Cco melanoma

Targeted Therapy for BRAF V600–
Mutant Melanoma
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Faculty
Keith T. Flaherty, MD
Director of Temeer Center for Targeted Therapy
Massachusetts General Hospital Cancer Center
Boston, Massachusetts
Keith T. Flaherty, MD has disclosed that he has received
consulting fees from GlaxoSmithKline, Novartis, and
Roche/Genentech.

Incidence of Key Driver Oncogenes in
Melanoma
 BRAF ~ 50%
 NRAS ~ 20%
 CKIT ~ 1%
– Primarily mucosal and acral lentiginous
 GNAQ/GNA11 ~ 1%
– Almost exclusively uveal
Nikolaou VA, et al. J Invest Dermatol. 2012;132:854-863.
Smalley KS, et al. Semin Oncol. 2012;39:204-214.

BRAF Mutations: Biology and Practice
BRAF mutations
 Stable across primary to metastatic
melanoma
 Detectable in formalin-fixed,
paraffin-embedded tumor samples
BRAF Mutation, % N = 677
All BRAF mutations 47
V600E 72
V600K 23
V600R/L 4
Non-V600 2
Jakob J, et al. ASCO 2011. Abstract 8500.
NRAS
CRAFBRAF
MEK
ERK

BRAF Mutation Testing
 BRAF mutations are present throughout melanoma
disease progression
– If metastasis biopsy not available, most recent melanoma
surgery sample adequate (eg, lymph node)
 BRAF mutation testing is commercially available
– FDA-approved tests
– Cobas 4800 BRAF V600 Mutation Test (vemurafenib)
– THxID BRAF Kit (dabrafenib with or without trametinib)
NCCN. Clinical practice guidelines in oncology: melanoma. v.1.2014.

BRAF “Inhibitors” Only Inhibit in the
Context of BRAF Mutation
CRAFBRAF
MEK
ERK
P
P
CRAF
MEK
ERK
P
P
CRAF
Heidorn SJ, et al. Cell. 2010;140:209-221. Poulikakos PI, et al. Nature. 2010; 464:427-430.
Hatzivassiliou G, et al. Nature. 2010;464:431-435.
RAS-GTP

BRAF-Mutant Melanoma
Initial Therapy

Key Target Selectivity of Raf Inhibitors
Target Kinase IC50 (nM)
Vemurafenib Dabrafenib
BRAF-V600E 31 0.6
CRAF 48 5
BRAF 100 12
Bollag G, et al. Nature. 2010;467:596-599. Kefford R, et al. ASCO 2010. Abstract 8503.

Sosman J, et al. N Engl J Med. 2012;366:707-714.
Tumor regression: ~ 90% of patients
8 confirmed CRs
BRIM-2 Phase II Study of Vemurafenib in
Metastatic Melanoma: Tumor Regression
60
40
20
0
-20
-40
-60
-80
-100
PercentChangeFromBaselinein
LongestDiameterofTargetLesion
Patients Treated With Vemurafenib
Disease Stage
M1a
M1b
M1c

1. Chapman PB, et al. N Engl J Med. 2011;364:2507-2516. 2. McArthur G, et al. ECCO-ESMO 2011.
Abstract LBA28. 3. Hauschild A, et al. Lancet. 2012;380:358-365. 4. Robert C, et al. ASCO 2012.
Abstract LBA8509. 5. Flaherty KT, et al. N Engl J Med. 2012;367:107-114.
Phase III Trials in BRAF V600E–Mutant
Melanoma
Trial Name NCT Identifier N Treatment Arms
BRIM-3[1,2]
NCT01006980 675 Vemurafenib 960 mg PO BID (n = 337)
Dacarbazine 1000 mg/m2
IV q3w
(n = 338)
BRF113683[3]
NCT01227889 250 Dabrafenib 150 mg PO BID (n = 187)
Dacarbazine 1000 mg/m2
IV q3w (n = 63)
METRIC[4,5]
NCT01245062 322 Trametinib 2 mg PO QD (n = 214)
Dacarbazine1000 mg/m2
IV q3w or
paclitaxel 175 mg/m2
q3w (n = 108)

Chapman PB, et al. N Engl J Med. 2011;364:2507-2516.
250
200
150
100
50
0
-50
-100
%ChangeFromBaselinein
DiametersofTargetLesions
Patients Treated With Vemurafenib
Unresectable
stage IIIc
M1a M1b M1c
Disease Stage 100
80
60
40
20
0
0 2 4 6 8 10 12
Mos
PFS(%)
HR: 0.26 (95% Cl: 0.20-0.33;
P < .001)
Vemurafenib (n = 275)
Dacarbazine (n = 274)
BRIM-3 Phase III Study of Vemurafenib vs
DTIC in Melanoma: Response and PFS

Mos
Vemurafenib (n = 337)
Est 6-mo survival: 83%
Median follow-up: 6.2 mos
Dacarbazine (n = 338)
Est 6-mo survival: 63%
Median follow-up: 4.5 mos
OS(%)
HR: 0.44
(95% CI: 0.33-0.59)
Dacarbazine
median OS:
7.9 mos
McArthur G, et al. ECCO-ESMO 2011. Abstract LBA28.
BRIM-3 Phase III Study of Vemurafenib vs
Dacarbazine in Melanoma: OS
100
90
80
70
60
50
40
30
20
10
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Phase III Study of Dabrafenib vs DTIC in
Melanoma: Response and PFS
Hauschild A, et al. Lancet Oncol. 2012;380:358-365.
Unresectable IIC
M1A
M1B
M1C
100
80
60
40
20
0
-20
-40
-60
-80
-100
ChangeatMaximumReductionFrom
BaselineMeasurement(%)
100
90
80
70
60
50
40
30
20
10
0PFS(%)
0 1 2 3 4 5 6 7 8 9
Dabrafenib
Dacarbazine
Mos

Trametinib (n = 214)
Single-Agent MEKi (Trametinib) in BRAF-
Mutant/BRAFi-Naive Metastatic Melanoma
Robert C, et al. ASCO 2012. Abstract LBA8509.
Disease Stage
39%
M1c
M1b
M1a
IIIC
Unknown
100
80
60
40
20
0
-20
-40
-60
-80
-100

Phase III METRIC: Trametinib (MEKi) vs
Dacarbazine or Paclitaxel
Flaherty KT, et al. N Engl J Med. 2012;367:107-
114.
1.0
0.8
0.6
0.4
0.2
0
0 2 4 6
8
Mos Since Randomization
ProbabilityofPFS
HR: 0.45
(95% Cl: 0.33-0.63;
P < .001)
Trametinib
(n = 214)
Chemotherapy
(n = 108)
ProbabilityofOS
1.0
0.8
0.6
0.4
0.2
0
0 2 4 6 8 10
Trametinib
(n = 214)
Chemotherapy
(n = 108)
HR: 0.54 (95% Cl: 0.32-0.92; P = .01)

Most Common AEs With Approved
Targeted Agents in Advanced Melanoma
AE (≥ Grade 2), % Vemurafenib[1]
Dabrafenib[2]
Trametinib[3]
Arthralgia 21 5 NR
Rash 18 NR 27
Fatigue 13 6 9
Cutaneous SCC/
keratoacanthoma
12/8 6 (combined) NR
Hyperkeratosis 6 13 NR
Pyrexia NR 11 NR
Headache 5 5 NR
Photosensitivity (any grade) 12 3 NR
Hypertension NR NR 12
1. Chapman PB, et al. N Engl J Med. 2011;364:2507-2516. 2. Hauschild A, et al. Lancet. 2012;380:358-
365. 3. Flaherty KT, et al N Engl J Med. 2012;367:107-114.

Vemurafenib + Ipilimumab: Hepatotoxicity
 Phase I study in patients with BRAF V600–mutant
melanoma
– Dose-limiting grade 3 aminotransferase elevation in 4 pts
– Lowering dose of vemurafenib still produced elevated
aminotransferase levels
– Hepatic adverse events asymptomatic and reversible
– Other adverse events of the combination: grade 2 temporal
arteritis, grade 3 rash
– Study has been closed to further accrual
Ribas A, et al. N Engl J Med. 2013;368:1365-1366.

Resistance to BRAF Inhibitors

Sosman J, et al. N Engl J Med. 2012;366:707-714.
BRIM-2 Phase II Study of Vemurafenib in
Metastatic Melanoma: PFSIndividualPatientsTreated
WithVemurafenib
TTP
Time to response
Died
Alive with response
Mos
0 202 4 6 8 10 12 14 16 18

Molecular Characteristics of Disease
Progression
 Variable restoration of signaling through ERK
 No new activating mutations in BRAF
– BRAFV600E persists at progression
300
250
200
150
100
50
0
H-Score
BL Day 15 DP
pERK
Time
N = 23 n = 12

Bypassing BRAF Inhibitor Blockade
Nazarian R, et al. Nature. 2010;468:973-977. Johannessen CM, et al. Nature. 2010;468:968-972. Villanueva J, et al. Cancer
Cell. 2010;18:683-695. Wagle N, et al. J Clin Oncol. 2011;29:3085-3096. Shi H, et al. Nat Commun. 2012;3:724. Poulikakos
PI,
et al. Nature. 2011;480:387-390. Straussman R, et al. Nature. 2012;487:500-504. Whittaker SR, et al. Cancer Discov. 2013;3:
350-362. Maertens O, et al. Cancer Discov. 2013;3:338-349.
CRAFBRAF
MEK
ERK
P
P
BRAF BRAF
BRAF
BRAF
NRAS
COT
MEK
Alternative splicing
Amplification
PI3K
NF1

Single-Agent MEKi (Trametinib) in BRAF-
Mutant/BRAFi-Naive Metastatic Melanoma
Robert C, et al. ASCO 2012. Abstract LBA8509.
Disease Stage
39%
Trametinib (n = 214)
M1c
M1b
M1a
IIIC
Unknown
100
80
60
40
20
0
-20
-40
-60
-80
-100

Single-Agent MEK Inhibitor Has Minimal
Activity in BRAFi-Refractory Patients
Unconfirmed RR: 5% (95% CI: 0.6-16.9)
1 CR, 1 PR, 11 SD
*Discontinued prior BRAFi due to toxicity
K = V600K
M1cM1a M1bM Stage at Screening
K
K
K
K
*
MaximumReductioninTargetLesions
FromBaseline(%)
*
*
Kim KB, et al. J Clin Oncol. 2013;31:482-489.
100
80
60
40
20
0
-20
-40
-60
-80
-100

Tumor Regression With BRAF/MEK
Combination in BRAFi-Refractory Patients
MaximumPercentReduction
FromBaseline
Mos Since
Prior BRAFi
PR
SD
PD
Best Response
on Prior BRAFiRR: 19%
M = Prior MEKi
Flaherty KT, et al. SMR 2011. Abstract LBA1-4.
--80
--60
--40
--20
0
20
40
1.0 0.4 0 0.6 4.2 -- 0.3 2.1 4.3 2.6 7.7 0.5 0.2 1.0 -- 6.2 0.5 1.0 0.2 7.4 9.21.1 1.1
M
M
M M
M

Dabrafenib + Trametinib Combination in
BRAF Inhibitor–Naive Patients
MaximumPercentReductionFromBaselineMeasurement
Best Confirmed Response
CR
PRPD
SD
Dabrafenib 150 mg BID/Trametinib 2 mg QD
Long G et al. ESMO 2012. Abstract LBA27_PR.
100
80
60
40
20
0
-20
-40
-60
-80
-100
100
80
60
40
20
0
-20
-40
-60
-80
-100
Dabrafenib Monotherapy

Delayed Resistance With BRAF/MEK
Combo vs Single-Agent BRAF Inhibition
Flaherty KT, et al. N Engl J Med. 2012;367:1694-1703.
Full-dose BRAF/MEK
Full-dose BRAF/half-dose MEK
Full-dose BRAF
Full-Dose BRAF/MEK Full-Dose BRAF
Median PFS, mos 9.4 5.8
HR 0.39 (P < .001)1.0
0.8
0.6
0.4
0.2
0
0 3 6 9 12 15 18
ProbabilityofPFS

Grade 3†
All Grades Grade 3†
All Grades Grade 3†
All Grades
Cutaneous SCCa‡
9 (17) 10 (19) 1 (2) 1 (2) 3 (5) 4 (7)
Skin papilloma 0 8 (15) 0 4 (7) 0 2 (4)
Hyperkeratosis 0 16 (30) 0 3 (6) 0 5 (9)
Decreased EF 0 0 1 (2) 2 (4) 0 5 (9)
Cardiac failure 0 0 1 (2) 1 (2) 0 0
Hypertension 0 2 (4) 0 2 (4) 1 (2) 5 (9)
Chorioretinopathy 0 0 0 0 1 (2) 1 (2)
BRAF/MEK vs BRAF Inhibition: AEs
Flaherty KT, et al. N Engl J Med. 2012;367:1694-1703.
Adverse Event, n
(%)
Dabrafenib Monotherapy
(n = 53)*
Grade 3/4 All Grades
Combination 150/1
(n = 54)
Combination 150/2
(n = 55)*
Any event 23 (43) 53 (100) 26 (48) 53 (98) 32 (58) 55 (100)
Pyrexia 0 14 (26) 5 (9) 37 (69) 3 (5) 39 (71)
Chills 0 9 (17) 1 (2) 27 (50) 1 (2) 32 (58)
Fatigue 3 (6) 21 (40) 1 (2) 31 (57) 2 (4) 29 (53)
Nausea 0 11 (21) 2 (6) 25 (46) 1 (2) 24 (44)
Vomiting 0 8 (15) 2 (4) 23 (43) 1 (2) 22 (40)
Diarrhea 0 15 (28) 0 14 (26) 1 (2) 20 (36)
*1 patient assigned to monotherapy received combination 150/2 and was included in the combination 150/2 safety analyses.
†
No grade 4 adverse events reported for these categories.
‡
Includes keratoacanthoma .

CRAFBRAF
MEK
ERK
P
P
CRAF
MEK
ERK
P
P
CRAF
RAS-GTP
Heidorn SJ, et al. Cell. 2010;140:209-221. Poulikakos PI, et al. Nature. 2010;464:427-430.

CRAFBRAF
MEK
ERK
P
P
CRAF
MEK
ERK
P
P
CRAF
RAS-GTP
BRAF
inhibitor BRAF
inhibitor
MEK
inhibitor MEK
inhibitor
Heidorn SJ, et al. Cell. 2010;140:209-221. Poulikakos PI, et al. Nature. 2010;464:427-430.

Conclusions
 For 50% of patients with melanoma, BRAF and MEK
inhibition have been validated as new therapies
 Building on BRAF or BRAF/MEK inhibition will proceed in
2 directions:
– Further optimizing MAPK-targeted therapy
– Combination targeted therapy antagonizing pathways
essential for melanomagenesis

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