martina angi, md phd ocular oncologist · integrative analysis identifies four molecular and...
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Uveal Melanoma
Martina Angi, MD PhD
Ocular Oncologist
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CaruncularTarsal Bulbar
Conjunctiva
Ocular melanoma
• Rare, develops in the mucous membrane lining the eyeball
• Mutation patterns similar to cutaneous melanoma (BRAF etc)
Conjunctival Melanoma
• Most common primaryintraocular tumorin adults
• Molecular affinities with melanocytic tumors of the CNS
Uveal Melanoma
Ciliary bodyIris
Uvea
Choroid
5% 3%
92%
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• Incidence 5-7: 1.000.000 / year worldwide (1500 cases/year in the USA)
• Increasing with latitude: max in Scandinavia
• 97% in Caucasians
Age at Presentation (yrs)
9070503010
Cou
nt
160
140
120
100
80
60
40
20
0
• Increasing incidence with age, median 60 years
• Only 1% in paediatricpopulation
Symptoms (n=590)
No Symptoms (n=233)
N=823
Data from the Liverpool Ocular Oncology Centre – Courtesy of Prof B.E. Damato
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• Up to 50% of UM patients develop metastatic disease, irrespectively of successful ocular treatment
• Typically 1-3 year latencybetween primary and metastatic disease
• No successful treatment
• Liver as first localisation in 90% of cases
• Metastatic spreading via venous circulation
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• Etiology unclear • Typically sporadic occurrence• Malignant transformation of choroidal naevus:
1:8000
• Known associations:• Oculo-dermal melanonocytosis• Familiali atypical mole and melanoma (FAM-
M) syndrome• Neurofibromatosis type 1• Li-Fraumeni syndrome
• BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS)
• uveal melanoma• renal cell carcinoma• malignant mesothelioma• cutaneous melanoma• possibly a range of other cancers
8/507 (1,6%)
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1) Indirect ophthalmoscopy of the fundus oculi
2) (A/) B-scan ultrasound (± UBM)
3) Ancillary imaging techniques
Tissue biopsy is not required for diagnosis and treatment
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n=1003
n=1317
Am J Ophthalmol 2004; 138:936-51 Arch Ophthalmol 2006;124:1684-93
❖ Ocular treatment of mediumand large UM does notinfluence survival
Treatment of primary uveal melanoma
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Radiotherapy SurgeryPhototherapy
Plaque Proton beam Stereotactic
Brachytherapy Teletherapy Transpupillarythermotherapy
Photodynamictherapy
Local resection
Enucleation
Exoresection Endoresection
Exenteration
Iodine Ruthenium
Centric Eccentric
+/- Plaque +/- Radiotherapy(before or after)
Single orMultiplefractions
Local tumour control 95-98%
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Plaque brachytherapy I125I: 9 mm106Ru: 5 mm
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Teletherapy
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TNM Staging of posterior uveal melanoma7th Edition, AJCC
Ciliary body involvement
No
Extraocular spread
Nil
Yes
<=5mm >5mm
Extraocular spread
Nil <=5mm >5mm
Txa Txc Txb TxdT4e T4e
Nodal mets
(Rare)
Tumour
Size category
I IIA IIB IIIA IIIB IIIC
T1a T1b-d & T2a T2b & T3a T2c-d & T3b-c & T4a T3d & T4b-c T4d-e
Stage: IV
Mets
Systemic mets
Th
ickn
ess. (m
m)
Basal diameter (mm)
Shields CL et al., Ophthalmology 2015
x3
x9
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Early detection and treatment of small uveal melanoma
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Can we improve survival by treating smaller lesions?
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courtesy of Aura Biosciences
Can we save life and sight?
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GNAQ = G protein alpha subunit qGNA11 = guanine nucleotide binding protein (G protein), alpha 11
46% of uveal melanomas with GNAQ mutations*83% had somatic mutations in GNAQ or GNA11**
-> Activation of MAK-kinase pathway-> Continuous growth signals
* Van Raamsdonk CD et al. Nature. 2009 Jan 29;457(7229):599-602Bauer J et al. Br J Cancer. 2009 Sep 1;101(5):813-5
** Van Raamsdonk CD et al. N Engl J Med. 2010 Dec 2;363(23):2191-9
Harbour JW Pigment Cell& Melanoma Research 2012 25(2):171-81
BAP1 is mutated in 47% of primary UMDo not duplica
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Chromosome 3 loss in uvealmelanoma
Prescher G, Bornfeld N, Hirche H, Horsthemke B, Jockel KH, Becher R
Cancer 1998;83:354–9
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A. Gordon Robertson, Juliann Shih, Christina Yau, Ewan A. Gibb, Junna Oba, Karen L. Mungall, Julian M. Hess, Vladislav
Uzunangelov, Vonn Walter, Ludmila Danilova, Tara M. Lichtenberg, Melanie Kucherlapati, Patrick K. Kimes...
Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma
Cancer Cell Volume 32, Issue 2, 2017, 204–220.e15
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Personalised medicine in uveal melanoma
Histology Immunohistochemistry Molecular PathClinical
PathogenesisDiagnosis
ClassificationPrognosis
Predicting therapeutic response
“Personalised medicine”
MelanA
MLPA
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Diagnosis
Prognostication
Purpose
High risk
Low risk
Prognostic biopsy of uveal melanoma
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• Reassurance of low-risk patients
• Psychological support
• Targetting screening at high-risk patients
• Early treatment of metastases
•Enrolment in clinical trials
Benefits of personalised prognosticationEnhanced patient care
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Multidisciplinary uveal melanoma team
Ocular Oncologist
Radiation Oncologist
Medical Oncologist
Physicist
PhysicologistCase manager
Palliative careOncologist
Pathologist
Radiologist Molecular Biologist
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Surveillance- early detection and access to therapy
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Valpione et al. Plos One 2015
Prognostic Nomogramfor Metastatic Uveal Melanoma
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Uveal Melanoma NICE Guidelines
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Mariani P, et al. EJSO 35: 1192-97, 2009
Median overall survivaltime from the detection ofmetastasis was 3.3-foldhigher in patients whounderwent complete liverresection than in non-operated patients.
Liver directed therapies
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Percutaneous Hepatic Perfusion with melphalan
Liver directed therapies
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• Comparison of intravenous and hepatic intra- arterial infusion of Fotemustine
• 171 patients randomised• Improvement in PFS and RR but
not OS (median about 14 months)
• Response to IV fotemustine 2.4%
• This and other studies discouraged investigation into standard chemotherapy in UM
• More interest in targeted therapies….
EORTC 18021
Leyvraz, S. et al. (2014) Annals of Oncology 25 (3)
Medical treatment
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Medical treatment
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pro
port
ion S
urv
ivin
g
0 12 24 36 48 60Overall Survival [months]
fotemustine
ipilimumab
sirt
tki
Poor prognosis, no standard of care
EJC 2018
ORR 2.5% (0-14)
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• Generally disappointing compared to cutaneous melanoma
• Response rates to antiCTLA4 and antiPD1 agents 3-8%
• Responses to combination ipi/nivo have been reported to be in the region of 10-15%, but significant toxicity
• Recently, promising activity observed with TIL therapy and IMCgp100
Immunotherapy
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• Conservative treatment is safe and effective in experienced hand
• Successful treatment of primary tumour does not prevent metastatic disease
• Molecular analysis of tumour tissue for personalisedprognostication
• Risk-dependent systemic surveillance and treatment of metastatic disease by multidisciplinary team in referral centre
Treatment of uveal melanoma: take home messages
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Chandran, SS et al. Lancet Oncology 2017
A phase II single arm study of TIL therapy for UM
• Relatively toxic therapy- 1 death due to toxicity
• Patient selection- very fit patients• Technically difficult- few centres can
offer
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34
The anatomy of a T cell redirector: Designing an ImmTAC
A cancer-specific
human TCR is cloned
as a starting point
The TCR affinity for the HLA-peptide
complex is enhanced by a million-fold
anti-CD3 effector
function added
truncated
transmembrane
domains
ImmTAC: Immune-mobilizing TCR against cancer
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35 C O N F I D E N T I A L
Cancer -
specific
T cell
Physiologic TCR:peptide-HLA interaction ImmTAC-mediated interaction
Cancer
cell
CD3
CD3
Cancer
specific TCR
Cancer
specific
pHLA
Cancer specific
ImmTAC
Any specificity
TCR
Key features:Key features:
Any CD3+ T cells can respond
Significantly enhanced TCR
affinity of an ImmTAC v.
physiologic anti-tumor TCR
Profound immunologic
responses seen within hours
ImmTAC molecules are bi-specific biologics that redirect T cells to kill cancer cells
Cancer
specific
pHLA
Any T cell
(cancer or
viral specific)
Only cancer specific T cells
respond
Natural lower affinity TCRs result in:
Poor target recognition
Susceptibility to HLA-downregulation
Observable responses typically slowDo not duplicate or d
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36 C O N F I D E N T I A L
Shoushtari, 2016 SMR
IMCgp100:
• ImmTAC against gp100 bound to HLA-A2 (50% of Caucasian population)
• Initial responses observed in UM patients on first in human study
• Second phase I study used an in intra-patient dose escalation approach (exclusively
in UM patients), now recruiting to dose expansion phase. 102 study, due to complete
recruitment (150 patients) in ~Feb 2019
• A first line randomised study versus investigator choice is recruiting across Europe
and the US- 202 study.
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Tumour target lesions from baseline by best overall response in the Phase I study IMCgp100-102 (NCT02570308)
Sato T, et al. 2018.
–60
Bes
t ch
ange
fro
m b
asel
ine
(%)
–40
–20
0
20
40
60
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Prolonged OS was observed with IMCgp100 and median OS has yet to be reached in the Phase I study IMCgp100-102 (NCT02570308)
irRECIST: immune-related Response Evaluation Criteria In Solid Tumours; PFS: progression-free survival. 1. Sato T, et al. 2018; 2. Immunocore Data on file, 2018.
VariableIMCgp100-102
N=19
PFS2
1-year PFS rate (irRECIST) 62%
OS1
Median OS Not reached
Median OS, follow up (months) 19.1
1-year OS rate 74%
100
75
50
25
00 3 6 9 12 15 18 21 24
Time (months)
Surv
ival
pro
bab
ility
(%
)
Number at risk
All 19 19 17 17 14 13 11 7 2
IMCgp100-102 overall survival for dose-escalation1
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Epidemiology Primary TherapyAdjuvant Therapy
SurveillanceManagement of
Advanced Disease
Vision preserving
therapy for
primary disease
Surveillance
strategies
Risk
stratification
Effective tx in
adjuvant setting
Effective tx in
metastatic setting
Risk
factors
Critical Gaps in the Uveal Melanoma Field
Research key to improving care- trials and observational studies both important
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02 2390 3896
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