management of patients with ocular or mucosal melanoma · 2016. 2. 22. · ocular or mucosal...
TRANSCRIPT
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