This document summarizes key information about the diagnosis and management of metastatic ocular melanoma. It discusses imaging and biopsy techniques used to detect metastasis, as well as liver-directed therapies like surgery, radioactive beads, and ablation. Systemic therapies covered include chemotherapy, immunotherapy like checkpoint inhibitors, and targeted therapies. Emerging treatments mentioned are IMCgp100 immunotherapy, hepatic perfusion chemotherapy, tumor infiltrating lymphocytes, and novel targeted therapies or combinations currently in clinical trials.

1. Diagnosis and Management of
Metastatic Ocular Melanoma
Matthew Rioth MD, MS
Assistant Professor of Medicine
Division of Biomedical Informatics and Personalized Medicine
Division of Medical Oncology
Director of Clinical Cancer Informatics, UCHealth
Colorado School of Public Health Department of Biostatistics and Informatics
November 29, 2017

2. Disclosures
• I have no
relevant
disclosures

3. Outline
• Definitions
• Imaging and biopsy
• Liver-directed therapy
• Systemic therapies
• Future directions

4. What is metastasis?
• The spread of cancer cells
from the place where they first
formed to another part of the
body.
• AKA “Stage four” cancer
• Where? When? How?

5. All those scans…
• Regular imaging and evaluation to detect early metastasis
• Imaging liver and lung (and as directed by symptoms)
• Options
• Ultrasound
• Computerized Tomography (CAT or CT)
• MRI
• Biopsy for confirmation

6. Ocular Melanoma vs Skin Melanoma
Ocular
• No BRAF mutation
• Low mutational burden
• Common liver metastases
• No brain metastases
• Common GNAQ/GNA11
mutation
Skin
• Common BRAF mutation
• High mutational burden
• Occasional liver metastases
• Common brain metastases
• Rare GNAQ/GNA11 mutation

7. Treating the Liver
• Dr. Eschelman is talking about this in greater depth tomorrow
• Several options for treating liver-only tumors
• Surgery
• Radioactive beads
• Ablation
• Chemotherapy perfusion

8. Systemic Therapies
• Chemotherapy
• Immunotherapy
• Targeted therapy
• Clinical trials

9. What is “Chemotherapy”
• Drugs that inhibit or kill dividing cells
• Cancer cells divide frequently, but so
do others
• This “off target” effect of
chemotherapy causes side effects
• Very narrow window to try to inhibit
cancer cells without normal cells
Sydney Farber, first
demonstrated
chemotherapy useful in
pediatric leukemia in 1948.
Image: Wikipedia

10. Cytotoxic chemotherapy in OM
• Many different regimens of chemotherapy have been tested in
metastatic ocular melanoma.
• Commonly drugs such as dacarbazine are used in this context,
but have underwhelming effectiveness.
• In a review of multiple studies using chemotherapy, tumors took
on average 2.6 months to start growing on chemotherapy. (JCO 34,
no. 15_suppl (May 20 2016) 9567-9567)
• Newer approaches are more frequently used now

11. What is Immunotherapy?
• In addition to fighting bacteria
and viruses, the immune system
can also destroy cancer cells.
• This probably happens more
than we know, because the cells
are destroyed before we ever
detect them
• In order to grow big, tumors
must avoid being destroyed by
the immune system.

12. xkcd.com/1907

13. Immunotherapy – Checkpoint Inhibitors
Ipilimumab Pembrolizumab
Nivolumab
Atezolizumab
JAMA. 2015;314(20):2117-2119

14. Checkpoint inhibitors in OM
PLoS One. 2015; 10(3): e0118564.
Cancer. 2016 Nov 15; 122(21): 3344–3353.
J Immunother Cancer. 2018; 6: 13.
Anti CTLA-4 (Ipilimumab) Anti PD-1 (Keytruda)
Exceptional responders

15. What is targeted therapy?
• Cancers are characterized
by mutations (changes) in
their DNA that give rise to
cells that grow too much
and/or die not enough.
• Those mutations in the DNA
can leave a tumor cell
susceptible to drugs
designed to inhibit those
mutations.

16. Targeted Therapy Successes
Blood. 2012 Mar 1; 119(9): 1981–1987.
The Lancet Oncology 2014 15, 954-965
Gleevec in chronic myelogenous leukemia BRAF inhibitors in cutaneous melanoma

17. Genetics of Ocular Melanoma
Br J Ophthalmol. 2017 Jan; 101(1): 38–44.

18. MEK inhibition in OM
JAMA. 2014 Jun 18; 311(23): 2397–2405.
Phase III SUMIT Trial:
- No difference in tumor growth between selemetinib +
chemotherapy versus selemetinib + placebo

19. Targeted therapies of the future
Therapy Mechanism of action Phase Identifier Trial status
Selumetinib+paclitaxel MEK1/2
inhibitor+chemotherapy
II EudraCT: 2014-004437-22 Recruiting
Trametinib+GSK21417
95
MEK inhibitor+AKT inhibitor II NCT01979523 Recruiting
Binimetinib+AEB071 MEK inhibitor+PKC inhibitor I/II NCT01801358 Recruitment held
Cabozantinib MET inhibitor II NCT01835145 Recruiting
Vorinostat Histone deacetylase inhibitor II NCT01587352 Recruiting
Sorafenib Multi-kinase inhibitor II NCT01377025 Recruitment complete
Ganetespib HSP90 inhibitor II NCT01200238 Recruitment held
Adoptive T-cell
transfer
Tumour-infiltrating
lymphocytes
II NCT01814046 Recruiting
AEB071+BYL719 PKC inhibitor+PI3K inhibitor Ib NCT02273219 Recruiting
AEB071 PKC inhibitor I NCT01430416 Recruitment complete
Br J Ophthalmol. 2017 Jan; 101(1): 38–44.

20. Brief note on clinical trials
Phase Objective Description
1 Is this new treatment safe? Outcomes relate to drug safety
and tolerability.
2 Is this treatment effective? Outcomes relate to does the
disease show a response to the
treatment.
3* Is this treatment better? Often with two groups that are
randomly assigned to determine
if one treatment is better than
another.
4 Is this treatment the best? Similar to phase 3 trials, but can
look at longer times, other
endpoints, more patients.
*Often the results of a positive phase 3 trial are used in an application for FDA approval. Once FDA
approval has been granted, then the therapy can be proscribed by any physician.

21. Future Directions
• IMCgp100
• Hepatic perfusion
• Tumor infiltrating lymphocytes
• Novel or combination targeted therapies

22. IMCgp100 (“Immunocore drug”)
• IMCgp100 is a drug in current phase II clinical trials for ocular
melanoma.
• This drug functions as an immunotherapy
• Encouraging preliminary data demonstrating prolonged survival

23. IMCgp100 Mechanism of Action
• IMCgp100 has two arms, one to grab the
tumor cell and another to recruit immune
cells to attack it.
• The handle on the tumor cell is gp100, which
is also present on skin melanocytes.
• The handle on the immune cell is HLA-
A*0201, which is present in about 50% of the
population.

24. IMCgp100 safety and effectiveness
• Most people will have skin rash with first few doses, some will
develop over active immune system reaction and require
intensive care.
• After several doses these risks diminish substantially.
• Preliminary data with IMCgp100 demonstrates about ~73%
survival at 1 year, compared to ~35% with other published
therapies.

25. Percutaneous Hepatic Perfusion (“Delcath”)
• Current phase 3 clinical trial
investigating high dose
chemotherapy delivered directly
to the liver vs dacarbazine;
transarterial chemoembolization;
ipilimumab; or pembrolizumab.
• Patients with extra-hepatic
tumor burden which is unable to
be resected or radiated must not
be included in the trial.
http://delcath.com/about-the-technology/

26. PHP safety and effectiveness
J Surg Oncol. 2017 Dec 28.

27. Tumor Infiltrating Lymphocytes (“TILs”)
Nat. Rev. Immunol. 12, 269-281

28. Tumor Infiltrating Lymphocytes (“TILs”)
Lancet Oncol. 2017 Jun;18(6):792-802

29. Novel or combination targeted therapies
Br J Ophthalmol. 2017 Jan; 101(1): 38–44.