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

Follow Up

recurrence

Late presentation

General Oncology

Skin melanoma protocols

Paucity of research

Initial Specialist CareDevolved Follow

up&

Late Relapse

Devolved Follow up&

Late Relapse

UK Uveal Melanoma Pathway

? Screening

LOORG

DecisionDx-UM gene expression profile test.

LUMPO

Ocularmelanomaonline.com

Is screening for metastases worthwhile?

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

For•Improved outcomes with early detection disease?

•Promotes standardised care and facilitate research in rare cancer setting

•Patient enthusiasm

Requires definitive randomised trial

Modality?Frequency?Endpoints?

High risk ocular melanoma: A prospective phase II study of liver MRI screening (Marshall et al, ASCO Proc 2012)

Total referred 279

Total screened 188

Male/Female 84/104

Median age 63 years (24-83)

Enucleation 149

Median Basal Diameter

16.5mm (1.5-23.6)

Monosomy 3 175

•Disease free survival is 33 months (95% CI 28-38)•92% asymptomatic•13% operable

•median survival for RO resection: 24 months (20.2-27) vs 10months (8.1-11.9) .

METHODSA single centre prospective cohort studyScreening consisted of 6 monthly:•Clinical examination, •Liver function tests including LDH and •non-contrast liver MRI•Serum Biomarker collection

Metastatic relapse

90

Inoperable on MRI

52

Potentially operable on MRI (≤ 4 metastases)

38

Inoperable on laparoscopy

25

R0 liver resection

12 (+1 RFA)

What is the role of Liver Resection in Uveal Melanoma?

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)

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)

Liverpool: 12/90ts R0 resection 24/10months

Response to Systemic TherapyAuthor 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 2%(1/48)

2-3 mo PFS

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

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

Multicentreseries

II 101 IA Fotemustine 36 15

MD Anderson

II 30 CE with Cisplatin 48 11

Berlin II 25 TACE with FotemustineOr 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

commonNo Effect on survival? Effect on quality of

life

Higher response rateCatheter

complications common

No Effect on survival? Effect on quality of

life

Major signaling pathways in uveal melanoma.

Patel M et al. Clin Cancer Res 2011;17:2087-2100

©2011 by American Association for Cancer Research

MAPkinase activation

Activating mutations in GNA11/GNAq

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 Phase II Imatinib (ITEM) CCC (UK)Somatostatin

Receptor/mTOR 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

Targets & Ongoing Trials for Uveal Melanoma

Endpoints2 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

ITEMA 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)

Liverpool

CRUK Centre

• recruit,ment

• Largest study

• Number of centres

Liverpool Manchester Sheffield Birmingham Leicester Cardiff

Mount Vernon Marsden

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 Post Pre Post Pre Post Pre Post Pre Post

pERK

ERK

CyclinD1

Tubulin

Response PR PR SD x 7 mos

POD POD

Adjuvant strategy remains hindered due to lack of a lead compound with sufficient activity

Adjuvant strategy remains hindered due to lack of a lead compound with sufficient activity

Adjuvant Therapy in High Risk Uveal Melanoma?

Rationale

Well defined high risk population with median PFS 3years

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

Bakalian S et al. Clin Cancer Res 2008;14:951-956

©2008 by American Association for Cancer Research

Inhibition of Migration by SU11274

BAP-1

HDAC

‘DRUG MAY SLOW SPREAD OF DEADLY CANCER’

?

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!

•NHS/Liverpool University

•Clatterbridge Cancer Centre

•LOOG

•& LOORG

Paul Nathan

ITEM & SUAVE

Investigators

Liverpool Clinical Trials Unit

•NCRI Melanoma CSG•NCRN •CRUK•Industry Partners•IRCI

•All patients and carers who continue to support essential research