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