IMMUNOTHERAPY OF MELANOMA

Anti PD1 Takes Center Stage

Dr Peter Hersey

Professor of Melanoma Biology

University of Sydney

What we have learnt about immunotherapy over the past 3

years

Inhibition of Physiologic Checkpoints is a more effective form of therapy than stimulation of the immune system

The Ig Super Family of Co-stimulators and Checkpoint inhibitors

Differences between blocking CTLA4/B7 and blocking PD-1/PD-L1

CTLA4 PD-1

Receptor T cell

expression

~48 h after antigen

exposure

Upon chronic antigen

exposure

Ligand

expression

CD80 (B7.1)/CD80

(B7.2) by APCs

PD-L1 (B7-H1) by

tumors and inflamed

tissues

PD-L2 (B7-DC) by

APCs

Knock out mouse

phenotype

Early death from

autoimmunity

Late onset

autoimmunity

Prediction upon

blockade

Less specific for

antitumor T cells

More specific for

antitumor T cells

PRESENTED BY: ANTONI RIBAS, MD

1. Co-stimulation via CD28 ligation transduces T-cell activating signals

MHC

TCR

3. Blocking CTLA-4 ligation enhances T-cell responses

MHC

TCR

T cell

APC

CD28

CTLA-4

T-cell inactivation

B7

2. CTLA-4 ligation on activated T cells down-regulates T-cell responses

MHC

TCR

T cell CTLA-4

APC

B7

T-cell activation

CD28

Ipilimumab

T cell

CTLA-4

APC

T-cell activation

B7

CD28

Ipilimumab (anti–CTLA-4): First in a New Class of Immunopotentiating Agents

Ipilimumab stimulates the immune system to destroy melanoma cells

APC, antigen-presenting cell; CTLA, cytotoxic T-lymphocyte antigen-4; MHC, major histocompatibility complex; TCR, T-cell receptor.

Kaplan-Meier Analysis of Survival Ipi + gp100 (A) Ipi alone (B) gp100 alone (C)

1 2 3 4 Years

Comparison HR p-value Arms A vs. C 0.68 0.0004 Arms B vs. C 0.66 0.0026

Pr

op

or

ti

on

Al

iv

e

0. 0

0. 1

0. 2

0. 3

0. 4

0. 5

0. 6

0. 7

0. 8

0. 9

1. 0

Years

0 1 2 3 4

Ipilimumab Study 024: Overall Survival

Ipilimumab + DTIC versus Placebo + DTIC HR (95% CI) 0.72 (0.59–0.87) Median OS 11.2 vs 9.1 months P value 0.0009

Ipilimumab + DTIC

Placebo + DTIC

8

APC T cell

Activation (cytokines, lysis, prolif., migration)

B7.1 CD28

TCR Signal 1 MHC-Ag

Tumor

Role of PD-1 in Suppressing Antitumor Immunity

Tumor

PD-L1

PD-1

Keir ME et al, Annu Rev Immunol 2008; Pardoll DM, Nat Rev Cancer 2012

(-) (-) (-)

Inhibition (anergy, exhaustion, death)

APC T cell

Activation (cytokines, lysis, prolif., migration)

B7.1 CD28

TCR Signal 1 MHC-Ag

Tumor

Role of PD-1 in Suppressing Antitumor Immunity

Tumor

PD-L1

PD-1

Keir ME et al, Annu Rev Immunol 2008; Pardoll DM, Nat Rev Cancer 2012

(-) (-) (-)

Inhibition (anergy, exhaustion, death)

Anti-PD-1

Clinical Activity of BMS-936558 NIVOLUMAB in Melanoma Patients (ASCO 2012)

• ORR was assessed using modified RECIST v1.0. 3 melanoma patients had a persistent reduction in baseline target lesions in the presence of new

lesions but were not classified as responders for the ORR calculation.

Pop Dose

(mg/kg)

Pts

n

ORR

n (%)

Duration of Response (mo)

SD 24 wk

n (%)

PFSR at

24 wk

(%)

All

MEL 0.1-10 94 26 (28) 1.9+ to 24.9+ 6 (6) 41

MEL

0.1 14 4 (29) 5.6 to 7.5+ 1 (7) 40

0.3 16 3 (19) 1.9+ to 3.8+ 1 (6) 31

1 27 8 (30) 5.3+ to 24.9+ 3 (11) 45

3 17 7 (41) 9.2+ to 22.4+ 1 (6) 55

10 20 4 (20) 17.0 to 24.6+ 0 30

Changes in Target Lesions Over Time in Melanoma Patients

Possible Effect of BMS 936558 Nivolumab on survival

• Phase 1 study only at different doses so effect on survival is a guess only

• 13 of 18 patients (72%) who had a response and were followed for 1 year or more, had ongoing responses at 1 year

• Compares with about 70% 1 year survival of responders to Ipilimumab and 40% 1 year survival of patients responding to DTIC

• ASCO 2013 Sznol. Overall Median 16.8 mths. Responders 24mths 1Year 61%, 2 years 44%

Lambrolizumab (MK3475)

• A new player on the block sponsored by Merck

Phase I Trial Design (NCT01295827)

Presented by: Antoni Ribas

2011 2012

Apr Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec

IPI-N 10Q2W

(n = 41)

IPI-N 10Q3W

(n = 24)

Cohort A:

Dose

Escalation

IPI-N 2Q3W

(n = 22)

IPI-T 10Q2W

(n = 16)

IPI-T 10Q3W

(n = 32)

Cohorts C-F: Additional MEL and NSCLC cohorts IPI-N, ipilimumab-naive; IPI-T, ipilimumab-pretreated;

MEL, melanoma; NSCLC, non-small cell lung cancer.

Cohort B: Metastatic or

locally advanced,

unresectable MEL

Cohort B: Confirmed Objective Response Rate by Dosing Regimen and Prior IPI Treatment

Presented by: Antoni Ribas

Lambrolizumab Dose

Prior IPI Treatment

RECIST 1.1, Independent Central Review

irRC, Investigator Assessment*

N ORR,

% (95% CI) Response Duration

Range, mo N ORR,

% (95% CI)

Total 117 38 (25–44)† 1.9+ – 10.8+ 135 37 (29–45)

10 mg/kg Q2W Naive 39 49 (32–65) 1.9+ – 10.8+ 41 56 (40–72)

Treated 13 62 (32–86) 2.8+ – 8.3+ 16 56 (30–80)

Total 52 52 (38–66) 1.9+ – 10.8+ 57 56 (42–69)

10 mg/kg Q3W Naive 19 26 (9–51) 2.6 – 5.6+ 24 33 (16–55)

Treated 26 27 (12–48) 2.8+ – 8.3+ 32 22 (9–40)

Total 45 27 (15–42) 2.6 – 8.3+ 56 27 (16–40)

2 mg/kg Q3W Naive 20 25 (9–49) 2.1+ – 5.5+ 22 14 (3–35)

“+” indicates censored observation. ORR, objective response rate. *Response rate per irRC (immune-related Response Criteria) was the primary study endpoint. †Including unconfirmed responses, ORR was 44% (95% CI, 35%–54%).

Cohort B: Maximum Change From Baseline in Tumor Size (Independent Central Review)

Presented by: Antoni Ribas

Individual Patients Treated with Lambrolizumab ‒100

‒80

‒60

‒40

‒20

0

20

40

60

80

100

120

140

160

Perc

en

t C

han

ge f

rom

Baseli

ne i

n

Lo

ng

est

Dia

mete

r o

f Targ

et

Lesio

n

IPI-Naive

IPI-Pretreated

Cohort B: Time to Response and Time on Study Treatment by Central Review

Presented by: Antoni Ribas

0 10 20 30 40 50 60 70 Weeks

Ind

ivid

ual

Pati

en

ts T

reate

d

Wit

h L

am

bro

lizu

mab

IPI-Pretreated IPI-Naive Complete Response Partial Response On Study

The median duration of response had not been reached at the time of analysis, with median follow-up time of 11 months.

Clinical Activity, Patient 015-105

Presented by: Antoni Ribas

Baseline: April 13, 2012 July 27, 2012

Images courtesy of A. Ribas, UCLA.

72-year-old male with symptomatic progression after bio-chemotherapy, HD IL-2, and ipilimumab

Baseline

After 3 cycles After 1 cycle

Clinical Activity, Patient 012-305

Images courtesy of W.J. Hwu, MD Anderson Cancer Center. Patient provided written, informed consent to have his images included in congress presentations.

76-year-old male with

desmoplastic melanoma who

progressed after ipilimumab

Clinical Activity, Patient 015-070

Presented by: Antoni Ribas

Images courtesy of A. Ribas and P. Tumeh, UCLA.

Baseline: February 29, 2012 August 20, 2012

CD8+ IHC CD8+ IHC

61-year-old with a previously untreated metastatic melanoma to the lung

Cohort B: Safety Profile by Dose

Presented by: Antoni Ribas

10 mg/kg Q2W n = 57

10 mg/kg Q3W n = 56

2 mg/kg Q3W n = 22

Total N = 135

Any grade treatment-related adverse events, n (%)

52 (91.2)

41 (73.2)

14 (63.6)

107 (79.3)

Grade 3-4 treatment-related adverse events, n (%)

13 (22.8)

2 (3.6)

2 (9.1)

17 (12.6)

Grade 3-4 adverse events of any causality, n (%)

25 (43.9)

17 (30.4)

7 (31.8)

49 (36.3)

Time on therapy, median (range), wk

40.1 (1.0–53.3+)

20.6 (1.0–48.1+)

18.1 (1.0–39.1+)

23.1 (1.0–53.3+)

Number of doses, median (range)

12 (1–26+)

6.5 (1–18+)

7 (1–14+)

8 (1–26+)

Cohort B: Drug-Related Adverse Events Observed in >5% of Patients (N = 135)

Presented by: Antoni Ribas

Adverse Event All Grades, n (%) Grade 3-4, n (%)

Any 107 (79.3) 17 (12.6)

Fatigue 41 (30.4) 2 (1.5)

Rash 28 (20.7) 3 (2.2)

Pruritus 28 (20.7) 1 (0.7)

Diarrhea 27 (20.0) 1 (0.7)

Myalgia 16 (11.9) 0

Headache 14 (10.4) 0

AST increased 13 (9.6) 2 (1.5)

Asthenia 13 (9.6) 0

Nausea 13 (9.6) 0

Vitiligo 12 (8.9) 0

Hypothyroidism 11 (8.1) 1 (0.7)

ALT increased 11 (8.1) 0

Cough 11 (8.1) 0

Pyrexia 10 (7.4) 0

Chills 9 (6.7) 0

Abdominal pain 7 (5.2) 1 (0.7)

Summary of Lambrolizumab Efficacy and Safety in Previously Treated, Advanced Melanoma

• Confirmed response rate per RECIST 1.1 of 38% across all dose levels – Complete response in 5% of patients

– Highest ORR with 10 mg/kg Q2W dosing (52%)

– Most responding patients (80%) were still on study at the time of analysis

• Acceptable, manageable toxicity profile – Highest rate of drug-related AEs observed with 10 mg/kg Q2W dosing

• Efficacy and safety appear similar in ipilimumab-naive and ipilimumab-treated patients

• Findings support on-going clinical development of lambrolizumab in melanoma and other cancers – Currently, studies are ongoing in patients with melanoma, NSCLC,

breast cancer, head and neck cancer, and bladder cancer

Presented by: Antoni Ribas

What Happens When Ipi and Nivolumab are Combined?

Clinical Activity: Concurrent Regimen

Dose (mg/kg)

Response Evaluable Patients

n

CR n

PR n

Objective Response

Rate

% [95% CI]

Aggregate Clinical

Activity Rate

% [95% CI]

≥80% Tumor

Reduction at 12 wk

n (%) Nivolumab Ipilimumab

0.3 3 14 1 2 21 [5-51] 50 [23-77] 4 (29)

1 3 17 3 6 53 [28-77] 65 [38-86] 7 (41)

3 1 15 1 5 40 [16-68] 73 [45-92] 5 (33)

3 3 6 0 3 50 [12-88] 83 [36-100] 0

Concurrent 52 5 16 40 [27-55] 65 [51-78] 16 (31)

Presented by: Jedd D. Wolchok, MD, PhD

• With concurrent treatment of nivolumab + ipilimumab, 40% (range 21-53%) of patients had confirmed objective responses

• About one third of patients (31%) had rapid and deep tumor regressions

Clinical Activity: Concurrent Regimen

Dose (mg/kg)

Response Evaluable Patients

n

CR n

PR n

Objective Response

Rate

% [95% CI]

Aggregate Clinical

Activity Rate

% [95% CI]

≥80% Tumor

Reduction at 12 wk

n (%) Nivolumab Ipilimumab

0.3 3 14 1 2 21 [5-51] 50 [23-77] 4 (29)

1 3 17 3 6 53 [28-77] 65 [38-86] 7 (41)

3 1 15 1 5 40 [16-68] 73 [45-92] 5 (33)

3 3 6 0 3 50 [12-88] 83 [36-100] 0

Concurrent 52 5 16 40 [27-55] 65 [51-78] 16 (31)

Presented by: Jedd D. Wolchok, MD, PhD

• With 1 mg/kg nivolumab + 3 mg/kb ipilimumab, 53% of patients had confirmed objective responses (3 CRs and 6 PRs)

• All 9 of these had ≥80% tumor reduction, 7 at 12 weeks and 2 at their first assessment, which was after week 12

• ≥80% tumor reductions appear infrequently (<10%) in the nivolumab and ipilimumab monotherapy experiences

Best Responses in All Evaluable Patients in Concurrent Cohorts

Presented by: Jedd D. Wolchok, MD, PhD

After ~13 months of follow-up, for all concurrent cohorts, 90% of all responding patients continue to respond as of Feb 2013.

Patients

Ch

ange

in t

arge

t le

sio

ns

fro

m b

asel

ine

(%)

-80

Rapid and Durable Changes in Target Lesions

Presented by: Jedd D. Wolchok, MD, PhD

1 mg/kg nivolumab + 3 mg/kg ipilimumab

First occurrence of new lesion

• A 52-year-old patient presented with extensive nodal

and visceral disease

• Baseline LDH was elevated (2.3 x ULN); symptoms

included nausea and vomiting

• Within 4 wk, LDH normalized and symptoms resolved

• At 12 wk, there was marked reduction in all areas of

disease as shown Weeks since treatment initiation

Ch

ange

in t

arge

t le

sio

ns

fro

m b

asel

ine

(%) Pre-

treatment

12 weeks

Patients at Risk

1 mg + 3 mg

All concurrent

17

53

16

47

16

36

14

29

10

19

5

10

3

7

2

4

2

4

1

3

0

1

0

1

0

0

n=17

n=53

Preliminary Survival of Patients Treated with the Concurrent Regimen

Presented by: Jedd D. Wolchok, MD, PhD

Months

9 / 53 Censored

All concurrent regimen

1 mg/kg nivolumab + 3 mg/kg ipilimumab

Died/Treated

2 / 17

1-year Survival 82%

95%CI (69.0%;94.4%)

Treatment-Related Select Adverse Events Occurring in ≥1 Patient

Select Adverse Event Number of Patients (%)

Concurrent Regimen All Cohorts (n=53)

Sequenced Regimen All Cohorts (n=33)

All Gr Gr 3-4 All Gr Gr 3-4

Pulmonary 3 (6) 1 (2) 1 (3 ) 0

Renal 3 (6) 3 (6) 0 0

Endocrinopathies 7 (13) 1 (2) 3 (9) 2 (6)

Uveitis 3 (6) 2 (4) 0 0

Skin 37 (70) 2 (4) 8 (24) 0

Gastrointestinal 20 (38) 5 (9) 3 (9) 0

Hepatic 12 (23) 8 (15) 1 (3) 0

Infusion reaction 1 (2) 0 0 0

Lipase 10 (19) 7 (13) 4 (12) 2 (6)

Amylase 8 (15) 3 (6) 1 (3) 1 (3)

Presented by: Jedd D. Wolchok, MD, PhD

Demographics

Variable Concurrent Regimen (n=53))) Sequenced Regimen (n=33)

Median age, yr (range) 58 (22-79) 64 (23-89)

Male, no. (%) 32 (60) 18 (55)

ECOG performance status, no. (%)

0 44 (83) 22 (67)

1 8 (15) 11 (33)

Unknown 1 (2) 0

M-stage at study entry, no. (%)

M1a 8 (15) 5 (15)

M1b 11 (21) 5 (15)

M1c 30 (57) 18 (55)

Unknown 4 (8) 5 (15)

Lactate dehydrogenase level, no. (%)

≤Upper limit of the normal range 33 (62) 21 (64)

>Upper limit of the normal range 20 (38) 12 (36)

Systemic cancer therapy, no. (%) 20 (38) 33 (100)

Immunotherapy 9 (17) 33 (100)

Prior ipilimumab therapy 0 33 (100)

B-RAF inhibitor 3 (6) 2 (6)

Number of prior systemic cancer therapies, no. (%)

0 33 (62) 0

1 14 (26) 18 (55)

≥2 6 (11) 15 (45)

Presented by: Jedd D. Wolchok, MD, PhD

Conclusions

• The concurrent combination of nivolumab and ipilimumab induced objective response rates appearing higher than published monotherapy values

• The nature of the responses appeared to be distinctly different from those of the nivolumab and ipilimumab monotherapies

– Responses were rapid and deep

– At the combined doses chosen for phase 3 study, all responding patients achieved deep or complete responses

• Treatment-related adverse events managed using standard protocols

– No treatment-related deaths

• Clinical activity in patients who previously progressed on ipilimumab and then received nivolumab

• Based on these results, a phase 3 trial is open to investigate the efficacy of the concurrent nivolumab/ipilimumab combination vs. nivolumab vs. ipilimumab in patients with advanced melanoma (NCT01844505)

– This combination is also being investigated in non-small-cell lung cancer and renal cell carcinoma

Presented by: Jedd D.

Wolchok, MD, PhD

THE NEW TREATMENT ALGORITHMS

• BMS 3 arm study. Ipi v Nivo v Ipi plus Nivo

• Merck 3 arm study Lambrolizumab 2mg v 10mg v Ipi

• NRAS failures

Novartis MEK 162 Nemo study

• BRAFV600 melanoma

Roche GO28141 Combi study-20% accrued .

Novartis LGX818 +-MEK162

WHAT ABOUT SELECTIVE BRAF INHIBITORS?

• BRAF mutation rates

• Side effects including new malignancies

• Resistance to BRAFi and BRAF plus MEK combinations

• LGX 818

NRAS

BRAF

ERK

MITF

MEK

BRAF mutations

• ̴ 50% cutaneous

melanomas

•20% continuous sun-

exposure

•50-80% intermittent

sun-exposure

• >80% mutations = V600E

Curtin, JA et al J Clin Oncol 24,4340 2006

Platz A et al Mol Oncol 1,395 2008

Long GV et al J Clin Oncol 29, 1239 2011

BRAF Mutation Rate by Decade

Menzies AM et al, ASCO 2011, Melanoma Oral Session, Abs# 8507 Jakob JA et al J Clin Oncol 29:526s, 2011 (suppl 15s; abstr 8500) Cheng S et al J Clin Oncol 29:549s, 2011 (suppl 15s; abstr 8597) Rubinstein JC et al J Transl Med 8:67, 2010

>25% V600K/D/R >90% V600E

Slide courtesy Alex Menzies

NRAS

BRAF

ERK

MITF

MEK

Potent BRAF inhibitors

vemurafenib (PLX4032)

dabrafenib (GSK2118436)

LGX818

Image courtesy of Grant McArthur, Peter MacCallum Cancer

Institute, Melbourne

Day 1 Day 15

FDG-PET response to vemurafenib (PLX4032) V600E+ melanoma

Flaherty KT, et al N Engl J Med 363:809, 2010

Confirmed objective response rates across

vem/dab clinical trial programmes

V600E

Phase I Phase 2 Phase 3

Vemurafenib 56.0% 53.0% 48.4%

Dabrafenib 50.0% 59%

53.0%

V600K: Dabrafenib ORR 25% (BREAK 2) Vemurafenib ORR 45% (BRIM 3) (McArthur G SMR Nov 2012 ).

What have we learnt?

AROUND 50% OF BRAFi-TREATED

V600 MUT MELANOMA PATIENTS

PROGRESS AT ABOUT 6 MTHS

OS 1.5X DTIC; 1/3rd alive > 2yrs

V600E SIMILAR TO V600K

Toxicity of BRAFi Vemurafenib

• SKIN – PHOTOSENSITIVITY – KERATOPATHY – SCC (19%) – New primary melanoma 2%

• CONSTITUTIONAL – FEVER RARE – ARTHRALGIA – FATIGUE

• LIVER – ↑↑LFTs COMMON 26%

10% G3

Dabrafenib

• SKIN – NO PHOTOSENSITIVITY

– KERATOPATHY

– SCC (5%)

– New primary melanoma 2%

• CONSTITUTIONAL – FEVER COMMON 30%

– ARTHRALGIA

– FATIGUE

• LIVER – ↑↑LFTs RARE

Photosensitivity - Off target effect of Vemurafenib

Keratotic Lesions

Dabrafenib Wks 5-7, 100mg BID Kefford R ASCO 2012

Falchook/Long Lancet 379 1893 2012

Squamous Cell Carcinoma (Skin)

Thigh: Week 6

Low-grade squamous

cell carcinoma

Paradoxical oncogenesis

via MAPK

stimulation1,2,3

1, Heidom SJ, Marais R, et al, Cell, 2010: 140, 209.

2. Poulikakos PI, Rosen R, et al, Nature, 2010, e 23 Feb.

3. Hatzivassiliou G, et al Nature, 2010, e 3 Feb. Kefford R ASCO 2012 Falchook/Long Lancet 379 1893 2012

Callahan M et al NEJM Nov 12 2012

NRAS-mutant Chronic Myelo-monocytic Leukemia exacerbated by vemurafenib

PI3K/AKT/mTOR pathway

RT

Ks

SOS

Grb2 SHC

P P P P

Proliferation, Survival

MEK

p90RSK MSK1

P P

B-RAF C-RAF

B-RAF V600

ERK1/2

NRAS NRAS

RT

Ks

PDGFR, IGF1R

COT

Targeting BRAFi Refractory and Resistant Tumours

MEKi :

selumetinib

trametinib

pimasertib

MEK162

GDC0973

© R Kefford 2012 not to be reproduced without written permission of the author

MEKi: What have we learnt?

MEKi: - SINGLE AGENT ACTIVITY AGAINST

MUT BRAF MELANOMA

PFS 4.8 mths

OS superior to chemo

WON’T SALVAGE BRAFi RESISTANCE

NRAS

BRAF

ERK

MITF

MEK

Combined MAPK inhibition

Dabrafenib

Trametinib

LGX818

MEK162

Vemurafenib

GDC0973

• Synergy in V600 BRAF xenografts • Abrogation of keratopathy

*1 patient in 150/1 group was not evaluable

Best Confirmed Response Rate

Dab (N=54)

Dab + Tra 150/1 (N=54)*

Dab + Tra 150/2 (N=54)

CR 2 (4) 3 (6) 5 (9)

PR 27 (50) 24 (44) 36 (67)

SD 22 (41) 24 (44) 13 (24)

PD 3 (6) 2 (4) 0

Response Rate P-value

29 (54%)

27 (50%) 0.77

41 (76%) 0.026

Duration of Response Months (95% CI)

5.6 (4.5, 7.4)

9.5 (7.4, NA)

10.5 (7.4, 14.9)

Long G et al ESMO Sept 2012 Flaherty K et al NEJM 29Sept 2012

Es

tim

ate

d s

urv

iva

l fu

nc

tio

n

Patients at risk Time since randomization (months)

1.0

0.8

0.6

0.4

0.2

0.0

0 3 6 9 12 15 18

54 46 25 13 2 0

54 47 33 26 11 1

54 52 36 29 15 1

Adapted from: Long G et al ESMO Sept 2012 Flaherty K et al NEJM 29Sept 2012

Dabrafenib N=54

Dabrafenib + trametinib (full dose) N=54

Combined dabrafenib + trametinib Randomized Phase II

9.4 m 5.8 m

RR 54%

RR 76%

What have we learnt? BRAFi + MEKi DELAYS RESISTANCE

– Med PFS 9.4 months vs 5.8 months; HR 0.39; p<0.0001

– 12-months PFS 41% vs 9%

– ORR 76% vs 54%; p=0.026

– Duration of response 10.5 vs 5.6 months

SALVAGES SOME BRAFi-RESISTANT

PATIENTS

REDUCTION IN SKIN ONCOGENICITY

PROBLEM OF FEVER

Can We Combine Immunotherapy plus BRAFi?

PRESENTED BY: Michael B. Atkins

E1612: Ipi to Vem vs Vem to Ipi

ECOG PS

1. 0

2. 1

Stage

1. St IIIc or

M1a/b

2. M1c

Prior therapy

1. No prior Rx

2. Prior Rx

R

A

N

D

O

M

I

Z

E

Arm 1:

Ipi 3 mg/kg

q3 wks x 4

Arm 2:

Vemurafenib

960mg BID

ECOG and SWOG protocol – Atkins, Chmielowski

Tumor measurements q12 wks

Ipi 3 mg/kg

q3 wks x 4

Vemurafenib

960mg BID

PD

PD

CONCLUSIONS-MUCH TO BE EXCITED ABOUT

• Emphasis in treatment now on immunotherapy

• Need to understand why patients fail anti PD1

• What combinations should be investigated

• How do we select patients?

*Skin toxicities include multiple terms No cases of RVO

MEKi and BRAFi Associated Adverse Events

Dab (n=53)

Dab + Tra 150/1 (n=54)

Dab + Tra 150/2 (n=55)

Rash/Skin toxicities* 36 (68) 31 (57) 36 (65)

Acneiform rash 2 (4) 6 (11) 9 (16)

Skin papilloma 8 (15) 4 (7) 2 (4)

Actinic keratosis 5 (9) 4 (7) 8 (15)

Hyperkeratosis 16 (30) 3 (6) 5 (9)

Squamous cell carcinoma/ keratoacanthoma P-value

10 (19)

1 (2) 0.004

4 (7) 0.09

Ejection Fraction 0 2 (4) 5 (9)

Chorioretinopathy 0 0 1 (2)

Part 2 – Partial Response in Brain

61 yo V600E Multiple Metastases

Baseline Week 4 Week 10

Long GV et al ESMO, Milan 2010

Max

imu

m p

erce

nt

chan

ge f

rom

b

ase

line

intr

acra

nia

l mea

sure

men

t

100

80

60

40

20

0

-20

-40

-60

-80

-100

BREAK-MB Trial Brain Metastases BRAFV600E melanoma

No prior brain treatment

OIRR: 39% ORR: 38% Intracranial disease control rate: 81% Overall disease control rate: 80%

Kirkwood ASCO 2012 Long, G et al Lancet Oncology Oct 2012

Combined dabrafenib + trametinib Randomized Phase II Study Design

Combination (d-t) – 150/2 N= 54

Combination (d-t) - 150/1 N= 54

RANDOMI Z E

•BRAF V600E/K metastatic melanoma •No prior BRAFi or MEKi •Up to 1 prior treatment •Stable and treated brain mets N=162

*cross over to Dab + Tra 150/2 after progression allowed

Objectives

• PFS, ORR, duration of response and incidence rate of cuSCC

• OS and safety

Monotherapy*(d) -150mg BID

N= 54

Long G et al ESMO Sept 2012 Flaherty K et al NEJM 29Sept 2012

Baseline Week 6

Kefford et al ASCO Chicago 2010; Melanoma2010 Sydney 2010 Falchook G,/Long G. et al Lancet May 2012

M82 V600K Metastatic melanoma dabrafenib 150 mg bid