Please note, these are the - PowerPoint Presentation

Slide1

Please note, these are the

actual

video-recorded proceedings from the

live

CME event and may include the use of trade names and other raw, unedited content.

Slide2

Moderator

Neil Love, MD

Faculty

Breakfast with the InvestigatorsSystemic Management of MelanomaSunday, June 5, 20166:45 AM – 7:45 AMChicago, Illinois

Keith T Flaherty, MD

Jeffrey Weber, MD, PhD

Slide3

Disclosures for Moderator Neil Love, MD

Dr

Love is president and CEO of Research To Practice, which receives funds in the form of educational grants to develop CME activities from the following commercial interests: AbbVie

Inc, Acerta Pharma, Agendia Inc, Amgen Inc, Array BioPharma Inc,

Astellas

Pharma

Global Development

Inc

, AstraZeneca Pharmaceuticals LP,

Baxalta

Inc

, Bayer HealthCare Pharmaceuticals,

Biodesix

Inc

,

bioTheranostics

Inc

,

Boehringer

Ingelheim

Pharmaceuticals

Inc

, Boston Biomedical

Pharma

Inc

, Bristol-Myers Squibb Company,

Celgene

Corporation, Clovis Oncology, CTI

BioPharma

Corp, Daiichi Sankyo

Inc

,

Dendreon

Pharmaceuticals

Inc

, Eisai

Inc

,

Exelixis

Inc

, Foundation Medicine, Genentech

BioOncology

, Genomic Health

Inc

, Gilead Sciences

Inc

,

ImmunoGen

Inc

,

Incyte

Corporation, Janssen Biotech

Inc

, Jazz Pharmaceuticals

Inc

, Lilly,

Medivation

Inc

, Merck, Merrimack Pharmaceuticals

Inc

, Myriad Genetic Laboratories

Inc

,

NanoString

Technologies,

Natera

Inc

, Novartis Pharmaceuticals Corporation,

Novocure

, Onyx Pharmaceuticals, an Amgen subsidiary,

Pharmacyclics

LLC, an

AbbVie

Company, Prometheus Laboratories

Inc

,

Regeneron

Pharmaceuticals,

Sanofi

, Seattle Genetics, Sigma-Tau Pharmaceuticals

Inc

,

Sirtex

Medical Ltd, Spectrum Pharmaceuticals

Inc

,

Taiho

Oncology

Inc

, Takeda Oncology,

Teva

Oncology, Tokai Pharmaceuticals

Inc

and

VisionGate

Inc.

Slide4

Courtesy of Christiana Care Health System

Slide5

Agenda

Module 1 –

Management of BRAF-Mutant DiseaseModule 2 – Targeted Therapy for BRAF Wild-Type Melanoma

Module 3 – Checkpoint Inhibitors in Melanoma

Slide6

Module

1:

Management of BRAF-Mutant Disease

Slide7

First-Line Therapy in Metastatic Melanoma with V600E/K Mutations: BRAF/MEK Inhibitors or Checkpoint Inhibitors? Phase III EA6134 Study

Stage

III/IV metastatic or unresectableBRAF V600E/KNo prior BRAFi, MEKi, PD-1 or CTLA4 inhibitorsPS 0-1

Estimated N = 300Nivolumab + Ipilimumab Days 1, 22 q6wk 2 cyclesTrametinib q1d + Dabrafenib BIDDays 1-42; q6wkPrimary Endpoint

OS rate

Nivolumab

days 1, 15, 29

q6wk x 12 cycles

Crossover at disease progression

www.clinicaltrials.gov

, May 2016

NCT02224781

R

Slide8

Case 1 (

Dr Weber)A 62-year-old woman with BRAF V600E-mutant melanoma metastatic to the lungs and porta

hepatis nodes Vemurafenib/cobimetinib with response

Develops transaminitis Treatment discontinuation and corticosteroids

Slide9

Case 2 (

Dr Weber)A 59-year-old woman with BRAF V600E-mutant melanoma metastatic to the bone and lungs

Dabrafenib/trametinib Near complete clinical response

(nCR)Recurrent febrile episodes requiring corticosteroidsAfter 4 years, while still in nCR, she develops congestive heart failure (ejection fraction: 23%) Therapy discontinued After 6 months her cardiovascular status stabilizes (EF 48%) Pembrolizumab initiated

Slide10

BRAF Pathway

Receptor tyrosine kinases

Ras

BRAF

MEK1/2

ERK1/2

Dabrafenib

Vemurafenib

Ras

BRAF

V600

MEK1/2

ERK1/2

Cell Proliferation

Trametinib

Ras

BRAF

V600

MEK1/2

ERK1/2

Cobimetinib

Adapted

from

Johnson

GL

et al.

Clin Cancer

Res

2014;20(10):2516-22.

Slide11

COMBI-d

1,2

Key Inclusion

Criteria

≥ 18

years

Stage IIIC/IV melanoma

BRAF

V600E/K positive

ECOG PS

0

or 1

No prior systemic therapy

No prior treatment with a BRAF inhibitor or MEK inhibitor

Treated/stable brain

metastases

BRAF

V600E/K

Dabrafenib +

trametinib

150 mg BID +

2 mg QD

(

n = 211)

Dabrafenib + placebo

150

mg BID +

placebo QD

(n = 212)

Final analysis (PFS)

Follow-up a

nalysis (OS)

S

C

R

E

ENING

RANDOMISATION

Phase 3 Studies with Dabrafenib + TrametinibCOMBI-v1,3

Key Inclusion Criteria≥ 18 years

Stage IIIC/IV melanomaBRAF V600E/K positiveECOG PS 0 or 1No prior systemic therapyNo prior treatment with a BRAF inhibitor or MEK inhibitorTreated/stable brain metastases

BRAF V600E/KDabrafenib + trametinib150 mg BID +

2 mg QD(n = 352)Vemurafenib960 mg BID(n = 352)

Interim OS analysisFinal OS analysisSCREENIN

GRANDOMISATION

1. Long GV et al. SMR 2015. 2. Long GV et al.

N Engl J Med 2014;371:1877-88; 3. Robert C et al. N Engl J Med 2015;372:30-9.

Slide12

Vemurafenib

960

mg BID

x 1

yr

Placebo

R

Eligibility (N = 475)

Surgically resected cutaneous melanoma

BRAF mutant

High-risk disease

BRIM8

Phase III Adjuvant Study

Primary Endpoint: Disease-free survival

www.clinicaltrials.gov

, May 2016

NCT01667419

Slide13

Dabrafenib

150 mg BID +

Trametinib

2 mg QD x 12 months

Placebo

R

Eligibility (N = 852)

Surgically resected cutaneous melanoma

BRAF V600E/K-mutant

High-risk Stage

IIIa,b,c

COMBI-AD Phase III Adjuvant Study

Primary Endpoint: Relapse-free survival

www.clinicaltrials.gov

, May 2016

NCT01682083

Slide14

Case 3 (

Dr Flaherty)A 61-year-old man with recurrent BRAF V600E-mutant melanomaEnrolls on a Phase I study of encorafenib-binimetinib

2 years on treatmentEssentially no toxicity

Slide15

LOGIC2: Phase 2, Multi-center, Open-label Study of Sequential

Encorafenib/Binimetinib Combination Followed by a Rational Combination with Targeted Agents After Progression, to Overcome Resistance in Adult Patients with Locally Advanced or Metastatic BRAF V600 Melanoma

Dummer R et al. Proc

ESMO 2015;Abstract P187.

Slide16

All-Cause AEs in >10% of Patients

No photosensitivity reported

Dummer

R et al. Proc ESMO 2015;Abstract P187.

CPK,

creatine

phosphokinase

 

BRAFi

+

MEKi

Naïve

ENCO 450 mg QD + BINI

(n = 45)

Prior

BRAFi

and/or

MEKi

ENCO 450 mg QD + BINI

(n = 43)

Adverse Event

All Grades

n (%)

Grade 3/4

n (%)

All Grades

n (%)

Grade 3/4

n (%)

Nausea

12 (26.7%)

3 (6.7%)

12 (27.9%)

2 (4.7%)

Diarrhea

14 (31.1%)

0

8 (18.6%)

0 Fatigue

9 (20.0%)1 (2.2%)12 (27.9%)

2 (4.7%) Retinopathy14 (31.1%)0

7 (16.3%)0 Vomiting

7 (15.6%)1 (2.2%)7 (16.3%)0

CPK increase11 (24.4%)1 (2.2%)

3 (7.0%)0 Pyrexia5 (11.1%)

1 (2.2%)6 (14.0%)0

Abdominal pain7 (15.6%)03 (7.0%)

0 Anemia4 (8.9%)

1 (2.2%)6 (14.0%)3 (7.0%)

Slide17

Module

2:

Targeted Therapy for BRAF Wild-Type Melanoma

Slide18

Case 4 (

Dr Flaherty)A 35-year-old man had surgery in 2011 for a primary melanoma on the chest wall

2014: Hepatic, pulmonary, adrenal and nodal metastasesNRAS mutation Ipilimumab

/nivolumabGrade 3 colitis and rashProgressive diseaseEnrolled on a Phase III study of binimetinibGrade 2 rash, CPK elevation and Grade 1 diarrheaPartial response for 8 months

Slide19

In

cidence and Clinical Relevance of NRAS Mutations in MelanomaIncidence: ~15-20%Normally do not coexist with BRAF alterations

Higher tumor proliferationPoor prognosis: OS approximately 8.5 monthsImproved response to immune checkpoint inhibitorsNo approved targeted

therapiesLong G et al. Proc AACR 2016;Abstract B16.Johnson DB et al. Cancer Immunol Res 2015;3(3):288

-95

.

www.onclive.com

/web-exclusives/

binimetinib

-improves-

pfs

-in-

nras

-mutant-melanoma

Slide20

Best Percentage Change from Baseline and Response with

Binimetinib 45 mg in NRAS-Mutant Melanoma

Median PFS: 3.6 monthsMedian OS: 12.2 months

N = 117ORR: 14.5%DCR: 56.4%

van

Herpen

CML et al.

Proc

ESMO

2014

;Abstract

LBA35.

Best Percentage Change from Baseline

-100

80

100

60

40

20

0

-20

-40

-60

-80

Slide21

Binimetinib

45 mg BID (

n =

262)

Dacarbazine

1,000 mg/m

2

q3wk

(

n =

131)

R

Eligibility (N = 393)

Locally advanced,

unresectable

or

metastic

cutaneous or unknown primary melanoma

NRAS Q61 mutation

No prior

MEKi

or immunotherapy for

metastic

melanoma

NEMO Phase III Study

2:1

Binimetinib

Dacarbazine

Hazard

ratio

p

-value

Median PFS

2.8

mo

1.5

mo

0.62

<0.001

Initial results of NEMO. ASCO 2016 (Abstract 9500)Monday, June 6, 1:15-4:15 PM, Arie Crown Theater

Flaherty K et al. Proc ASCO 2014;Abstract TPS9102. www.arraybiopharma.com/product-pipeline/binimetinib/

Slide22

Binimetinib

and Ribociclib (28-Day Regimen) in NRAS-Mutant, Metastatic Melanoma

ORR: 41%Disease control rate: 82%

Individual Patient ResponsesVan Herpen C et al. European Cancer Conference 2015;Abstract 3300.

n/N (%) = 21/22 (95.5%)

28-day regimen

RIBO 200mg + BINI 45mg

RIBO 250mg + BINI 45mg

RIBO 300mg + BINI 30mg

RIBO 300mg + BINI 45mg

Treatment group

-100

80

100

60

40

20

0

-20

-40

-60

-80

Median PFS: 6.7 months

Slide23

Safety Profile: All-Cause AEs

Adverse Event

RIBO 200/250/300 mg +

BINI 45 mg and RIBO 300 mg + BINI 30 mg(N = 22)All Grade

Grade 3/4

Blood CPK increase

15 (68%)

4 (18%)

Nausea

14 (64%)

3 (14%)

Vomiting

14 (64%)

2 (9%)

Diarrhea

12 (55%)

0

Peripheral edema

11 (50%)

1 (5%)

Anemia

11 (50%)

2 (9%)

Fatigue

9 (41%)

1 (5%)

Dermatitis

acneiform

9 (41%)

1 (5%)

Constipation

9 (41%)

1 (5%)

Hypoalbuminemia

9 (41%)

2 (9%)

AST increase

8 (36%)

1 (5%)

Van

Herpen

C et al.

European Cancer Conference 2015;Abstract 3300.

Slide24

Imatinib

for Melanoma with Activating Mutations of C-KITMulticenter phase II trial of imatinib in metastatic mucosal, acral

, or chronically sun-damaged (CSD) melanoma with KIT amplifications and/or mutations (N = 24 evaluable)Best ORR: 29%

KIT mutated: 54%KIT amplified: 0%Disease control rate: 50%KIT mutated: 77%KIT amplified: 18%Hodi FS et al. J Clin Oncol 2013;31:3182-90.

Slide25

Select Investigational Targeted Agents in Melanoma

CDK4/6 InhibitorsPalbociclibRibociclibAbemaciclib

PI3K/AKT/mTOR

InhibitorsBuparlisibPictilisibDactolisibPAN-RAF selective InhibitorsTAK-632ARQ736

ERK1/2 Inhibitors

MK-8353

BVD-523

TGF-Beta Pathway Inhibitors

Trabedersen

Fresolimumab

Other Targeted Drugs

Cabozantinib

Pazopanib

Axitinib

Gonzalez-Cao M et al. Ann

Transl

Med 2015;3(18):266.

Slide26

Module 3:

Checkpoint Inhibitors in Melanoma

Slide27

Case 5 (

Dr Flaherty)A 76-year-old man with BRAF WT M1c metastatic melanoma Ipilimumab with response 

disease progressionPembrolizumab with response

Slide28

Updated results of

CheckMate

067 (

Abstract 9505)ASCO 2016, Monday, June 6, 1:15-4:15 PM, Arie Crown Theater

Slide29

CheckMate-067:

Nivolumab, Ipilimumab or the Combination in Untreated, Unresectable or Metastatic Melanoma

Nivo

/Ipi (n = 314)Nivolumab (n = 316)

Ipilimumab

(n

= 315)

Best ORR (all

pts

)

58%

44%

19%

PD-L1+

72%

58%

21%

Median PFS (all

pts

)

11.5

mo

6.9

mo

2.9

mo

PD-L1+

14

mo

14

mo

3.9

mo

Median tumor burden change = -51.9%

Nivo

alone = -34.5%

Ipi alone = 5.9%

Larkin J et al. N Engl J Med 2015;373(1):23-34.

Slide30

CheckMate 067 Treatment-Related AEs

Larkin

J et al. N Engl J Med 2015;373(1):23-34.

AEs

Nivo

+ Ipi

n = 313

Nivolumab

n = 313

Ipilimumab

n = 311

Grade

Any

3 or 4

Any

3 or 4

Any

3 or 4

Treatment-related AE

95.5%

55.0%

82.1%

16.3%

86.2%

27.3%

Diarrhea

44.1%

9.3%

19.2%

2.2%

33.1%

6.1%

Fatigue

35.1%

4.2%

34.2%

1.3%

28.0%

1.0%

Pruritus

33.2%

1.9%

18.8%

0%

35.4%

0.3%

Rash

40.3%

4.8%

25.9%

0.6%

32.8%

1.9%

Nausea25.9%

2.2%13.1%

0%16.1%

0.6%Pyrexia

18.5%0.6%5.8%

0%6.8%

0.3%Decreased appetite

17.9%1.3%

10.9%0%

12.5%0.3%Increased ALT

17.6%8.3%

3.8%1.3%

3.9%1.6%

Vomiting15.3%

2.6%6.4%0.3%

7.4%0.3%

Increased AST15.3%

6.1%3.8%

1.0%3.5%0.6%

Hypothyroidism15.0%

0.3%8.6%

0%4.2%

0%

Slide31

CheckMate 067 Treatment-Related AEs

Larkin

J et al. N Engl J Med 2015;373(1):23-34.

AEs

Nivo

+ Ipi

n = 313

Nivolumab

n = 313

Ipilimumab

n = 311

Grade

3 or 4

3 or 4

3 or 4

Treatment-related AE

55.0%

16.3%

27.3%

Diarrhea

9.3%

2.2%

6.1%

Rash

4.8%

0.6%

1.9%

Increased ALT

8.3%

1.3%

1.6%

Slide32

Pembrolizumab (

Pembro

) Plus Ipilimumab (

Ipi) for Advanced Melanoma: Results of the KEYNOTE-029 Expansion CohortLong GV et al.Proc ASCO 2016;Abstract 9506.Monday, June 6, 2016, 1:15-4:15 PM, Arie Crown Theater

Slide33

Systemic response rate: 45%

Brain metastasis response rate: 45% Duration of response in the brain was at least 12 weeks for 4 of 5 respondersAll responses were ongoing at the time of data analysis

A Phase II Trial of Pembrolizumab for Melanoma or NSCLC and Untreated Brain Metastases

Goldberg SB et al.

Proc

ASCO

2015;Abstract 8035.

Kluger

HM et al.

Proc

ASCO

2015;Abstract 9009.

Slide34

Case 6 (

Dr Weber)A 62-year-old man with BRAF WT M1c metastatic melanoma IpilimumabD

evelops mood and behavioral alterations after 3 doses

Slide35

Case 7 (

Dr Weber)A 58-year-old man presents with BRAF WT metastases to the liver Radiofrequency ablation followed by

ipilimumabBloody diarrhea

Slide36

Colonoscopy performed on a 51-year-old man with metastatic

melanoma who developed watery diarrhea after receiving

an immune checkpoint-blocking drug 

Autoimmune colitis

Images courtesy of

Animesh

Jain, MD,

Johns

Hopkins University School of Medicine

Slide37

Radiographs

New or changes Ground-glass changesNodular or interstitial Symptoms

New or worsening Cough, shortness of breathSignsDecrease in oxygen saturation

Diffuse interstitial infiltrates L > R

Pneumonitis

Courtesy

of Julie

R

Brahmer

, MD, MSc

Slide38

Retrospective characterization of clinical outcomes in 30 patients with preexisting

AiDs who received ipilimumab

15/30 patients (50%) experienced irAEs or flares of their underlying

AiD, which were generally manageable with standard treatment6/30 (20%) experienced complete or partial responses to therapyMedian overall survival was 12.5 monthsIpilimumab appears to be safe and effective for many patients with advanced melanoma and concurrent, preexisting AiDsPatients should be monitored closely for irAEs and autoimmune flaresAiDs (n = 30)

Rheumatoid arthritis (RA)

6 (20%)

Psoriasis (5/30)

5

(17%)

Multiple sclerosis

2

(7%)

Crohn’s

disease or ulcerative colitis

6

(20%)

Thyroiditis

3

(10%)

Systemic lupus

erythematosus

2 (7%)

Sarcoidosis

2 (7%)

Other

7 (23%)

Ipilimumab Therapy in Patients with Advanced Melanoma and Preexisting Autoimmune Disorders (

AiDs

)

Johnson DB et al.

JAMA Oncology

2016;[

Epub

ahead of print].

Slide39

Prevalence of Autoimmune Comorbidities in Patients with Metastatic Melanoma in the

US

Qiufei

M et al.Proc ASCO 2016;Abstract 9529.

Anti-PD-1 Therapy in Patients with Advanced Melanoma and Preexisting Autoimmune Disorders (AD) or Major Toxicity with Ipilimumab (IPI

)

Menzies

AM et al.

Proc

ASCO

2016

;Abstract

9515.