MPNErare2017 session3 ocular melanoma by MPNE

MPNErare2017 Session 3 Ocular Melanoma 7th October 2017 Leiden

Systemic treatment of metastasized uveal melanoma Ellen Kapiteijn, medical oncologist, LUMC 7 oktober 2017

Disclosures Advisory boards Roche, BMS, MSD, Novartis, SIRTEX, Delcath

Background UM

• Low incidence (0.6-0.7 pts/100.000/yr) • Primary treatment aims for curation: radiotherapy (ruthenium), proton beam irradiation or enucleation • Difference with skin melanoma with regard to molecular biology: GNA11 or GNAQ mutations (approx. 90% in metastasized setting), no braf mutations, low mutational load, low PDL1-expression

Background UM

• Metastases: < 5 yr: 30% of the pts < 15 jr: 50% of the pts • Metastases mostly to liver (up to 90% of the pts), lungs (30%), bone (23%) and skin (17%) • Limited prognosis in case of metastatic disease • 1980-2008: 28 phase I-II studies with systemic therapy (mostly chemotherapy): no survival benefit

Metastasized UM

Immunotherapy

Anti-CTLA4 in metastatic UM

Author

Site(s)

Response

3 mnth DCR*

PFS (mnths)

OS (mnths)

Kelderman ‘13

Neth

1/14 (7%)

2/14 (14%)

2.9

5.2

Luke ‘13

2/39 (5%)

18/39 (46%)

NR**

9.6

Maio ‘13

Italy

4/83 (5%)

29/83 (35%)

3.6

6.0

Piulats ‘14

Spain

2/25 (8%)

NR**

9.8

Zimmer ‘15

Germany 53

0/34 (0%)

16/34 (47%)

2.8

6.8

9/195 (5%)

65/170 (38%)

229 *DCR: disease control rate **NR: not reported

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Anti-PD1 or anti-PDL1 in metastatic UM Author

Agent

Site(s)

Prior Ipi

Responses

PFS (mnths)

OS (mnths)

Algazi

Pembro, Nivo, Atezo

US, Spain

36 (62%)

2.8

6.8

Karydis

Pembro

25 (100%)

3.0

Not reached

PipernoNeumann

Pembro, Nivo

Paris

NR*

2.6

NR*

Kottschade

Pembro

Mayo

10 (100%)

30%

4.1

NR*

Vd Kooij

Pembro, Nivo

Neth

NR*

2.3

9.6

131

8/131 (6%)

*NR: not reported

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Conclusions checkpoint-inhibitors in metastatic UM

•

International case-series: CTLA4, PD-1 and PD-L1 antibodies rarely confer durable remissions in patients with metastatic uveal melanoma. Due to low mutational load and/or less PDL1-expression?

•

Several studies ongoing

•

New clinical trials are necessary: combination-therapies?

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IMCgp100 Shoustari et al SMR, nov 2016 A Phase I study of IMCgp100, a soluble HLA-A2 restricted gp100-specific T cell receptor-CD3 therapeutic with solid tumour activity in pts with advanced uveal melanoma • 15 pts were reported • Durable objective responses were observed: disease control rate was 53% at 16 wks, and 40% at 24 wks. A Phase II Randomized, Open-label, Multi-center Study of the Safety and Efficacy of IMCgp100 Compared with Investigator’s Choice in HLA-A*0201 Positive Patients with Previously Untreated Advanced Uveal Melanoma will start Q4 2017 / Q1 2018

TIL-therapy in uveal melanoma. Chandran et al, Lancet Oncology 2017

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Metastatic UM

Targeted therapy

AEB071- study (PKC-inh), Piperno-Neumann et al, ASCO â&#x20AC;&#x2DC;14 COEB071X2102 - AS CO P os ter - Cut-off date: 07AP R2014 Figure 14.2-1.3 (P age 1 of 1)

Figure. Best percentage change from in sum of longest diameters Bes t % change from bas eline baseline in s um of longes t diameters for all patients Full analys is s et of target lesions for all patients (N=118/141; full analysis set) n/N (%) = 118/141 (83.69%) 100

Bes t %change from bas eline

80 60 40 20 0 -20 -40

* * **** ** *

* *** ***** ******** ******** * * * *** *** ******** ****** ** *** *

* ****** ******* * **** * * * *

-60 -80 -100

*Progression-free survival event. n: number of subjects with a baseline and at least one post-baseline assessment of target lesions based on local investigator assessment.

Phase I study with AEB071 (PKC-inh) + MEK162

Study preliminary closed due to too much toxicity

Phase II trial selumetinib (MEK-inhibitor)

Phase III trial selumetinib (MEK-inhibitor)

LXS196 (PKC-inhibitor) A Phase I/II, multi-center, open-label, study of LXS196, an oral protein kinase C inhibitor in patients with metastatic uveal melanoma: 4 centers worldwide, Jan 2016 â&#x20AC;&#x201C; Sept 2017, 67 pts included. Results will be presented at SMR 2017.

New combination study LXS196 (PKC-inh) + HDM-201 (MDM2-inh) A Phase I/II, multi-center, open-label, study of LXS196 and HDM-201 in patients with metastatic uveal melanoma: 5 centers worldwide, start Q4 2017 / Q1 2018.

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Ongoing trials in metastatic UM Mechanism

Agent

Phase

Sponsor / Lead center

Clinicaltrials.gov ID

Checkpoint blockade

Ipilimumab/ Nivolumab

MDACC

NCT01585194

Pembrolizumab + Entinostat

Vastra Gotaland Region, Sweden

NCT02697630

Ipilimumab / Nivolumab + radioembolization

CPMC

NCT02913417

TILs

Cellular Adoptive Immunotherapy + ipilimumab

MDACC

NCT03068624

T cell redirection

IMCgp100

Immunocore

NCT03070392

T-cell receptor

T-cel Receptor Gene Therapy

I/IIa

AvL

NCT02654821

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Ongoing trials in metastatic UM Mechanism

Agent

Phase

Sponsor/Lead center

MEK-inhibitor

Intermittent selumetinib

Columbia, several NCT02768766 other US centers

PKC-inhibitor

AEB071+BYL71 9

Columbia, several NCT02273219 other US centers

CSF-1R, Kit and Flt3 PLX2853 inhibitor

Ib/IIa (incl. other tumor types)

HHS, Arizona

NCT03297424

PEGylated arginine ADI-PEG 20 deiminase

I (incl. other tumor types)

CECM, London

NCT02029690

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Clinicaltrials.gov ID

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Conclusions •

No proven effective systemic treatment options yet in metastatic UM

•

Increased insight in the molecular biology of uveal melanoma has led to studies with specific targeted agents (PKC- and MEK-inhibitors), also studies with immunotherapy ongoing (checkpoint-inhibitors, TILtherapy, IMCgp100)

•

New (combination)-studies are very important for the development of effective treatment options

Thank you for your attention!

For contact: h.w.kapiteijn@lumc.nl

Genetic testing for uveal melanoma Helen Kalirai

Senior Research Fellow Dept. of Molecular and Clinical Cancer Medicine; University of Liverpool, UK

www.loorg.org

Chromosome 3 loss in uveal melanoma

Prescher G, Bornfeld N, Hirche H, Horsthemke B, Jockel KH, Becher R

Cancer 1998;83:354â&#x20AC;&#x201C;9

Identification of chromosome aberrations in UM

Genetic testing of UM samples Cytospin

Damato B, Groenewald C Vitreo-retinal surgery (2007)

MSA*

MLPA*

MelanA

Low risk

Choroidal melanoma Requires 10ng DNA

Choroidal melanoma Requires ≥ 100ng DNA

* MLPA kit for UM - DEKRA Certified to ISO 13485 standard; under the ‘In Vitro Diagnostic Medical Devices directive’ (98/79/EC) permitted for clinical use ** CPA-Accredited molecular pathology laboratory; internal and external quality assessment

High risk

Genetic testing of UM samples Cytospin

Damato B, Groenewald C Vitreo-retinal surgery (2007)

MLPA* Low risk

Choroidal melanoma

Post-PBR TX * MLPA kit for UM - DEKRA Certified to ISO 13485 standard; under the â&#x20AC;&#x2DC;In Vitro Diagnostic Medical Devices directiveâ&#x20AC;&#x2122; (98/79/EC) permitted for clinical use ** CPA-Accredited molecular pathology laboratory; internal and external quality assessment

High risk

Are FNAB representative of the whole UM?

Damato B, Groenewald C Vitreo-retinal surgery (2007)

Prognostication in UM

Parameters

Clinical

Age Gender Tumour Size Location Extraocular melanoma

Histomorphological Cell type Mitotic count Closed loops ‘Inflammation’ EOM

Genetic Chr. 3 loss Chr. 8 gain Chr. 6 gain

Date:

Prognostication model - LUMPO Patient's Name:

Hospital Number:

Apical part

Practitioner's Name:

Clinical

Position:

years

www.ocularmelanomaonline.org

Age

Sex

Male

Epithelioid cells

Large ultrasound diameter

15.1-18.0

Mitotic rate /40

Ultrasound thickness

9.1-12.0

Monosomy 3

Yes

Ciliary body involvement*

Regional lymph nodes

Extraocular extension*

Distant metastasis

N/A

Years since treatment

0-1

First scan

0.5

Threshold for next scan

N/A

Closed PAS +ve loops

years

Histopathological N/A

Cytogenetic N/A

years

Accelerated Failure Time

Resetfeatures need to be taken All into account

Kaplan-Meier

Melanoma Patients

Evaluate

General Population

Impact Genetics 1100 Bennett Road â&#x20AC;&#x201C; Unit 4 Bowmanville, ON L1C 3K5 CANADA

Chromosome 8q gains are also associated with a poor prognosis

LUMPO III

Genetic testing in UM: other techniques Gene expression profiling

Tschentscher F et al. 2003

Onken et al, 2007

Incorporation of PRAME into GEP of UM. Matthew G. Field et al. Clin Cancer Res 2016;22:1234-1242

Mutation profiling â&#x20AC;&#x201C; refining uveal melanoma classification for prognosis and therapy

GNAQ/GNA11 activating mutations • Mutually exclusive mutations found in approx. 84% of UM. • Early events associated with UM development. • Clinical utility: Ø Differential diagnosis Ø Targeted therapy

GNA11 c.626A>T (Q209L) mutation in a UM specimen

BAP1 inactivating mutations • BAP1 (Chr.3p21) inactivating mutations are found in ~85% metastasising UM • Mutations associated with reduced disease free survival • Clinical utility: Ø Prognosis Ø Targeted therapy

Monosomy 3/nBAP1+ve UM represent a subset with better prognosis

SF3B1 mutations • SF3B1 mutations found mainly in D3 tumours. Associated with a late metastatic onset

EIF1AX mutations • EIF1AX mutations are associated with a good prognosis

• Mutations found in 9 -19% of all UM

• Mutations in EIF1AX reported in 19 – 24% of all UM

• Clinical utility: Ø Prognosis Ø Targeted therapy

Other developments in UM genetics

Subgrouping of UM according to chromosomal alterations 80 primary UM samples

4 subgroups (Clusters): 1. Disomy 3, partial or total 6p gain 2. Disomy 3, 6p gain, partial 8q gains 3. Monosomy 3, 8q gain (median 1 extra copy) 4. Monosomy 3, 8q gain (median 3 extra copies; commonly 8q isochromosome) Caines R, Eleuteri A, Kalirai H, Fisher A, Heimann H, Damato B, Coupland SE and Taktak A. Cluster analysis of Multiplex Ligation-dependent Probe Amplification (MLPA) data in uveal melanoma: review of 602 cases. Molecular Vision, 2015; 21:1-11

Nine* significantly mutated genes in UM

*PLCB4

Subgrouping of UM according to chromosomal alterations

EIFAX1 mutations

BAP1 mutations

Four transcription-based UM subgroups RNA sequencing revealed the expression of 20,531 mRNAs and processed transcripts, identified 4 consensus subgroups for mRNA

Class1B

Correlation of biological UM subsets with clinical prognosis CNA

GEP

Characteristics of Immune-Infiltrated UM

WP4: Increased understanding of molecular Characterisation changes in metastatic UM and generation of UM metastases of new target hypotheses for WP2 WP4: Increased understanding of molecular Characterisation changes in metastatic UM and generation of UM metastases of new target hypotheses for WP2

Decipher the: Decipher the: • genetic alterations • genetic alterations

• dysregulated signalling pathways

• dysregulated signalling pathways • characteristics of the UM immune landscape

• characteristics of the UM immune landscape

Thank you for your attention

Dawn

h.kalirai@liverpool.ac.uk

Dusk

Why is prognostication important in UM? Management of primary UM

Surveillance Detection of Metastases Contrast MRI CT body Biopsy Tumour board Laparoscopy

R0 resection

Operable

•

• • •

Identify “high risk” patients for more frequent and intense screening (MRI) of liver Surgical removal of isolated metastases Involvement in clinical trials Patient demand

Inoperable Chemo

Surgery

Locoregional therapy

Systemic therapy

Targeted Immune

MPNErare2017 LIVER DIRECTED THERAPY IN UVEAL MELANOMATHE SOUTHAMPTON EXPERIENCE DR IOANNIS KARYDIS ASSOCIATE PROFESSOR IN MEDICAL ONCOLOGY UNIVERSITY OF SOUTHAMPTON AND SOUTHAMPTON UNIVERSITY HOSPITAL

UVEAL MELANOMA – BACKGROUND • Incidence 2-8/million in Europe • 400-450 new cases / year in UK

• 50% will develop metastatic disease within 15 years • Historic data: • Median expected survival 4-6 months • At 1 year post diagnosis of metastasis only 10-15% still alive without treatment

UVEAL MELANOMA – AN ORPHAN DISEASE • No effective molecular targeted treatments available • Chemo-resistant (ORR<10 % even with combination regimes) • Immunotherapies unproven

LIVER DIRECTED THERAPIES

WHY? • 85-95% will develop liver metastases • In >~ 50% liver is the only site of metastatic disease

• Less than 5-10% qualify for surgical resection • Imaging often underestimates extent of disease

• Uncontrolled liver disease often behaves aggressively • Immunotherapeutics less likely to work

OPTIONS? • Ablation modalities (MW/LITT/RFA/Cryo) • Comparable to surgery (~3y OS)

• Chemo- / Immuno- / Radioembolisation • RR <~20% , OS 9-20m

• Hepatic Chemoperfusion

UVEAL MELANOMA IN SOUTHAMPTON • 30-40 high risk UM patients a year referred for follow-up post treatment of primary tumour • Direct referrals from UK and abroad for management of metastatic disease • Ocular Melanoma Multidisciplinary team • Interventional radiologists • Medical Oncologists • Hepatobiliary Surgeons • Perfusionists Anaesthetists • Nurse Specialists

INTEGRATING LIVER DIRECTED AND SYSTEMIC MANAGEMENT Early diagnosis of metastatic disease Liver directed management Systemic treatment

• Serial imaging • 6 - monthly liver MRI

• Surgery • Melphalan PHP / TACE • SIRTS • Ipilimumab • Anti PD-1 agents • Clinical Trials

PERCUTANEOUS HEPATIC PERFUSION (“PHP”) Chemofiltration circuit

Hepatic vein & IVC Isolation

Hepatic Artery cannulation

WORK-UP FOR MELPHALAN PHP Accurate Staging Clinical Assessment Management plan

MRI liver, body CT Liver angio

Staging laparoscopy

CPET testing

Oncology & Anaesthetic Review

OM MDT

Final consultation with patient

THE SOUTHAMPTON EXPERIENCE • 25 patients received 43 cycles (median 2, range 1-4) • 2 treatments abandoned on day of procedure due to unsuitable anatomy on angiography

• Median length of stay: 4 days • range 3-8, though only 3 episodes were longer than 5 days

HEPATIC RESPONSE ASSESSMENT • Best hepatic response (by liver MRI): • Overall Response Rate (CR+PR):

37 %

• Disease control rate (CR+PR+SD):

83 %

• Median liver Progression Free Survival : 242 days Best liver Response

N (%)

Complete Response

1 (4%)

Partial Response

8 (33%)

Stable Disease >3 months

11 (46%)

Progressive Disease

4 (17%)

OUTCOMES • Median Survival : 511 days (17 months) • 12/25 patients still alive after a median of 315 days (~10.5 months) • 1 year survival rate ~ 65%

• Progression Free Survival • Median overall PFS ~ 182 days (~6 mo) • Median liver PFS ~ 242 days (~8 mo) • In 9/21 (~42%) cases systemic progression preceded liver progression.

COMPARATOR: PHASE III TRIAL

• Hepatic median PFS: 242 vs 245 days • Overall median PFS:

182 vs 186 days

• Median OS:

511 vs 301 days

From: Hughes et al, Ann Surg Onc Apr 2016, Vol 23, Issue 4, pp 1309–1319 “Results of a Randomized Controlled Multicenter Phase III Trial of Percutaneous Hepatic Perfusion Compared with Best Available Care for Patients with Melanoma Liver Metastases”

WHAT ABOUT SIDE EFFECTS? Adverse Events

UHS

Phase III trial

G3-4 Neutropenia

7/25 (28%)

60/70 (86%)

Febrile neutropenia

2/25 (8%)

12/70 (17%)

G3-4 Anaemia

10/25 (40%)

44/70 (63%)

G3-4 Thrombocytopenia

7/25 (28%)

56/80 (80%)

Cardiac arrhythmias

2/25 (8%)

4/70 (6%)

Troponin rise

1/25 (4%)

6/70 (9%)

SEVERE NON-HAEMATOLOGICAL TOXICITIES • No treatment related fatalities • Immediate toxicities: • Cardiovascular : 3/25 •

1 case of pulmonary oedema

•

2 cases of cardiac arrhythmias

• Vascular access complication : 2/25 •

1 case of intraabdominal haemorrhage

•

1 case of IVC thrombus (with subsequent PE)

• Late toxicities • Thromboembolic (4/25) •

•

3 cases of PE, 1 DVT diagnosed within 3 months of procedure

1 case of G3 fatigue

NON-HAEMATOLOGICAL MILDMODERATE TOXICITIES • Mild abnormalities in liver function tests • common (32%) but resolve rapidly

• Other notable mild toxicities include: • Nausea / Vomiting ( 12% & 8% respectively) • Epigastric discomfort (12%) • Constipation (8%) • Mucositis/ Alopecia (4%)

HAEMATOLOGICAL TOXICITIES • Immediate haematological toxicities common but easily manageable: Grade

Anaemia

4 (16%)

10 (40%)

Thrombocytopenia

5 (20%)

11 (44%)

3 (12%)

4 (16%)

Neutropenia

1(4%)

2 (8%)

5 (20%)

• 2 episodes of neutropenic sepsis were documented • Platelet and blood transfusions were needed in 19 (76%) and 13 (52%) respectively, typically in the peri/immediate post-procedure setting • There was 1 case of systemic coagulopathy (DIC) requiring extensive coagulation factor support

PROS/CONS OF M-PHP • PROS: • High hepatic disease control rates • Generally well tolerated in appropriately selected patients

• CONS • Risk of potentially life threatening complications • Technically demanding & expensive

BIG ISSUE • Lack of concrete evidence of survival benefit/ superiority versus alternatives

FOCUS TRIAL – WHY? • Phase 3 trial allowed crossover • -> survival benefit diluted, not statistically significant • In the absence of evidence from randomised clinical trials NHS funding extremely unlikely

• Since then – technique has improved • New Immunotherapies have also arrived! • <-> less effective in patients with uncontrolled liver disease

* Is M-PHP superior to current alternatives? *

• Randomised: • Melphalan PHP vs alternative Standard of Care (TACE/immunotherapy/chemotherapy)

• Inclusion criteria • Histologically proven & measurable liver metastatic disease • No previous intra-arterial hepatic therapy • No contraindication to Melphalan PHP

MELPHALAN CHEMOPERFUSION A TECHNIQUE AT CROSSROADS • Appropriate patient selection and optimised perioperative management have resulted in improved side-effect profile • Role in a rapidly developing field of multiple –potentially complementary – treatment approaches remains to be determined

SOUTHAMPTON PHP EXPERIENCE SUMMARY • Melphalan PHP can be delivered safely by an experienced multidisciplinary team in the UHS • Can provide significant benefits in a carefully selected group of patients as part of a multidisciplinary approach • Further research is needed to establish its place in the context of new systemic and especially immunotherapeutic treatment Randomised Phase III study now open for recruitment!

Current Position for OM patients in Scotland • Single Specialist Centre based at Gartnavel Hospital, Glasgow • Detached from other specialist centres in the UK • Only offered US as routine follow up/surveillance • GPs have little or no knowledge of OM to support patients with disease or challenge the position on surveillance

PETITION TO SCOTTISH PARLIAMENT • To provide OM patients in Scotland with best surveillance Options • Ensure enhanced Abdominal MRI with contrast are offered as standard for early detection of liver metastases • Ensure consistency across all NHS Regions • Allow Scottish patients the opportunity to become their own advocates and change the current position WHY are patients in Scotland being denied the option of MRI?

Prevalence â&#x20AC;&#x201C; Numbers of registrations for melanomas of the uveal tract and other sites within the eye for all ages/persons, Scotland 2010-2014 â&#x20AC;&#x201C; Source: Scottish Cancer Registry ISD Data extracted Dec 2016 Year

Uveal Tract

Other sites within the eye

2010

2011

2012

2013

2014

According to National Services Scotland, Glasgow see 35-40 patients per year with the remainder being seen by centres in England

Scottish Government Action BEATING CANCER – Ambition & Action –

strategy dedicated to improving Cancer Services across Scotland

EYE CANCER does not appear in this strategy document

Specialist Cancer Organisations submissions Cancer Research UK “Having consulted extensively within the charity – including with our Health Information, Public & Patient Involvement and Policy teams – we regret to inform that Cancer Research UK does not have an existing view on this specific issue, and is therefore unable to advise on the potential clinical implications of these tests being used on Ocular Melanoma sufferers in Scotland.”

MacMillan Cancer Support Scotland “Following discussion with various MacMillan colleagues we are at the moment not able to take a firm position on this issue – but would welcome the committee looking into gaining further evidence around how best to take forward better detection and treatment for people with Ocular Melanoma.”

Royal College of Ophthalmologist's â&#x20AC;&#x153;There is not enough evidence to suggest that if liver US is competently performed, 6 monthly MRI of the liver with contrast is indicated. In England, US is still the accepted mode of surveillance. MRI should however be used for high risk cases or when US detects an abnormality. There is national guidance from experts1 in the field and the college supports the view taken by Ocular Oncologists in the publication referenced until new evidence-base suggests a change is needed.â&#x20AC;? 1 - Reference: uveal Melanoma UK National Guidelines, European Journal of Cancer (2015) 51, 2404-2412

OcuMel UK – support our petition

• Some patients are informed of Risk others are not! • High Risk and “Not knowing” both cause anxiety. OM patients mental health is affected • Anxiety also stems from not trusting US • Low risk does not mean “No Risk therefore all should receive MRI

US vs MRI • English Uveal Melanoma Guidelines (2015) are accredited by NICE – guideline development group follow these guidelines, made recommendations and used expert opinion. Agreed on contrast enhanced MRI of liver with diffusion weight imaging • MRI has made it possible to evaluate treatments for metastases at earlier stages of disease

Southampton quotes • MRI gives images which one can go back to and review – much more difficult with US which is also very operator dependent • MRI is now high quality and contrast improves this looking at changes in behaviour and how the contrast medium behaves • Some areas of the liver are hard to image on US – depth of vision; overlay of lung tissue; size of patient. Some groups of patients can be assessed by a skilled US operator. In US you can only document what you can see NOT what you cannot see • If we go for interval scanning we should be using the best available test

• Cost • Clinic time • Travel distance or time for patient • Country of Residence

None of the above should discriminate against having MRI scanning

Scottish Ocular Oncology Centre Offers only US annually or 6 monthly States – Approach consistent with guidelines – very little evidence on which to base decisions on either frequency or duration of follow up – due to the lack evidence (linked to the rarity of OM) variation exists amongst 4 UK centres which is the appropriate surveillance to use! They state 2-3 other centres offer only US Follow NICE guidelines with a review due in 2019

Scottish Government state • Limited hospitals in England offer MRI • Commissioning for Quality and Innovation (CQUIN) group will set up a group to improve consistency in hospitals across the UK. Will share expertise to develop a UK wide guidance/recommendations for surveillance of OM patients. • There is insufficient evidence to change surveillance protocol from US to MRI • Scottish Ocular Oncology Service will undertake a study of metastatic patients to ascertain whether a delay in diagnosis was incurred due to use of US. This study will take some time due to the small number of patients in Scotland