Management of Patients With

Ocular or Mucosal Melanoma

Richard D. Carvajal, M.D.Director, Experimental Therapeutics

Director, Melanoma ServiceAssociate Professor of Medicine

Columbia University Medical Center

Disclosures

• Consulting: Novartis

AstraZeneca

Merck

Janssen

Thomson Reuters

Aura Biosciences

Rgenix

• Scientific Advisory Board: Aura Biosciences

• Clinical Advisory Board: Rgenix

The Clinical Heterogeneity of Melanoma

Melanoma in

Non-Sun

Damaged Skin

Melanoma in

Sun Damaged

Skin

Acral

Melanoma

Mucosal

MelanomaConjunctival

Melanoma

80% <10% <5%

<2% <1%

Uveal

Melanoma

<5%

Furney S J et al. Cancer Discovery 2013;3:1122-1129.

The Molecular Heterogeneity of Melanoma

Cutaneous Mucosal Acral Uveal

SourceBerger et al,

2012Furney et al,

2013Turajlic et al,

2012Furney et al,

2013

Somatic SNVs/ Genome ~30,000 ~8,000 ~5,000 ~2,100

Agenda

1. Immunotherapy for Advanced Mucosal and UvealMelanoma

2. Targeted Therapy for Advanced Mucosal and UvealMelanoma

Mucosal Melanoma

• 0.8 - 1.8% of all melanomas

• Most common sites:

– 55% head and neck mucosa

– 24% anorectal mucosa

– 18% vulvovaginal mucosa

• MM outcomes inferior to cutaneous melanoma outcomes irrespective of stage

Carvajal et al, JNCCN 2012;10:345

Bitas et al, ASCO 2014.

• Single center retrospective analysis

• n = 81 who were treated at MSKCC between 1998-2012 for advanced mucosal melanoma with central radiology review

The Memorial Sloan Kettering Cancer Center (MSKCC) Experience of Systemic

Therapy in Mucosal MelanomaChristiana Bitas1, Alexander Noor Shoushtari1, Mark J. Bluth2, Gauri Bhuchar1, Robert Harrison Hester1, Jacqueline Romero1, Laura

Fitzpatrick1, Robert A. Lefkowitz2, Katherine Panageas3, Gary K. Schwartz1, Margaret K. Callahan1, Michael Andrew Postow1, Jedd D.

Wolchok1, Paul B. Chapman1, Richard D. Carvajal1

Departments of Medicine1, Radiology2, and Epidemiology & Biostatistics3; Memorial Sloan Kettering Cancer Center, New York, NY;

Anorectal

(N = 31)

Head & Neck

(N = 21)

Vulvovaginal

(N = 27 )

Median Age at Dx, Years (range) 61 (36 - 82) 63 (33 - 82) 65 (40 - 84)

Sex

Male 8 (25.8%) 14 (66.7%) 0 (0%)

Female 23 (74.2%) 7 (33.3%) 27 (100%)

Stage at First Non-Adjuvant Tx

M1a 8 (25.8%) 0 (0%) 4 (14.8%)

M1b 2 (6.5%) 3 (14.3%) 1 (3.7%)

M1c 19 (61.3%) 15 (71.4%) 17 (63.0%)

Locally advanced/recurrent 2 (6.5%) 3 (14.3%) 5 (18.5%)

Bitas et al, ASCO 2014.

The Memorial Sloan Kettering Cancer Center (MSKCC) Experience of Systemic

Therapy in Mucosal MelanomaChristiana Bitas1, Alexander Noor Shoushtari1, Mark J. Bluth2, Gauri Bhuchar1, Robert Harrison Hester1, Jacqueline Romero1, Laura

Fitzpatrick1, Robert A. Lefkowitz2, Katherine Panageas3, Gary K. Schwartz1, Margaret K. Callahan1, Michael Andrew Postow1, Jedd D.

Wolchok1, Paul B. Chapman1, Richard D. Carvajal1

Departments of Medicine1, Radiology2, and Epidemiology & Biostatistics3; Memorial Sloan Kettering Cancer Center, New York, NY;

-100.0%

-80.0%

-60.0%

-40.0%

-20.0%

0.0%

20.0%

40.0%

60.0%

80.0%

100.0%

Be

st R

esp

on

se (

% C

han

ge f

rom

Bas

elin

e)

Best Response, 1st Line Therapy(N = 71 patients)

-

*

KEY (RECIST Responses):

Single-agent alkylator (2/20)

Combination alkylator (3/37)

Other (2/2)

Non-alkylating cytotoxic (1/4)

Immunotherapy (1/4)

Biochemotherapy (0/3)

Targeted agent (1/4)

* Patient progressed due to new lesions.

Other: TMZ + SorafenibTMZ + Imatinib

13.5%

RR

Overview

• We conducted a pooled analysis of data from patients with metastatic mucosal melanoma who had received NIVO monotherapy (3 mg/kg),NIVO (1 mg/kg) plus IPI (3 mg/kg), or IPI monotherapy (3 mg/kg)in one of six trials:

– Phase I: CA209-003 and CA209-038

– Phase II: CheckMate 069

– Phase III: CheckMate 037, CheckMate 066, and CheckMate 067

9

NIVO Monotherapy NIVO+IPI IPI Monotherapy

Studies 003/037/038/066/067 067/069 067/069

Total patients, N 889 407 357

Mucosal mel, n (%) 86 (10%) 35 (9%) 36 (10%)

Cutaneous mel, n (%) 665 (75%) 326 (80%) 269 (75%)

Acral/Ocular/Other 138 (15%) 46 (11%) 52 (15%)

Larkin et al, SMR 2015

PFS – Mucosal Melanoma

10

Number of Patients at Risk

NIVO 01722294086

NIVO+IPI --0211121935

IPI --0002836

Pro

bab

ilit

y o

f P

rog

ressio

n-F

ree S

urv

ival

Months

1815129630

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

NIVO

NIVO+IPI

IPI

NIVO

(N=86)

NIVO+IPI

(N=35)

IPI

(N=36)

Median, mos (95% CI) 3.0 (2.2‒5.4) 5.9 (2.8‒NR) 2.7 (2.6‒2.8)

HR (95% CI) vs IPI 0.61 (0.39‒0.96) 0.42 (0.23‒0.75) --

P value vs IPI* 0.12 0.003 --

Median follow-up, mos (range) 6.2 (0.5‒17.4) 8.1 (0.5‒16.9) 8.6 (1.9‒17.1)

*Unstratified log-rank test.

Larkin et al, SMR 2015

Response to Treatment

11

NIVO NIVO+IPI IPI

Mucosal

(N=86)

Cutaneous

(N=665)

Mucosal

(N=35)

Cutaneous

(N=326)

Mucosal

(N=36)

Cutaneous

(N=269)

ORR, % (95% CI)* 23.3

(14.8‒33.6)

40.9

(37.1‒44.7)

37.1

(21.5‒55.1)

60.4

(54.9‒65.8)

8.3

(1.8‒22.5)

21.2

(16.5‒26.6)

P value vs IPI 0.075 <0.0001 0.005 <0.0001 -- --

Best overall response, n (%)

Complete response 5 (5.8) 46 (6.9) 1 (2.9) 44 (13.5) 0 7 (2.6)

Partial response 15 (17.4) 226 (34.0) 12 (34.3) 153 (46.9) 3 (8.3) 50 (18.6)

Stable disease 19 (22.1) 112 (16.8) 7 (20.0) 41 (12.6) 3 (8.3) 67 (24.9)

Progressive disease 40 (46.5) 245 (36.8) 11 (31.4) 66 (20.2) 27 (75.0) 120 (44.6)

Duration of response (mos)

Median (95% CI) NR 22.0 (22.0‒NR) NR (7.6‒NR) NR (13.1‒NR) 2.4 (1.8‒3.0) NR (8.8‒NR)

CI, confidence interval; NR, not reached; ORR, objective response rate.

*By RECIST v1.1 in all studies except CA209-003 in which RECIST v1.0 was used.

Larkin et al, SMR 2015

Uveal Melanoma Most common primary intraocular malignancy

in adults

Represents 5% of all melanomas

Biologically distinct from cutaneous disease

50% of patients develop metastases

Resistant to systemic treatment, with no therapy demonstrated to improve survival

Author Study n RR OS/PFS

Leyvraz et al, 2014 HAI vs IV Fotemustine 17110% vs 2%

(9/86 vs 2/85)14.6 vs 13.8mo/

4.5 vs 3.7mo

Sacco et al, 2013 SUAVE: Sunitinib vs DTIC 740% vs 8%

(0/38 vs 3/36)6.4 vs 8.6mo/2.8 vs 3.9mo

Bhatia et al, 2012 Phase 2 Carbo/Paclitaxel + Sorafenib 24 0% 11mo/4mo

Homsi et al, 2010Phase 2 Docosahexaenoic acid-

Paclitaxel22

4%(1/22)

9.8mo OS

Penel et al, 2008 Phase 2 Imatinib 10 0% 10.8mo OS

Schmittel et al, 2006 Phase 2 Gem/Treosulfan vs Treosulfan 482%

(1/48)2-3mo PFS

Oneill et al, 2006 Phase 2 DTIC/Treosulfan 15 0% 3mo PFS

Schmittel et al, 2005 Phase 2 Gem/Cis/Treosulfan 17 0% 3mo PFS

Bedikian et al, 2004 Phase 2 Temozolomide 14 0% 1.8mo TTP

3954%

16/395

No Effective Therapy for Uveal Melanoma

Author Site(s) n irResponse 3-Month DCRPFS

(months)OS

(months)

Kelderman et al, 2013 Netherlands 221/14 (7%)

2/14 (14%)

2.9 mo 5.2 mo

Luke et al, 2013MSKCC, DFCI,

MGH, Lausanne39

2/39 (5%)

18/39 (46%)

NR 9.6 mo

Maio et al, 2013 Italy 834/83 (5%)

29/83 (35%)

3.6 mo 6.0 mo

Piulats et al, 2014Spain

(GEM-1)32

2/25(8%)

NR NR 9.8 mo

Zimmer et al, 2015Germany (DeCOG)

530/34(0%)

16/34 (47%)

2.8 mo 6.8 mo

2299/195

5%65/170

38%

Ipilimumab Benefits a Subset of Patients with Advanced UM

Experience of Anti-PD1/PDL1 Therapy in Uveal Melanoma

Author Site(s) nImmune Related

ResponsesPFS

(weeks)

Kottschade et al, ASCO 2015

Mayo Clinic 71 CR1 PR1 SD

12.2 wks

Multi-Arm Expansion Study of Durvalumab

(MEDI4736)

Segal et al, ASCO 2014 (Abst3002)

Immunotherapy Trials for Uveal Melanoma

Agent Phase Sponsor/Lead Center Clinicaltrials.gov ID

Pembrolizumab IIVanderbilt

(PI: Doug Johnson)NCT02359851

Ipilimumab/Nivolumab IIMDACC

(PI: Sapna Patel)NCT01585194

Tumor Infiltrating Lymphocytes IINCI

(PI: Udai Kammula)NCT01814046

IMCgp100 I Immunocore NCT02570308

(as of 01/18/2016)

17 C O N F I D E N T I A L

IMCgp100 overview

Target - gp100280-288 peptide presented by HLA-A2

HLA-A2 in ~ 50% of patients

Indications – Cutaneous melanoma, uveal melanoma &

glioblastoma

Pharmacokinetics – Plasma clearance T1/2 ~ 7-9 hours in humans

Clinical status

Phase 0 complete

Phase I/IIa (UK and US):

Enrollment completed December 2015

Dosing for phase 2 established with intra-patient

escalation

Phase 1 in uveal with intra-patient further escalation to

initiate January 2016

TCR affinity increased 3,500,000

fold from 85μM to 24 pM

KD ~24 pM

Residence T½

~24 hrs at 37ºC

KD nM

Residence

T½ mins

Targ

eting e

nd

Effecto

r

end

Courtesy of Christina Coughlin, MD PhD

18 C O N F I D E N T I A L

The spectrum of gp100 expression in cutaneous and uveal melanoma

RNAseq data generated from The

Cancer Genome Atlas Program

Gp

10

0 p

ositiv

eG

p1

00

ne

ga

tive

Uveal pt#1

Cutaneous pt#2

Cutaneous pt#3

Cutaneous pt#4

IMCgp100/01 biopsies (IHC)

Middleton et al, Soc for Mel Res, November 2015

19

Antitumor activity in uveal melanoma

Two patients with mixed responses: regression of non-target lesions (skin) and SD (minor progressions) of liver lesions

Day 17(2 days post 3rd weekly dose)

gp100

CD3

Granzyme B

PD-L1

- 1 0 0

- 9 0

- 8 0

- 7 0

- 6 0

- 5 0

- 4 0

- 3 0

- 2 0

- 1 0

0

1 0

2 0

3 0

4 0

5 0

6 0

U v e a l M e l a n o m a P a t i e n t s

% B

est

ch

an

ge

in

SL

D o

f

targ

et

lesi

on

s fr

om

ba

seli

ne

(Left) A waterfall plot representing best responses from the 5 evaluable patients with metastatic uveal melanoma treated on the

IMCgp100 weekly regimen. One patient treated at the first dose in dose escalation was considered not evaluable for efficacy.

(Right) A biopsy was sampled from a patient’s (* in waterfall) responding psoas muscle lesion with evidence of T cell infiltration

(CD3 stain), activation (PDL-1 stain) and commit to killing (Granzyme B stain), two days post third weekly dose.

Middleton et al, Soc for Mel Res, November 2015

Agenda

1. Immunotherapy for Advanced Mucosal and UvealMelanoma

2. Targeted Therapy for Advanced Mucosal and UvealMelanoma

Distinct Melanoma Subtypes

Curtin et al. NEJM 2005; Curtin et al. JCO 2006; Carvajal et al. JAMA 2011.

Skin Without

Chronic Sun

Damage

Skin With Chronic

Sun Damage

Mucosal Surfaces

Acral Surfaces

50% BRAF20% NRAS

0% KIT

22% BRAF0% NRAS

19% KIT

9% BRAF12% NRAS

25% KIT

22% BRAF16% NRAS

24% KIT

Uveal Tract<1% BRAF<1% NRAS

96% Gq/11

Baseline Week 6 Week 18

MRI

PET

(8/28/08) (10/13/08) (1/2/09)

(8/21/08) (10/13/08) (1/2/09)

Vaginal Melanoma, KIT Exon 11 L576P/Amp

Carvajal et al. JAMA 2011.

Phase II Studies of Imatinib in Melanoma Harboring KIT Alterations

Carvajal et al (n=25) Hodi et al (n=25) Guo et al (n=43)

Starting Dose 400 mg po bid 400 mg po qd 400 mg po qd

Median PFS 3.0 months 3.7 months 3.5 months

PR 8% 21% 23.3%

CR 8% 0% 0%

ORR 16% 21% 23.3%

Guo et al. JCO 2011; Carvajal et al. JAMA 2011; Hodi et al. JCO 2013.

9 vs 1.5 months

p < 0.001

15 vs 9 months

p = .036

Study Agent N Responders Responsive Mutations

Hodi et al, 2008 Imatinib 1 1 Exon 11 7 codon duplication (n=1)

Lutzky et al, 2008 Imatinib 1 1 Exon 13 K642E (n=1)

Salzger et al, 2010 Imatinib 1 1 Exon 11 L576P (n=1)

Handolias et al, 2010 Imatinib 3 2 Exon 11 7 codon duplication (n=1)

Exon 11 L576P (n=1); Exon 13 K642E (n=1)

Carvajal et al, 2011 Imatinib 25 6 Exon 11 L576P (n=4); Exon 13 K642E (n=2)

Guo et al, 2011 Imatinib 43 10 Exon 11 (n=6); Exon 13 (n=3)

Cho et al, 2011 Nilotinib 9 2 Exon 11 L576P (n=1); Exon 11 V559A (n=1)

Woodman et al, 2009 Dasatinib 2 2 Exon 11 L576P (n=2)

Kluger et al, 201 Dasatinib 39 1 Exon 13

Zhu et al, 2009 Sunitinib 1 1 Exon 11 V559A (n=1)

Minor et al, 2012 Sunitinib 10 3 Exon 11 L576P (n=2); Exon 11 W557G

(n=1)

Quintas-Cardama et al, 2008 Sorafenib 1 1 Exon 11 V560A (n=1)

Handolias et al, 2010 Sorafenib 1 0/1 Exon 13 K642E (n=1)

KIT alterations in patients with RECIST responses to KIT inhibition

ASCO 2014 #9043

1. GNAQ/11mut

2. BAP1 LOH

3. BAP1mut

4. SF3B1mut

5. Gain of chr 8

• RUNX1T1

• MYC

• NBN

• PRKDC

• n = 75

• Metastatic

samples

• Median depth:

646X

PIP2

PIP3

mTOR

GPCR

GDPINACTIVE

Ga

GTP

GNAQ/11Mutant

ACTIVE

Ga

CELL GROWTH

Akt

AEB071

MEKP

ERKP

PPKC

PRAF

NFkB

PLC

GSK2141795

PYAP

YAP

Rho Rac

Trio

LATS

YAP

TEAD

Inactive

ActiveAmot

YAP

AmotG-ActinHippo

signaling

F-Actin

The Gα Pathway LXS196

Binimetinib

JAMA. 2014;311(23):2397-2405.

HR 0.46 (95% CI, .30 - .71)

p = 0.0005

15.9 weeks

(95%CI, 8.4 – 21.1)

vs

7.0 weeks

(95% CI, 4.3 – 8.4)

Carvajal et al, Society for Melanoma Research, 2015.

No Improvement Observed with Selumetinib/DTIC vs Placebo/ DTIC

DTIC/Placebo vs DTIC/SelumetinibTMZ vs SelumetinibP

FSR

R

Carvajal et al, JAMA 2014

Carvajal et al, SMR 2015

14% Response Rate

(n = 5/49)

0% Response Rate

(n = 0/97)

mPFS: 2.8 vs 1.8 months

Strategies to Improve MEK Inhibition Efficacy

2. Vertical Pathway Blockade 3. Dual Pathway Blockade

1. Optimizing Single Agent MEK Inhibition

• Might other MEK inhibitors be more effective?

• Are there alternative dosing schedules that can

improve efficacy?

• Can we block the MAPK pathway

at multiple levels to improve

outcomes?

• Can we block other parallel growth

pathways to improve outcomes?

A A B

MEK Inhibitor

Drug X

MEK InhibitorDrug Y

MEK and PKC Based Trials for Uveal Melanoma

Agent Phase Sponsor/Lead Center Clinicaltrials.gov ID

AEB071 + BYL719 I CUMC NCT02273219

Trametinib +/- GSK2141795 II NCI/MSKCC NCT01979523

Intermittent Selumetinib I CUMC pending

Binimetinib + AEB071 I/II Novartis NCT01801358

LXS196 I Novartis NCT02601378

(as of 01/18/2016)

Initial Therapeutic Options for Advanced Mucosal & Uveal Melanoma

Mucosal Melanoma Uveal Melanoma

Chemotherapy No No

Immunotherapy PD1 +/- Ipilimumab PD1 +/- Ipilimumab?

Targeted TherapyBRAF Targeted TxKIT Targeted Tx

Trametinib?Cobimetinib?

Clinical Trials Yes Yes

Conclusions• Uveal and mucosal melanomas are unique biological and clinical subsets of melanoma

that require therapeutic considerations distinct from those required for cutaneous disease

• Clinical benefit can be achieved with anti-PD1 with or without ipilimumab in mucosal melanoma but the benefit is generally less than that observed in cutaneous disease

• Therapies targeting BRAF and KIT can be considered in appropriate molecular subsets of mucosal melanoma

• Treatment of advanced uveal melanoma remains challenging, with no approved agent having significant efficacy; thus, clinical trial participation remains the standard of care for this patient population