi n al\ Fi n al O n: 0 8- O ct- 2 0 2 4 1 5: 4 5 ( 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 3 5 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 1. 0 , 0 8 Fe br uar 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 2 4. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -J u n -2 0 2 2   
Pa ge 1 9 of 2 6
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 re q 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 co m mittee (I E C)
T his retr os pecti ve data base a nal ys is does 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 d y 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 RB 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 ntifia ble healt h i nf or mati o n u n der 4 5 C F R 1 6 4. 5 1 4, HI P A A re q uire me nts d o n ot 
a p pl y.
9. 4. Et hic al c o n d uct of t he s t 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 wit h 
scie ntific p ur p ose, val ue a n d ri gor a n d f oll o w ge nerall y 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 Inter nati o nal S ociet y 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 Res earc 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 d 4 1 6 a 8 2\ Fi n al\ Fi n al O n: 0 8- O ct- 2 0 2 4 1 5: 4 5 ( 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 3 5 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 1. 0 , 0 8 Fe br uar 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 2 4. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -J u n -2 0 2 2   
Pa ge 2 0 of 2 6
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 ucture 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  b y 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 
li n 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 d 4 1 6 a 8 2\ Fi n al\ Fi n al O n: 0 8- O ct- 2 0 2 4 1 5: 4 5 ( 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 3 5 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 1. 0 , 0 8 Fe br uar 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 2 4. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -J u n -2 0 2 2   
Pa ge 2 1 of 2 6
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 co m pete nt 
aut h orit y  i n a ny 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 ny 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 diately.
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 pare d. If feasi ble, a n a bstract will be s u b mitte d t o t he E ur o pea n S ociet y of Me dical O nc ol o g y  
( E S M O) 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 d 4 1 6 a 8 2\ Fi n al\ Fi n al O n: 0 8- O ct- 2 0 2 4 1 5: 4 5 ( 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 3 5 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 1. 0 , 0 8 Fe br uar 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 2 4. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -J u n -2 0 2 2   
Pa ge 2 2 of 2 6
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 act s & 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 ociety. 
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. 33 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 py:  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 p r 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 m eti 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 oc 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 d y 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 b sc 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 y sis of a 
c o m p osite real -w orl d m ortalit y  e n d poi 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
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 I S P O R ‐I S 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. 
0 9 0 1 7 7 e 1 9 d 4 1 6 a 8 2\ Fi n al\ Fi n al O n: 0 8- O ct- 2 0 2 4 1 5: 4 5 ( 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 3 5 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 1. 0 , 0 8 Fe br uar 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 2 4. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -J u n -2 0 2 2   
Pa ge 2 3 of 2 6
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 SP 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 C O L U M B U S 
trial data a n d Flatir o n Healt h E H R data
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 E N C O + BI NI c o h orts i n C ol u m b us 
trial a n d Flatir o n R W D
Ta ble s u m marizi n g K M a nal ys es fr o m t he C T D 
a n d R W D E N C O + BI NI c o h orts
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 E N C O + BI NI c o h orts i n 
C ol u m b us trial a n d F latir o n R W D
Ta ble s u m marizi n g hazar d ra ti os c o m pari n g 
C T D a n d R W D E N C O + BI NI c o h orts
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 d 4 1 6 a 8 2\ Fi n al\ Fi n al O n: 0 8- O ct- 2 0 2 4 1 5: 4 5 ( 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 3 5 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 1. 0 , 0 8 Fe br uar 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 2 4. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -J u n -2 0 2 2   
Pa ge 2 4 of 2 6
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 p atie nt characteristics f or E N C O + BI NI c o h orts i n C ol u m b us trial 
vers us i n Flatir o n R W D
A p pe n di x Ta ble 1 as ill ustrate d bel o w will be ge nerate d b ot h bef ore a n d after i m p utati o n of missi n g 
data.
C ol u m b us tri al
Fl atir o n R W D
E N C O + BI NI   
E N C O + BI NI   
N = 
N = 
De m o gr a p hic C h ar acteristics
A ge ( years) 
Mea n ( S D)
X X. X ( X X. X)
X X. X ( X X. X)
Me dia n (I Q R)
X X. X ( X X. X, X X. X)
X X. X ( X X. X, X X. X)
Se x, n ( %)
Fe male
X X ( X X. X)
X X ( X X. X)
Male
X X ( X X. X)
X X ( X X. X)
Missi n g, n ( %)
X X ( X X. X)
X X ( X X. X)
Race, n ( %)
W hite/ Ca ucasia n
X X ( X X. X)
X X ( X X. X)
Blac k/ Africa n A merica n
X X ( X X. X)
X X ( X X. X)
Asia n
X X ( X X. X)
X X ( X X. X)
Nati ve A merica n or Pacific Isla n der
X X ( X X. X)
X X ( X X. X)
Ot her
X X ( X X. X)
X X ( X X. X)
Missi n g
X X ( X X. X)
X X ( X X. X)
Et h nicit y, n ( %)
His pa nic/ Lati n o
X X ( X X. X)
X X ( X X. X)
N ot His pa nic/ Lati n o
X X ( X X. X)
X X ( X X. X)
Missi n g
X X ( X X. X)
X X ( X X. X)
B MI ( k g/ m 2)
Mea n ( S D)
X X. X ( X X. X)
X X. X ( X X. X)
Me dia n (I Q R)
X X. X ( X X. X, X X. X)
X X. X ( X X. X, X X. X)
Missi n g, n ( %)
X X ( X X. X)
X X ( X X. X)
Year of treat me nt i nitiati o n, n ( %)
2 0 1 1
X X ( X X. X)
X X ( X X. X)
2 0 1 2
X X ( X X. X)
X X ( X X. X)
2 0 1 3
X X ( X X. X)
X X ( X X. X)
2 0 1 4
X X ( X X. X)
X X ( X X. X)
2 0 1 5
X X ( X X. X)
X X ( X X. X)
2 0 1 6
X X ( X X. X)
X X ( X X. X)
2 0 1 7
X X ( X X. X)
X X ( X X. X)
2 0 1 8
X X ( X X. X)
X X ( X X. X)
2 0 1 9
X X ( X X. X)
X X ( X X. X)
2 0 2 0
X X ( X X. X)
X X ( X X. X)
2 0 2 1
X X ( X X. X)
X X ( X X. X)
2 0 2 2
X X ( X X. X)
X X ( X X. X)
Ge o gra p hic l ocati o n, n ( %)
N ort h A merica
X X ( X X. X)
X X ( X X. X)
0 9 0 1 7 7 e 1 9 d 4 1 6 a 8 2\ Fi n al\ Fi n al O n: 0 8- O ct- 2 0 2 4 1 5: 4 5 ( 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 3 5 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 1. 0 , 0 8 Fe br uar 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 2 4. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -J u n -2 0 2 2   
Pa ge 2 5 of 2 6
E ur o pe
X X ( X X. X)
X X ( X X. X)
A ustralia
X X ( X X. X)
X X ( X X. X)
Ot her
X X ( X X. X)
X X ( X X. X)
Missi n g
X X ( X X. X)
X X ( X X. X)
Dise ase -Rel ate d C h ar acteristics
Mea n ( S D)
X X. X ( X X. X)
X X. X ( X X. X)
Me dia n (I Q R)
X X. X ( X X. X, X X. X)
X X. X ( X X. X, X X. X)
Missi n g, n ( %)
X X ( X X. X)
X X ( X X. X)
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)
X X. X ( X X. X)
X X. X ( X X. X)
Me dia n (I Q R)
X X. X ( X X. X, X X. X)
X X. X ( X X. X, X X. X)
Missi n g, n ( %)
X X ( X X. X)
X X ( X X. X)
B R A F + m utati o n
V 6 0 0 E
X X ( X X. X)
X X ( X X. X)
V 6 0 0 K
X X ( X X. X)
X X ( X X. X)
E C O G perf or ma nce stat us, n ( %)
0
X X ( X X. X)
X X ( X X. X)
1
X X ( X X. X)
X X ( X X. X)
≥2
X X ( X X. X)
X X ( X X. X)
Missi n g
X X ( X X. X)
X X ( X X. X)
AJ C C sta ge, n ( %)
Sta ge III B
X X ( X X. X)
X X ( X X. X)
Sta ge III C
X X ( X X. X)
X X ( X X. X)
Sta ge I V
X X ( X X. X)
X X ( X X. X)
Missi n g
X X ( X X. X)
X X ( X X. X)
L D H ( U/ L)
Mea n ( S D)
X X. X ( X X. X)
X X. X ( X X. X)
Me dia n (I Q R)
X X. X ( X X. X, X X. X)
X X. X ( X X. X, X X. X)
Missi n g, n ( %)
X X ( X X. X)
X X ( X X. X)
L D H Le vel, n ( %)
L o w
X X ( X X. X)
X X ( X X. X)
N or mal
X X ( X X. X)
X X ( X X. X)
Hi g h
X X ( X X. X)
X X ( X X. X)
Missi n g
X X ( X X. X)
X X ( X X. X)
Tre at me nt -Rel ate d C h ar acteristics
Pri or t hera pies, n ( %)
Treat me nt nai ve
X X ( X X. X)
X X ( X X. X)
Disease pr o gressi o n after 1 L I O
X X ( X X. X)
X X ( X X. X)
Pri or s yste mic t hera pies, n ( %)
A n y t hera p y
X X ( X X. X)
X X ( X X. X)
Me dicati o n
X X ( X X. X)
X X ( X X. X)
S ur ger y
X X ( X X. X)
X X ( X X. X)
Ra di ot hera p y
X X ( X X. X)
X X ( X X. X)
0 9 0 1 7 7 e 1 9 d 4 1 6 a 8 2\ Fi n al\ Fi n al O n: 0 8- O ct- 2 0 2 4 1 5: 4 5 ( 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 3 5 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 1. 0 , 0 8 Fe br uar 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 2 4. 0 N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy 0 1 -J u n -2 0 2 2   
Pa ge 2 6 of 2 6
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 E N C O + BI NI c o h orts i n 
C ol u m b us trial a n d Flatir o n R W D
C ol u m b us Tri al
Fl atir o n R W D
E N C O- BI NI
E N C O- BI NI
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 ( %)
X X ( X X. X)
X X ( X X. X)
Ce ns ore d, n ( %)
X X ( X X. X)
X X ( X X. X)
Me dia n O S ( 9 5 % CI)
X X ( X X, X X)
X X ( X X, X X)
K a pl a n -Meier b ase d esti m at es 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
X X
X X
1 2 M o nt hs
X X
X X
1 8 M o nt hs
X X
X X
2 4 M o nt hs
X X
X X
3 0 M o nt hs
X X
X X
3 6 M o nt hs
X X
X X
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 E N C O + BI NI 
c o h orts i n C ol u m b us trial a n d F latir o n R W D
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)
E x p os ure v ari a ble
E N C O + BI NI i n C ol u m b us trial (ref. 
E N C O + BI NI i n Flatir o n R W D)
X .X X ( X. XX, X . XX)
X. X X ( X. X X, X. X X)
A dj ust me nt f act ors
-
X. X X ( X. X X, X. X X)
A ge
-
X. X X ( X. X X, X. X X)
Male vs fe male
-
X. X X ( X. X X, X. X X)
Race
-
X. X X ( X. X X, X. X X)
B MI
Disease sta ge
-
X. X X ( X. X X, X. X X)
E C O G
-
X. X X ( X. X X, X. X X)
L D H
-
X. X X ( X. X X, X. X X)
Ti me fr o m first dia g n osis t o 
metastatic disease …
X. X X ( X. X X, X. X X)
Ti me fr o m metastatic disease t o 
treat me nt i nitiati o n
Use of pri or t hera pies
X. X X ( X. X X, X. X X)
0 9 0 1 7 7 e 1 9 d 4 1 6 a 8 2\ Fi n al\ Fi n al O n: 0 8- O ct- 2 0 2 4 1 5: 4 5 ( G M T)