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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