“Single-agent or combined BRAF
and MEK inhibitors - when & how”
G ra n t M cA rth u r M B B S P h D
P e te r M a cC a llu m C a n ce r C e n tre
M e lb o u rn e , A u stra lia
T h e U n ive rsity o f M e lb o u rn e
P a rkville , A u stra lia
Disclosures
• R esearch S upport – P fizer & C ellgene
• C onsultant – P rovectus
It’s all about
the economy
stupid
Steve Lomas,
Footballer
"Germany are a
very difficult team
to play...they had
11 internationals
out there today."
RAS
Raf V600E
BRAF
ATP
MEK
ATP
ERK
It’s all about
the pathway
stupid!
Melanoma The Cancer Genome Atlas
 Cutaneous melanomas
 Non-glabrous skin
 Mainly regional metastases
NRAS m ut (28% )
BRAF m ut (52% )
NF1 m ut (14% )
MITF am p (4% )
BRAF am p (12% )
MDM2 am p(12 % )
NOTCH2 am p (5% )
KIT am p (3% )
KIT m ut (3% )
PDGFRα a m p (3 % )
PDGFRα m u t (1 0 % )
CCND1 am p (4% )
TERT am p (5% )
PPP6C m ut (7% )
TP53 m ut (7% )
PTEN m ut (8% )
PTEN del (12% )
CDKN2A m ut (13% )
CDKN2A del(4 0% )
MAPK
C e ll C ycle
N R A S G 12/G 13/Q 61
50
Cancer Genome Atlas Research Network,
Ian R. Watson, Lihua Zou, Chang-Jiun Wu, TCGA Workshop, 2012
P resented by: M ichael A . D avies, M D , P hD
B R A F V 600
100
“W ild -Typ e”:
150
215
Mechanisms of Resistance to BRAFinhibitors
ERK
P a th w a y
P I3 K AKT
P a th w a y
Van A llen et al, Cancer Discovery, 2014
Mechanisms of Resistance to BRAFinhibitors
ERK
P a th w a y
ERK
Pathway
P I3 K -A K T
P a th w a y
S hi et al, Cancer Discovery, 2014
Mechanisms of Resistance to BRAF or
Combined BRAF and MEK -inhibition
RAS
N R A S m utation
CRAF BRAF
MEK
ERK
V600E
BRAFin h ib ito r
NF1
N F 1-m utation
B R A F -S plice Variant
CRAF BRAF
CRAF BRAF
CRAF BRAF
CRAF BRAF
CRAF BRAF
CRAF BRAF
B R A F -A m plification
Van A llen et al, Cancer Discovery, 2014; S hi et al, Cancer Discovery, 2014
Emerging Aspects of the
RAS/RAF/MEK/ERK Pathway
RAS
BRAF
V600E
Dabrafenib
Vemurafenib
Encorafenib
MEK
Trametinib
Cobimetinib
Binimetnib
ERK
SCH772984
COMBI-d: Study Design
n=947 screened
•B R A F V 6 0 0 E /K
•U n re se cta b le sta g e
IIIC /IV
•Tre a tm e n t n a ïve
•E C O G P S 0 /1
•N o b ra in m e ts, u n le ss
-Tre a te d
-S ta b le > 1 2 w ks
dabrafenib + placebo
150 m g B ID + placebo once
daily
n=212
n=423
S tra tifica tio n
•B R A F m u t V 6 0 0 E v K
•L D H (> U L N v ≤ U L N )
dabrafenib + tram etinib
150 m g B ID + 2 m g once daily
n=211
Primary Endpoint = Investigator-assessed PFS
Secondary Endpoints = Overall Survival, Overall Response Rate,
Duration of Response, Safety
P resented by: G eorgina V. Long
COMBI-d: Investigator-Assessed PFS
Data cut August 2013*
P ro p o rtion a live a n d p ro g ression-free
1.0
Dabrafenib + Trametinib
M ed. P F S 9.3 m o
6 m onth P F S = 70 %
0.9
0.8
0.7
Dabrafenib
M ed. P F S 8.8 m o
6 m onth P F S = 57%
0.6
0.5
0.4
0.3
0.2
HR 0.75 (95% CI: 0.57, 0.99)
p=0.035
0.1
0.0
0
2
4
6
8
10
12
14
9
10
0
0
Tim e fro m ra n d o m isatio n (m o n th s)
Patients at risk
D abrafenib + tram etinib 211
D abrafenib 212
196
173
164
136
138
107
82
68
33
31
*M e d f/u 9 m o n th s. 4 2 % (d a b ) vs 5 3 % (d a b + tram ) re m a in ed o n stu d y d ru g a t d a ta cu t
P resented by: G eorgina V. Long
COMBI-d: Overall Survival
Data cut August 2013
Dabrafenib + Trametinib
6 m onth O S = 93%
1.0
D ied (events): 40 (19% )
0.9
P ro p o rtion a live
0.8
Dabrafenib
6 m onth O S = 85%
0.7
0.6
D ied (events): 55 (26% )
0.5
0.4
0.3
HR 0.63 (95% CI: 0.42, 0.94)
p=0.023*
0.2
0.1
M e d f/u p 9 m o n th s
0.0
0
Patients at risk
D abrafenib + tram etinib 211
D abrafenib 212
2
4
6
8
10
12
14
16
18
20
2
0
0
0
0
0
Tim e fro m ra n d o m isatio n (m o n th s)
208
205
199
190
185
174
160
142
102
90
44
41
11
11
*d e scrip tive p va lu e ; n o t sta tistica lly sig n ifica n t a n d
d id n o t cro ss sto p p in g b o u n d ary fo r in te rim a n a lysis = tw o -sid e d α < 0 .0 0 0 28
COMBI-d: PFS by Baseline Characteristics*
Number
of patients
Factor
Favours Favours
dabrafenib + trametinib dabrafenib
0.75
All patients
Age:
BRAF mut:
Stage:
LDH :
<65 yrs
≥65 yrs
423
305
118
V600E
V600K
360
62
IIIc/M1a/M1b*
M1c
142
280
Normal*
Elevated
No Disease Sites ≤2*
≥3
0.71
1.09
0.81
0.68
0.90
0.74
0.83
273
148
0.64
1.02
228
193
0.60
0.0
0.5
1.0
1.5
2.0
Hazard ratio and 95% Confidence Interval
*Low n o of events data im m ature
P resented by: G eorgina V. Long
COMBI-d: Adverse Events (≥20%) of Patients
Preferred Term
All Events
Pyrexia
Fatigue
Headache
Nausea
Chills
Arthralgia
Diarrhoea
Rash
Hypertension
Vomiting
Alopecia
Hyperkeratosis
Skin papilloma
Dabrafenib + Placebo
N=211
n (%)
All Grades
Grade 3
Grade 4
203 (96)
72 (34)
7 (3)
59 (28)
4 (2)
0
74 (35)
2 (<1)
0
62 (29)
3 (1)
0
54 (26)
3 (1)
0
33 (16)
0
0
58 (27)
0
0
30 (14)
2 (<1)
0
46 (22)
2 (<1)
0
29 (14)
10 (5)
0
29 (14)
1 (<1)
0
55 (26)
0
0
68 (32)
1 (<1)
0
45 (21)
0
0
Dabrafenib + Trametinib*
N=209
n (%)
All Grades
Grade 3
Grade 4
199 (95)
66 (32)
7 (3)
107 (51)
12 (6)
0
74 (35)
4 (2)
0
63 (30)
1 (<1)
0
63 (30)
0
0
62 (30)
0
0
51 (24)
1 (<1)
0
51 (24)
2 (<1)
0
48 (23)
0
0
46 (22)
8 (4)
0
0
42 (20)
2 (<1)
15 (7)
0
0
7 (3)
0
0
3 (1)
0
0
*4 fatal S A E s, not treatm ent related: 3 intracranial hem orrhage, 1 pneum onia
P resented by: G eorgina V. Long
COMBI-d: BRAF- and MEK-inhibitor Related AEs
BRAF-Inhibitor Related AEs
cuSCC + KA
Hyperkeratosis
Skin papilloma
Hand-Foot Syndrome*
Alopecia
Non-cutaneous Malignancy
New Primary Melanoma
MEK-Inhibitor-Related AEs#
Diarrhoea
Hypertension
Acneiform Rash
Ejection Fraction Decrease
Chorioretinopathy#
Dabrafenib + Placebo
N=211
n (%)
Dabrafenib + Trametinib
N=209
n (%)
20 (9)
68 (32)
45 (21)
58 (27)
55 (26)
3(1)
3(1)
5 (2)
7 (3)
3 (1)
10 (5)
15 (7)
2 (<1)
1 (<1)
30 (14)
29 (14)
7 (3)
5 (2)
1 (<1)
51 (24)
46 (22)
16 (8)
9 (4)
1 (<1)
*H and F oot S yndrom e = palm ar-plantar hyperkeratosis, palm oplantar keratoderm a,palm ar plantar erythrodysesthesia
#T here w ere no cases of retinal vein occlusion
V600E
CRAF
BRAF
BRAF
CRAF
BRAF
BRAFin h ib ito r
MEK
P roliferatio n
S urvival
MEK
MEKin h ib ito r
P roliferatio n
S urvival
V600E
BRAF
BRAFin h ib ito r
MEK
MEK
MEKin h ib ito r
P roliferatio n P roliferatio n
S urvival
S urvival
Headline Results: Combi-V
(July 18 2014)
• Independent data m onitoring com m ittee
recom m end the opportunity be given for
eligible patients in the vem urafenib arm to
crossover to receive the com bination due
to prim ary endpoint of the study (overall
survival) being m et.
Untreated BRAFV600
melanoma
n=500
Stratify:
• Geographic Region:
•Metastatic Classification
R
A
N
D
O
M
I
Z
E
Vemurafenib 960mg BID d1-28
+
Placebo d1-21
1:1
No crossover
Vemurafenib 960mg BID d1-28
+
Cobimetinib 60mg QD d1-21
Secondary Efficacy Objectives
Primary Efficacy Objective
Investigator-assessed Progression- Overall Response Rate
Duration of Response
Free Survival
Overall Survival
PFS by independent review
Headline Results: CoBRIM
(July 13 2014)
• cobim etinib, used in com bination w ith
G enentech's B R A F inhibitor Z elboraf,
helped patients w ith previously untreated
B R A F V 600 m utation-positive advanced
m elanom a live significantly longer w ithout
their disease w orsening (progression-free
survival; P F S ) com pared to Z elboraf
alone.
BRIM7: Best target lesion response & RECIST 1.1 ORR
% Change from Baseline in SLD of Target Lesions
in patients who progressed on prior vemurafenib
100
720mg
7 2 0m gVem
V e m and
+ 6 060mg
m g C oGDC-14/14
b i 2 1 /7 (N = 1(N=4)
9)
720mg
9 6 0m gVem
V e m and
+ 6 060mg
m g C oGDC-21/7
b i 2 1 /7 (N =(N=19)
25)
960mg
7 2 0m gVem
V e m and
+ 6 060mg
m g C oGDC-21/7
b i 2 8 /0 (N =(N=25)
2)
720mg
Vem
and
60mg
GDC-28/0
(N=2)
7 2 0m g V e m + 6 0 m g C o b i 1 4 /1 4 (N = 4 )
720mg
7 2 0m gVem
V e m and
+ 8 080mg
m g C oGDC-14/14
b i 1 4 /1 4 (N =(N=4)
4)
720mg
7 2 0m gVem
V e m and
+ 1 0100mg
0 m g C oGDC-14/14
b i 1 4 /14 (N =(N=2)
2)
9 6 0m gVem
V e m and
+ 6 060mg
m g C oGDC-14/14
b i 1 4 /1 4 (N =(N=3)
3)
960mg
9 6 0m gVem
V e m and
+ 8 080mg
m g C oGDC-14/14
b i 1 4 /1 4 (N =(N=2)
2)
960mg
50
0
-30
-50
RECIST 1.1 Confirmed ORR
-100
(n = 66)
Individual
Patients Treated with Vemurafenib 10
and (15
GDC-0973
Objective
responses
.2% )
C o m p le te R e sp o n se
0
P a rtia l R e sp o n se
10 (15 .2% )
S ta b le d ise a se
28 (42 .4% )
P ro g re ssive d ise a se
24 (36 .4% )
N o t d o n e / a cce ssib le
4 (6 .0% )
S LD , sum of longest diam eters
20
D a ta cu t: O ct 1 , 2 0 1 3
BRIM7: Best target lesion response & RECIST 1.1 ORR in
% Change from Baseline in SLD of Target Lesions
BRAF inhibitor naïve patients
100
7720mg
2 0m g VVem
e m +and
6 0 m60mg
g co bGDC-21/7
i 2 1 /7 (N = 1 (N=14)
4)
9960mg
6 0m g VVem
e m +and
6 0 m60mg
g co bGDC-21/7
i 2 1 /7 (N = 3 (N=39)
9)
7720mg
2 0m g VVem
e m +and
6 0 m60mg
g co bGDC-28/0
i 2 8 /0 (N = 1 (N=1)
)
9960mg
6 0m g VVem
e m +and
6 0 m60mg
g co bGDC-28/0
i 2 8 /0 (N = 4 (N=4)
)
7720mg
2 0m g VVem
e m +and
1 0 0100mg
m g co b GDC-14/14
i1 4/14 (N = 2 ) (N=2)
9960mg
6 0m g VVem
e m +and
8 0 m80mg
g co bGDC-14/14
i 1 4 /14 (N = 3 )(N=3)
50
0
-30
-50
-100
Individual Patients Treated with Vemurafenib and GDC-0973
RECIST 1.1 Confirmed ORR
Objective responses
C o m p le te R e sp o n se
P a rtia l R e sp o n se
(n = 63)
55 (87.3%)
6 (9 .5 % )
4 9 (7 7 .8 % )
S ta b le d ise a se
6 (9 .5 % )
P ro g re ssive d ise a se
2 (3 .2 % )
21
S LD - sum of longest diam eters
D a ta cu t: O ct 1 , 2 0 1 3
BRIM7: Time to first response, progression and death in
patients who progressed on prior vemurafenib
Vem-Progressors
(n = 66)
P atients w ith response
10
Median duration of response (months)
6.7
95% C I for M edian
4.9 − N E
22
BRIM7: Time to first response, progression and death in
BRAF inhibitor naïve patients
BRAFi−naïve
(n = 63)
P atients w ith response
Median duration of response (months)
95% C I for M edian
55
12.5
9.7 − N E
23
BRIM7: Adverse Events Regardless of Attribution in
patients treated with vemurafenib + cobimetinib
Non-acneiform rash *
Diarrhea
Fatigue
Photosensitivity / Sunburn *
Nausea
Liver lab abnormality *
Arthralgia
CPK elevation
Fever
Vomiting
Peripheral Edema
Acneiform rash *
Anemia
Vem progressor
n=66
Grade ≥ 3 All Grades
1 (2% )
22 (33% )
2 (3% )
31 (47% )
1 (2% )
18 (27% )
1 (2% )
10 (15% )
2 (3% )
22 (33% )
4 (6% )
22 (33% )
1 (2% )
8 (12% )
1 (2% )
10 (15% )
1 (2% )
11 (17% )
1 (2% )
13 (20% )
0
11 (17% )
1 (2% )
9 (13.6% )
4 (6% )
10 (15% )
BRAFi naïve
n=63
Grade ≥ 3 All Grades
9 (14% )
55 (87% )
5 (8% )
52 (83% )
6 (10% )
44 (70% )
2 (3% )
42 (67% )
2 (3% )
36 (57% )
12 (19% )
42 (67% )
7 (11% )
30 (48% )
2 (3% )
27 (43% )
1 (2% )
27 (43% )
0
27 (43% )
0
26 (41% )
2 (3% )
23 (37% )
5 (8% )
20 (32% )
Selected Adverse Events
SCC of skin / KA *
Serous retinal detachment *
Cardiomyopathy
5 (8% )
0
0
5 (8% )
2 (3% )^
0
7 (11% )
0
1
* G roup term s ^ includes 1 patient w ith blurred vision w ho had underlying serous retinal detachm ent
7 (11% )
7 (11% )
1 (2% )
D a ta cu t: O ct 1 , 2 0 1 3
24
BRAFi + MEKi Upfront or Following
Progression on Single Agent BRAFi?
Vemurafenib + Cobimetinib
Progressed
on Vem
Upfront
R ibas et al, Lancet O ncology, 2014
BRIM7 FDG-PET: Baseline Disease Burden - OS
B a se lin e m e ta b o lic tu m o r b u rd e n h a ve b e e n sh o w n to b e p ro g n o stic fo r sh o rt- to
in te rm e d ia te -te rm su rviva l o u tco m e s in m u ltip le tu m o r typ e s 1
P re lim in a ry d a ta , w ith o n ly 8 O S e ve n ts o u t o f 4 6 p a tie n ts to d a te , in d ica te th a t lo w e r
b a se lin e d ise a se b u rd e n is a sso cia te d w ith lo n g e r O S in B R A F m u ta te d m e la n o m a
% Injected
Dose
0
200
400
OS, days
600
1.0
0.4
H R = 1.08,
(95% C I: 0.27-4.36)
p= 0.91
0.2
B aseline M T V < M edian
Baseline MTV > Median
B aseline S LD < M edian
Baseline SLD > Median
0.0
F raction survival
0.2
p= 0.03
0.6
0.8
1.0
0.4
H R = 0.14,
(95% C I: 0.02-1.10)
0.0
F raction survival
B aseline % ID < M edian
Baseline %ID> Median
0.6
0.8
1.0
0.8
0.6
0.4
0.2
p= 0.02
0.0
F raction survival
H R = 0.12,
(95% C I: 0.02-1.00)
Sum of longest
diameters of
target lesions
by RECIST1.1
(SLD)
Metabolic
Tumor Volume
0
200
400
600
OS, days
O S = overall survival.
F ull cohort of 46 patients used for O S analysis because all had m easurable baseline tum or burden.
1. R eview ed in V an de W iele C et al. Eur J Nucl Med Mol Imaging. 2013;40(2):290-301.
0
200
400
600
OS, days
26
Parts B and C: Overall Survival by Study Arm
- Dabrafenib 150mg bid + Trametinib 2mg daily
Data as of 15JAN2014
P art C 150/2 (n = 54)
Part C 150/2
P art B 150/2
B BRAF
R A FNaive
i naïve (n= 24)
Part B 150/2
Part B 150/2
BRAF
P art B 150/2
BR
A FFailure
i failure (n = 26)
1.0
|| |
0.8
Proportion Alive
|
|
|
|
|
|
0.6
|
|||| |
|
0.4
0.2
| ||
||||
|
|
|
| |
| | | || | ||
|| |
0.0
0
6
12
18
24
Months from Randomization/First Dose
Jo hnson, D . e t a l JCO 2 0 14
A d apted fro m F la h e rty A S C O 2 0 1 4
30
36
42
Mechanisms of Resistance to
Combined BRAF and MEK inhibition
ERK
P a th w a y
ERK
P a th w a y
W agle et al,
Cancer Discovery, 2014
P I3 K -A K T
P a th w a y
ERK
P a th w a y
RAS
BRAF
Raf V600E
ATP
MEK
ATP
ERK
It’s all about
the pathway
stupid!
So we must find
ways to more
effectively inhibit the
pathway
Acknowledgements
Karen Sheppard
A llen F oo
Laura K irby
R ichard Y oung
K elly W aldeck
S tephen F ox
Antoni Ribas
Nick Choong
R ene G onzalez
A dil D aud
A nna P avlick
O m id H am id
Igor P uzanov
T hom as F. G ajew ski
M ing Y in
Jinay S hah
Study Coordinators
Patients & their
families