10/5/11

1

BRAF/MAPK & BRAF/PI3K combination to abrogate BRAF

inhibitor resistance

Keith T. Flaherty, M.D.

Massachusetts General HospitalCancer Center

Duration of therapy with vemurafenib

Legend

0 2 4 6 8 10 12

LegendM1aM1bM1cThreshold reached for PRPD Patient remaining in study

Months

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2

ERK phosphorylation is restored in some patients at progression

300

pERK1/2 cytoplasmatic H-Score

300

pMEK1/2 cytoplasmatic H-Score

250

200

150

100

50

0

H-S

core

250

200

150

100

50

0

H-S

core

• Recovery of ERK and MEK phosphorylation at disease progression was observed in some but not all patients

0BL Day 15 DP

Time

0BL Day 15 DP

Time

pERK through response & progression

Baseline

Day 15

Disease progression

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3

BRAF NRAS

MAP kinase pathway mechanisms of resistance

BRAF NRASNRAS

CRAF

BRAF

MEK

BRAFi

1. NRAS mutationsCOT

ERK

1. NRAS mutations2. Increase COT expression3. Truncated BRAF

Nazarian et al. Nature 2010Johannesen et al. Nature 2010

Poulikakos et al. AACR 2011

GSK2118436

Infante J et al. ASCO 2011CRAFBRAF

MEK

• squamous cell carcinoma < 1% vs. 7-15%

GSK1120212

ERK

• decreased skin toxicity

# of Pts

CompleteResponse

Partial Response

Stable disease

Disease Control

BRAFi refractory patients

# of Pts

CompleteResponse

Partial Response

Stable disease

Disease Control

58 5 (9%) 30 (52%) 20 (34%) 54 (93%)

BRAFi naïve patients

13 0 2 (15%) 8 (62%) 10 (77%)

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4

AKT activation variable following initiation of treatment

300

250

pAKT cytoplasmatic H-Score

250

200

150

100

50

0

H-S

core

Trend for a decrease from baseline to Day 15 for pAKT

BL Day 15Time

PI3K

1. PDGF receptor β2. IGF receptor

NRAS

AKTP

PTEN3.

mTOR

Nazarian et al. Nature 2010Villanueva et al. Cancer Cell 2010

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Building on BRAF inhibition

PI3K/AktPI3K/Akt

BRAFBRAF/MEK

PTEN loss confers BRAFi & is reversed with

PI3K inhibitor

Paraiso KHT et al. Cancer Res 2011

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6

Lack of apoptosis in PTEN null melanoma, reversed with MEK/PI3K combination

Xing F et al. Oncogene 2011

Building on BRAF inhibition

PI3K/AktVEGF

inhibitionMDM2

MITF/ apoptosis

PI3K/Akt

BRAF

Lineage development CDK4

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7

CDK4 & cyclin D mediate resistance to BRAF inhibitors

control cyclin D1 CDK4 + cyclin D1Smalley KSM et al. MCT 2008

Chemical screen identifies compound that poisons melanocyte lineage

White RM et al. Nature 2011

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BRAF inhibitor based combinations

• Mechanisms of acquired resistance appear to reactivate MAP kinase pathway or maintain PI3K pathway

• De novo resistance relates to concomitant genetic alterations in PTEN & cyclin D/CDK4

• Focus must remain on developing in therapies in molecularly defined subgroups