Winship Cancer Institute of Emory University

Uveal Melanoma

Melinda L. Yushak, MD MPH

Winship Cancer Institute

Emory University

Outline

• Background

• Surveillance

• Treatment of Metastatic Disease

– Liver Directed Therapies

– Targeted Therapies

– Immunotherapy

Uveal Melanoma

• 5% of all melanomas

• 2000 new cases/year in the US

• Caucasian

• Mostly sporadic cases

– BAP1 familial cancer syndrome in 2-3% of cases

Biologically Different Disease

• No basement membrane exists in the eye

• No lymphatic regional spread

• Genetic Driver Mutations

– Rare BRAF

– GNAQ/GNA11 common

Pigment Cell & Melanoma Research1 SEP 2014 DOI: 10.1111/pcmr.12304http://onlinelibrary.wiley.com/doi/10.1111/pcmr.12304/full#pcmr12304-fig-0001

Biology of Uveal Melanoma

• GNAQ and GNA11 mutations are common and lead to constitutive activation

Characteristics of Uveal Melanoma

• Collaborative Ocular Melanoma Study– 5 and 10 year cumulative metastasis rates of 25

and 34%

– Median time from diagnosis of metastasis to death 6 months

– Metastases at death• Liver 91%

• Lung 21%

• Bone 18%

• Skin 12%

• Lymph nodes 11%

Surveillance

• No prospective randomized trials of routine surveillance

• Controversy regarding best surveillance options

– Benefit of detection of oligometastatic disease

– False positives, cost of screening

Surveillance

Surveillance Options for Patients with Uveal Melanoma Following Definitive Management. ASCO Education Book 2013.

Surveillance

• Individualized to patient

• Higher risk patients imaging every 3-6 months

• Lower risk patients every 6-12 months

Treatment of Metastatic Disease

Liver Directed Therapies

• Local therapies to the liver

– Surgery

– Selective Internal Radiation Therapy (SIRT)

– Transarterial Chemoembolization (TACE)

– Hepatic Artery Infusion

• Isolated Hepatic Perfusion (IHP)

• Percutaneous Hepatic Perfusion (PHP)

Surgery

• Salmon, et al. Oncology 2009– 798 patients, 228 deemed

resectable

– Only 29% underwent R0 resections

– Median OS 12 months

• Positive predictors – Greater than 5 years from

primary diagnosis

– R0 resection

Selective Internal Radiation Therapy

• Microbrachytherapy technique using yttrium-90 embedded microspheres

• Northwestern Series (Memon, et al. Melanoma Research

2014)

– 16 patients with hepatic mets (7 ocular)

– Ocular patients the h-PFS 4.2 months with OS 5.9 months

Transarterial Chemoembolization

• Various chemotherapies used (cisplatin, BCNU, fotmustine, etc)

• Schuster, et al. Melanoma Res 2010– 25 patients: 14 SD, 4 PR– Median PFS 3 months, OS 6 months

• Patel, et al. Melanoma Res 2005– 24 evaluable pts: 1 CR, 4 PR, 13 SD;

median OS 5.2 months

Immunoembolization (GM-CSF)• Sato, et al. JCO 2008

– 34 uveal melanoma patients: 2 CR, 8 PR, 10 SD

– Median OS 14.4 months

Chemo Filtration Circuit Chemo Isolation & Delivery Circuit

Percutaneous Hepatic Perfusion

PHP – 245 daysBAC – 49 daysp<0.0001HR=0.30

Hepatic Progression Free Survival

PHP – 186 daysBAC – 46 daysp<0.0001HR=0.404

Overall Progression Free Survival

Overall Survival

• No improvement in overall survival

• Phase III study upcoming

– Delcath

Pigment Cell & Melanoma Research1 SEP 2014 DOI: 10.1111/pcmr.12304http://onlinelibrary.wiley.com/doi/10.1111/pcmr.12304/full#pcmr12304-fig-0001

Targeted Therapy

• GNAQ and GNA11 mutations are common and lead to constitutive activation

PFS Selumetinib vs Chemotherapy• All patients ( 49 chemo vs 42 selumetinib)

• Median PFS 7 weeks vs 15.9 weeks (HR 0.46)

• RR to selumetinib 14% with 49% of patients experiencing any degree of tumor regression (0 RR of chemotherapy)

JAMA. 2014;311(23):2397-2405.

• Phase III trial of selumetinib vs chemotherapy

• Clinical trial on-going with trametinib + AKT inhibitor

Immunotherapy• Ipilimumab

• Anti-PD1

Drake CG, Lipson EJ, Brahmer JR. Nat Rev Clin Oncol. 2014;11(1):24-37.

Ipilimumab

• Maio, et al. Ann Oncol 2013– 82 advanced uveal patients with IPI 3 mg/kg x 4

• 5% objective response rate

• 29% stable disease

• 3.6 median PFS, 1-year OS 31%

• Luke, et al. Cancer 2012– 39 patients with uveal melanoma ( 34 with

3mg/kg and 5 treated with 10mg/kg of IPI)• 2.6% objective response rate

• 25.6% stable disease

• Median OS 9.6 months

Pembrolizumab

• 10 Patients

• Progression on ipilimumab

• PFS 18 weeks

• 1 CR, 2 PR, 1 SD, and 4 rapidly progressive disease

Melanoma Res. 2016 Feb 4. [Epub ahead of print]

Conclusions

• Uveal melanoma is biologically and clinically different from cutaneous melanoma

• Metastatic uveal melanoma remains a clinical challenge

– Importance of clinical trials

Thank you

• Ragi Kudchadkar, MD

• David Lawson, MD

• Melanoma Team

Contact Information

Melinda.l.yushak@emory.edu