Download 0% - Melanoma Focus

Uveal Melanoma
Prognosis & Treatment Options
Dr Ernie Marshall
Macmillan consultant in medical oncology
Clatterbridge Cancer Centre
Liverpool CRUK Centre
Malignant melanoma: Subtypes
5%
Uveal
melanoma
5-600/yr
Ocular Melanoma: Facts
• Presentation
– Subtypes
• Choroid (90%),
• ciliary body,
• iris
• conjunctiva
• Molecular drivers
– C/s 3 loss, 8q gains in 40%
Prescher et al, 1996
– Frequent (47%) mutations
in BAP1 (c/s 3p21.1)
Harbour et al 2010
– Frequent (83%) mutations
in GNAQ/GNA11(c/s 9) van
Raamsdonk et al 2010
Visual
symptoms
UK Uveal Melanoma Pathway
Initial Specialist Care
Devolved Follow up
&
Late Relapse
? Screening
General
Oncology
recurrence
Skin melanoma
protocols
Late
presentation
Follow Up
Paucity of research
LOORG
DecisionDx-UM gene expression profile test.
LUMPO
Ocularmelanomaonline.com
Is screening for metastases
worthwhile?
For
•Improved outcomes with
early detection disease?
•Promotes standardised care
and facilitate research in rare
cancer setting
•Patient enthusiasm
Against
•Lack of evidence
•Literature review 4222 articles
(Augsburger 2011). Poor quality,
no randomised trials, no survival
gain
•Lack of treatment options
•Patient anxiety
•cost
Modality?
Frequency?
Endpoints?
Requires definitive
randomised trial
High risk ocular melanoma: A prospective phase II
study of liver MRI screening (Marshall et al, ASCO Proc 2012)
METHODS
A single centre prospective cohort study
Screening consisted of 6 monthly:
•Clinical examination,
•Liver function tests including LDH and
•non-contrast liver MRI
•Serum Biomarker collection
•Disease free survival is 33
months (95% CI 28-38)
•92% asymptomatic
•13% operable
Total referred
279
Metastatic
relapse
90
Total screened
188
52
Male/Female
84/104
Inoperable
on MRI
63 years (2483)
Enucleation
149
Potentially
operable on
MRI (≤ 4
metastases)
38
Median age
Median Basal
Diameter
16.5mm (1.523.6)
Inoperable
on
laparoscopy
25
Monosomy 3
175
R0 liver
resection
12 (+1 RFA)
•median survival for RO
resection: 24 months (20.227) vs 10months (8.1-11.9) .
What is the role of Liver Resection in Uveal
Melanoma?
Liverpool: 12/90ts
R0 resection 24/10months
Conclusions
•Insensitivity of imaging (MRI/PET) in
preoperative phase
•Many upstaged at laparoscopy
•Outcomes correlate with R0 resection, <4
mets, DFI >24mths
•Further liver relapse common (<12mths)
Response to Systemic Therapy
Author
Study
n
RR
OS/PFS
Homsi et al, 2010
Phase 2 Docosahexaenoic
acid-Paclitaxel
22
4%
(1/22)
9.8 mo OS
Penel et al, 2008
Phase 2 Imatinib
10
0%
10.8 mo OS
Schmittel et al,
2006
Phase 2 Gem/Treosulfan vs
Treosulfan
48
Oneill et al, 2006
Phase 2 DTIC/Treosulfan
15
0%
3 mo PFS
Schmittel et al,
2005
Phase 2
Gem/Cis/Treosulfan
17
0%
3 mo PFS
Schmidt-Hieber et
al, 2004
Phase 2 Bendamustine
9
0%
NR
Bedikian et al,
2004
Phase 2 Temozolomide
14
0%
1.8 mo TTP
Kivelä et al, 2003
Phase 2 BOLD + IFN
22
0%
1.9 mo PFS
157
1.3%
2/157
2% 2-3 mo PFS
(1/48)
Regional (Intrahepatic) Therapy
Trial
phase no
treatment
RR (%)
OS (mths)
Philadelphia
II
24
IA BCNU
20
5.2
Italy
II
8
IA Carboplatin
38
15
lausanne
II
30
IA Fotemustine
40
11
Multicentre
series
II
101
IA Fotemustine
36
15
MD
Anderson
II
30
CE with Cisplatin
48
11
Berlin
II
25
TACE with Fotemustine
Or cisplatin
16
6
NCI
II
22
IHP melphalan/TNF
62
11
Gonsalves
II
32
Radioembolisation
6
10
Fiorentini
II
10
Irinotecan Drug eluting
beads
100
NR
Regional versus Systemic?
Phase III Trials
• EORTC 18021 (Leyvraz, 2012): Randomised trial of intrahepatic versus
intravenous fotemustine (171 pts).
– Response rate 10% vs 2%
– PFS 4.5mths vs 3.7mths (p 0.02)
– OS 14.6mths vs 13mths (NS)
•
PHP Melphalan (Pingpank, 2010): Randomised trial of percutaneous
isloated hepatic perfusion (melphalan) versus BAC (93 pts).
– Response rate 34% vs 2%
– H-PFS 6.1mths vs 1.4mths (p= 0.001)
– OS 11.4 mths vs 9.9 mths (NS) - cross over allowed
Higher response rate
Catheter complications
common
No Effect on survival
? Effect on quality of life
Major signaling pathways in uveal melanoma.
Activating mutations
in GNA11/GNAq
MAPkinase
activation
Patel M et al. Clin Cancer Res 2011;17:2087-2100
©2011 by American Association for Cancer Research
Targets & Ongoing Trials for Uveal Melanoma
Target
Trial
Sponsor/Lead Center
IGF1R
Phase II IMC-A12
MDACC
VEGFR,PDGFR RAF
Phase II Sorafenib
Essen
VEGF
Phase II Temozolomide & Bevacizumab
Institut Curie
VEGFR, PDGFR, KIT
Phase II Sunitinib versus dacarbazine (SUAVE)
CCC (UK)
VEGFR, PDGFR, KIT
Phase I/II Temozolomide & Sunitinib
UCLA
KIT, PDGFR, ABL
Somatostatin
Receptor/mTOR
Phase II Imatinib (ITEM)
CCC (UK)
Phase II SOM230 & RAD001
MSKCC
PKC
Phase I AEB071
Novartis
MEK
Phase II AZD6244 versus temozolomide
MSKCC
VEGFR
Phase II Ranibizumab (NITRO)
RLUH (UK)
HDAC
Phase II SAHA
MSKCC
Bcl-2
Phase II Genasense, Carbo & Taxol
MDACC
HSP90
Phase II STA-9090
DFCI
CTLA4
Phase II CP-675,206
Alberta Health Services
ITEM
A CRUK phase II study of Imatinib in c-kit positive metastatic uveal melanoma.
RECRUITMENT
4 centre study (liverpool, Sheffield, Leeds, Mount Vernon)
 37 patients screened n 16months (1.6 patients recruited
per month)
Endpoints
2 responses but no overall
benefit
•PFS 12 wks, OS 29wks.
•No KIT mutations
•Clinical network of centres
•Prospective tumour and serum
sample collection (GCLP labs)
•UK reputation
Liverpool
CRUK Centre
Liverpool Manchester
Sheffield Birmingham
Leicester Cardiff
Mount Vernon Marsden
• recruit,ment
• Largest study
• Number of centres
Southampton Exeter
Glasgow Cambridge
Clinical Experience of MEK Inhibition in UM:
Randomized Study to Compare the Efficacy of
Selumetinib vs TMZ (NCT00338130)
Matched Tumor Biopsies (18pts)- Carvajal et al, ASCO 2012
WRC
BAS
RPS
JBP
SS
G11 Q209L
G11 Q209L
G11
Q209L
Gq Q209L
Q11 Q209L
Pre
Pre
Pre
Pre
Post
Post
Pre Post
Post
Post
pERK
ERK
CyclinD1
Tubulin
Response
PR
PR
SD x 7
mos
POD
POD
Adjuvant Therapy in High Risk Uveal Melanoma?
Rationale
Well defined high risk population with
median PFS 3years
Adjuvant strategy remains hindered
due to lack of a lead compound with
sufficient activity
Good PS and liver function
Ongoing Trials
Phase Therapy
N
Centre
I/II
Dendritic cells vaccination
30
Rotterdam
II
Sunitinib, tamoxifen, cisplatin
50
NCI
II
Dacarbazine/interferon
36
Case Comprehensive
I/II
Ipilimumab
141
MD Anderson
III
Fotemustine
302
Curie institute
Pathways involved in the formation of liver
metastasis in uveal melanoma
‘DRUG MAY SLOW SPREAD OF
DEADLY CANCER’
BAP-1
?
HDAC
Bakalian S et al. Clin Cancer Res 2008;14:951-956
©2008 by American Association for Cancer Research
Inhibition of Migration by SU11274
Future Trial Development &
Clinical Collaboration
UK Guideline Development Group
•National collaboration with NCRI, RCP,
FOCUS on melanoma and Cochrane
Review
•Aim; Promote evidence-based
multidisciplinary guidance
•Treatment and follow up
International Rare Cancer Initiative (IRCI)
•International initiative with CRUK/NCRI, EORTC &
NCI
•Aim. Promote collaboration and develop
international trial portfolio in rare cancers
• Metastatic multi-arm randomised phase II trial
• Adjuvant randomised phase II/III trial
Thank You!
Paul Nathan
•NHS/Liverpool
University
•Clatterbridge
Cancer Centre
•LOOG
ITEM & SUAVE
Investigators
Liverpool
Clinical Trials
Unit
•NCRI
Melanoma CSG
•NCRN
•CRUK
•Industry
Partners
•IRCI
•& LOORG
•All patients and carers who continue to support essential research