Martina Angi, MD PhD Ocular Oncologist · Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma Cancer Cell Volume 32, Issue 2, 2017, 204–220.e15

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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[email protected]

02 2390 3896


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Documents

Martina Angi, MD PhD Ocular Oncologist · Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma Cancer Cell Volume 32, Issue 2, 2017, 204–220.e15