Post on 01-Apr-2018
Targeted therapy in melanoma: the present and what's to come
Keith T. Flaherty, M.D. Massachusetts General Hospital Cancer Center
Melanomas without activating BRAF or NRAS mutations commonly have NF1 mutations
Cancer Genome Atlas Research Network et al. TCGA symposium 2012
200
Melanoma oncogenes
CRAF BRAF
MEK
ERK
P
P
NRAS alternative splicing
amplification
c-kit
NF1
BRAF
Bollag G. Nat Rev Cancer 2007 Apr;7(4):295
Davies H et al. Nature 2002:
BRAF mutations in: 7% of cancer
60% of melanoma
Age </= 45 69% 46-60 61% 61-70 39% >70 32%
Bauer et al. PCMR 2011
Melanomas with activating BRAF mutations commonly have CDKN2A deletion or mutation
Cancer Genome Atlas Research Network et al. TCGA symposium 2012
AKT3
MDM2
BRAF
MITF
Assay IC50 nM
B-RAF-V600E 31 C-RAF 48 B-RAF 100 SRMS 18 ACK1 19 MAP4K5 (KHS1) 51 FGR 63 LCK 183 BRK 213 NEK11 317 BLK 547 LYNB 599 YES1 604 WNK3 877 MNK2 1717 FRK (PTK5) 1884 CSK 2339 SRC 2389
Selective BRAF inhibitor in the clinic: vemurafenib
Bollag et al. Nature 2010; 467: 596-99
Selective BRAF inhibitor is selective for BRAF mutant melanoma in vitro
Yang H et al. Cancer Res 2010;70:5518-5527
BRAF “inhibitors” only inhibit in the context of BRAF mutation
CRAF BRAF
MEK
ERK
P
P
CRAF
MEK
ERK
P
P
CRAF
Heidorn et al. Cell 2010; Poulikakos et al. Nature 2010; Hatzivassiliou et al. Nature 2010
RAS-GTP
Change in tumor size in 122 V600EBRAF mutant melanoma patients (vemurafenib)
Phase II
RECIST 30% Decrease
Sosman J et al. NEJM 2012
Progression-free survival in vemurafenib phase II trial
Sosman J et al. NEJM 2012
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0 0 1 2 3 4 5 6 7 8 9 10 11 12
Time (months)
Overall survival
13 14
Vemurafenib (N=337)
Est 6 mo survival 83%
Median follow-up 6.2 mo
Dacarbazine* (N=338)
Est 6 mo survival 63%
Median follow-up 4.5 mo
Ove
rall
surv
ival
(%)
Hazard ratio 0.44 (95% CI; 0.33 - 0.59)
McArthur G et al. ESMO 2011
Drug-related adverse events Vemurafenib phase II
All grades n (%)
Grade 3 n (%)
Grade 4 n (%)
Overall 130 (99) 79 (60) 5 (4) Arthralgia 78 (59) 8 (6) – Rash 69 (52) 9 (7) – Photosensitivity reaction 69 (52) 4 (3) – Fatigue 56 (42) 2 (2) – Alopecia 48 (36 ) – –
Pruritus 38 (29) 3 (2) –
Skin papilloma 38 (29) – – cuSCC / KA‡ 34 (26) 34 (26) – Nausea 30 (23) 2 (2) – Elevated liver enzymes 23 (17) 8 (6) 4 (3)
Ribas A et al. ASCO 2011
ERK phosphorylation is restored variably at progression
300
250
200
150
100
50
0
H-S
core
BL Day 15 DP
pERK
Time
H-S
core
N=23 n=12
No new activating mutations in BRAF
BRAFV600E persists at the time of disease progression
Bypassing BRAF inhibitor blockade
CRAF BRAF
MEK
ERK
P
P
Nazarian et al. Nature 2010; Johannesen et al. Nature 2010; Villanueva J et al. Cancer Cell 2010; Wagle N et al JCO 2011; Shi et al. Nature 2012; Poulikakos et al. Nature 2012; Straussman R et al. Nature 2012;
Whittaker S et al. Cancer Discovery 2013; Maertens O et al. Cancer Discovery 2013
BRAF BRAF
BRAF
BRAF
NRAS
COT
MEK
alternative splicing
amplification
PI3K
c-met, PDGFR, IGFR, FGFR3
NF1
Single agent MEK inhibition (trametinib) in BRAF mutant/BRAF inhibitor naive metastatic melanoma
Disease stage
–100
–80
–60
–40
–20
0
Trametinib (n=214) Confirmed RR = 22%; 95% CI (16.6, 28.1)
20
40
60
80
100
M1c
M1b
M1a
IIIC
Unknown
39%
Robert C et al. ASCO 2012
Single-agent MEK inhibitor has minimal activity in BRAFi refractory patients
Unconfirmed Response Rate (RR): 5% (95% CI, 0.6, 16.9) 1 CR, 1 PR, 10 SD
* Discontinued prior BRAFi due to toxicity
K = V600K
M1c M1a M1b M-Stage at screening
K K
K
K
*
Chan
ge a
t max
imum
redu
ctio
n fr
om
base
line
mea
sure
men
t (%
)
*
*
Kim KB et al. SMR 2011
Tumor regression on BRAF/MEK combination in BRAF inhibitor refractory patients
Max
imum
per
cent
redu
ctio
n fro
m b
asel
ine
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 9.2 1.1 1.1 Time since prior BRAFi (months)
M M
M
M
M
Partial response Stable disease Progressive disease
Best response on prior BRAFi
Response Rate = 19%
M = Prior MEKi
Flaherty KT et al. SMR 2011
-100 -80 -60 -40 -20
0 20 40 60 80
100
Dabrafenib/trametinib combination in BRAF inhibitor naïve patients
Max
imum
per
cent
redu
ctio
n fr
om b
asel
ine
mea
sure
men
t
Best confirmed response
Complete response Partial response Progressive disease
Stable disease
-100 -80 -60 -40 -20
0 20 40 60 80
100
Dabrafenib monotherapy
Dabrafenib 150 mg BID/Trametinib 2 mg QD
Long G et al. ESMO 2012
Delayed resistance with BRAF/MEK combination versus single-agent BRAF inhibition
Flaherty KT et al. N Engl J Med. 2012 Nov;367(18):1694-703.
Overall survival: BRAF/MEK vs. BRAF
Flaherty KT et al. NEJM 2012
Historical control: 25% 1-year survival Korn et al. JCO 2009
Adverse events: BRAF/MEK vs BRAF
Flaherty KT et al. N Engl J Med. 2012 Nov;367(18):1694-703.
Bypassing BRAF/MEK combiation blockade
CRAF BRAF
MEK
ERK
alternative splicing
amplification
PI3K
c-met, PDGFR, IGFR
RAS
Melanomas with activating BRAF mutations commonly have CDKN2A deletion or mutation
Cancer Genome Atlas Research Network et al. TCGA symposium 2012
AKT3
MDM2
BRAF
MITF
BRAF RAF RAF
MEK
ERK
PTEN
AKT3
PI3K NRAS
BAD
BCL2
COT
Tumor microenvironment mediated resistance
endothelial cell
pericyte
fibroblast
macrophage
T cell
Fibroblasts conferred resistance to BRAF inhibition 576 cytokines
Ravid Straussman et al. Nature 2012
Immunologic consequences of BRAF inhibition
% o
f new
clo
nes
on B
RA
Fi
0
20
40
60
80
100
% o
f N
ew
Clo
ne
s
p t 10 (S
D -13%
)
p t 16 (S
D -19 .5
%)
p t 9 (P
R -45%
)
p t 19 (P
R -48 .7
%)
p t 24 (P
R -53%
)
p t 14 (P
R -64 .9
%)
p t 11 (P
R -80%
)
p t 7 (C
R -10 0%
)
BLC2A1 PI3K/Akt
BRAF/ MEK
Immune therapy
CDK4
MDM2
HGF
Melanomas without activating BRAF or NRAS mutations commonly have NF1 mutations
Cancer Genome Atlas Research Network et al. TCGA symposium 2012
200
Single-agent MEK inhibitor in NRAS mutant metastatic melanoma patients
N=28 Progressive Disease (PD) Stable Disease (SD) Partial Response (PR) Unconfirmed PR
Ongoing pts
Conclusions • For 50% of melanoma patients, BRAF and
MEK inhibition have been validated as new therapies
• Building on BRAF or BRAF/MEK inhibition
will proceed in two directions: – Combination targeted therapy antagonizing
pathways essential for melanomagenesis – Taking advantage of the downstream
consequences of oncogene targeted therapy
Acknowledgements
Medical oncology:
Don Lawrence
Ryan Sullivan
Krista Rubin
Rizwan Haq
Melanoma surgery:
Jen Wargo
Ken Tanabe
Jim Cusack
Dermatopathology:
Adriano Piris
Lyn Duncan
Fisher lab: David Fisher Rizwan Haq
Adam Friedman Tsao lab: Hensin Tsao Jenny Njauw Zhenyu Ji Wargo lab: Jen Wargo Zach Cooper
Dennie Frederick Haber lab: Daniel Haber Mike Rothenberg
Golub lab: Todd Golub Ravid Straussman
Chin lab: Lynda Chin
Larry Kwong Cichowski lab:
Karen Cichowski Ophélia Maertens
Garraway lab: Levi Garraway Nick Wagle Cory Johannesen